Conditions: Primary Sclerosing Cholangitis (PSC)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 59
Healthy volunteers: no

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

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: HTD1801 intervention 2: Placebo
Intervention descriptions: intervention 1: HTD1801 tablets, 250 mg intervention 2: tablets manufactured to mimic HTD1801 tablets

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
 
 
 
 
 
CONFIDENTIAL 
 
 
CLINICAL PROTOCOL 
 
 
 
 
 
TITLE OF STUDY: 
 
A Proof-of-Concept and Dose-Ranging Study Investigating the Efficacy and Safety of 
HTD1801 in Adult Subjects with Primary Sclerosing Cholangitis (PSC) 
 
 
 
 
Protocol HTD1801.PCT003 
 
Trial Registration: NCT03333928 
 
 
 
 
 
 
 
 
Date of issue: 
07 January 2019 
 
 
Version number: 
1.4PK  
 
 
Sponsor: 
HighTide Biopharma Pty. Ltd.  
1 Melissa Street, 
Mount Waverley, Vic 3149 
Australia 
 
 
 


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
 
 
Page 2 
 
Signatures of Approval of Protocol (Version 1.4PK) 
 
This protocol was subject to critical review and has been approved by the following persons: 
 
Affiliation 
Name 
Signature 
Date: 
Sponsor: 
Steven Linberg, PhD 
 
 
Statistician: 
Thomas Soeder, MS 
 
 
Medical Monitor: 
Jackson Snyder, MD 
 
 
 
 
 
 
Sponsor: 
HighTide Biopharma Pty. Ltd.  
 
1 Melissa Street, 
Mount Waverley, Vic 3149 
Australia 
 
 
Sponsor Contact: 
Steven E. Linberg, PhD 
 
HighTide Biopharma Pty, Ltd. 
 
Phone: 240-731-3891 
 
E-mail: slinberg@hightidebio.com 
 
 
Medical Monitor: 
Jackson Snyder, MD, PhD, JD 
 
Clinical Research Physician 
 
Cato Research 
 
9605 Medical Center Drive, Suite 350 
 
Rockville, MD 20850 USA 
 
Phone: 301-309-1260 
 
Fax: 919-361-2290 
 
E-mail: jsnyder@cato.com 
 
 
 
 
 


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
 
 
Page 3 
STUDY SYNOPSIS 
Name of sponsor company: HighTide BioPharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate (HTD1801) 
Title of study: A Proof-of-Concept Study Investigating the Efficacy and Safety of HTD1801 in Adult 
Subjects with Primary Sclerosing Cholangitis (PSC) 
Investigator(s): TBD  
Number of sites: TBD  
Study period: 18 weeks 
Phase of development: 2 
Objectives:  
 
The primary objective of this proof-of-concept study is to evaluate the effects of HTD1801 on alkaline 
phosphatase (ALP) in adult subjects with PSC.  
 
The secondary objectives of this study are to evaluate the effects of HTD1801 on concurrent disease 
activity of inflammatory bowel disease (IBD), and on the safety and tolerability of HTD1801 over 
18 weeks in adult subjects with PSC. 
 
Pharmacokinetic (PK) and pharmacodynamics (PD) objectives include: 
• 
Develop and validate population PK models for the components of HTD1801: berberine (BBR) and 
ursodeoxycholic acid (UDCA); 
• 
Calculate individual single-dose and steady-state exposure metrics based on non-compartmental 
analysis methods in adult patients with PSC; 
• 
Evaluate exposure-response models for efficacy; 
• 
Evaluate the relationship between exposure, adverse events, and serious adverse events. 
 
Methodology: A 6-week randomized, double-blind, placebo- and dose-controlled, parallel group 
clinical trial with a PK substudy, followed by a 6-week, dose-controlled extension period, followed by 
a 6-week placebo controlled randomized withdrawal period. 
Number of subjects (planned): 90 subjects in total.  If a subject discontinues from the study for any 
reason other than safety prior to the first post-dose assessment, a replacement subject may be enrolled.  
Approximately 36 subjects enrolled at selected sites will undergo additional blood draws for PK/PD 
analysis. 
Inclusion criteria:  
 
1. 
Male or female between 18 and 75 years of age; 
2. 
Have a clinical diagnosis of PSC as evident by chronic cholestasis of more than six months 
duration with either a consistent magnetic resonance cholangiopancreatography (MRCP) or 
endoscopic retrograde cholangiopancreatography (ERCP) showing sclerosing cholangitis; 
3. 
If subjects have Inflammatory Bowel Disease (IBD) they will be eligible to participate. If a 
subject has IBD, documented evidence of IBD must have been evident by prior endoscopy or in 
previous medical records for ≥6 months. In addition, subjects may only enter the study with a 


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
STUDY SYNOPSIS (continued) 
 
 
Page 4 
Name of sponsor company: HighTide BioPharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate (HTD1801) 
Partial Mayo Score of 0-4, inclusively.  Subjects who are on treatment are allowed, provided 
they are stable for 3 months if taking:  
a. 5-amino salicylic acid drugs, 
b. azathioprine, 
c. 6-mercaptopurine, or methotrexate 
d. biologics; 
4. 
Have a serum ALP ≥1.5 × upper limit of normal (ULN); 
5. 
Females of child-bearing potential and males participating in the study must either agree to use 
at least 2 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 3 months after stopping study drug. Females who are postmenopausal must have appropriate 
documentation; 
6. 
Be able to understand and sign a written informed consent form (ICF); 
7. 
Subjects receiving allowed concomitant medications need to be on stable therapy for 28 days 
prior to the Baseline visit, with the exception of ursodeoxycholic acid (UDCA), which should be 
stable for at least 6 weeks prior to the Baseline visit. 
Exclusion criteria: 
 
1. 
Presence of documented secondary sclerosing cholangitis (such as ischemic cholangitis, 
recurrent pancreatitis, intraductal stone disease, severe bacterial cholangitis, surgical or blunt 
abdominal trauma, recurrent pyogenic cholangitis, choledocholithiasis, toxic sclerosing 
cholangitis due to chemical agents, or any other cause of secondary sclerosing cholangitis) on 
prior clinical investigations; 
2. 
Small duct PSC; 
3. 
Presence of percutaneous drain or bile duct stent; 
4. 
History of cholangiocarcinoma or clinical suspicion of new dominant stricture within 1 year by 
MRCP/ERCP.  Presence of dominant stricture without ERCP evidence of cholangiocarcinoma is 
acceptable if stable for ≥ 1 year.; 
5. 
Ascending cholangitis within 60 days prior to Screening; 
6. 
Concomitant overlap syndrome with autoimmune hepatitis (AIH) as diagnosed by AST or ALT 
> 5x ULN, AND 
i. 
positive smooth muscle antibody and/or liver-kidney microsomal antibody (LKM), or 
ii. 
IgG >ULN, or 
iii. 
Biopsy suggestive for AIH 
7. 
Concomitant overlap syndrome with primary biliary cholangitis (PBC) as diagnosed by either:  


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
STUDY SYNOPSIS (continued) 
 
 
Page 5 
Name of sponsor company: HighTide BioPharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate (HTD1801) 
i. 
positive AMA, or 
ii. 
biopsy suggestive for PBC 
8. 
History of alcohol or substance abuse or dependence; 
9. 
Prior or planned liver transplantation; 
10. Presence of alternative causes of chronic liver disease, including alcoholic liver disease, 
nonalcoholic steatohepatitis, primary biliary cirrhosis, autoimmune hepatitis; 
11. Platelet count below 125,000/mm3, albumin below 3.0 g/dL, International Normalized Ratio 
(INR) > 1.2, or a history of ascites, or encephalopathy, or history of esophageal variceal 
bleeding; 
12. Anticoagulant therapy, with the exception of acetylsalicylic acid; 
13. Severe active IBD or flare in colitis activity within the last 90 days requiring intensification of 
therapy beyond baseline treatment;  
14. Use of oral prednisone/prednisolone > 10 mg/day; 
15. Hospitalization for colitis within 90 days; 
16. AST > 5 x ULN; 
17. ALT > 5 x ULN; 
18. Total bilirubin > 1.2 x ULN.  If total bilirubin result at screening is > ULN but ≤ 1.2 x ULN, 
a confirmatory total bilirubin should be collected after 21 days.  If the confirmatory total 
bilirubin remains ≤ 1.2 x ULN, and all other eligibility criteria continue to be met, the 
subject will be eligible.; 
19. Evidence of Gilbert’s Syndrome; 
20. Immunoglobulin G4 (IgG4) > 2 × ULN at screening or evidence of IgG4-related sclerosing 
cholangitis; 
21. Estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m2, calculated by the local 
laboratory; 
22. Hemoglobin < 10 g/dL for males or females; 
23. Hepatitis B surface antigen positive; 
24. Hepatitis C antibody positive; 
25. Human immunodeficiency virus (HIV)-1 or HIV-2 infection; 
26. Glucose-6-phosphate dehydrogenase (G6PD) deficiency. 
27. History of malignancy within the past 2 years or ongoing malignancy other than basal cell 
carcinoma, or resected noninvasive cutaneous squamous cell carcinoma; 
28. Active, serious infections that require parenteral antibiotic or antifungal therapy within 30 days 
prior to Screening; 
29. Major surgical procedure within 30 days of Screening or prior organ transplantation; 
30. Females who are pregnant or breastfeeding; 


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
STUDY SYNOPSIS (continued) 
 
 
Page 6 
Name of sponsor company: HighTide BioPharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate (HTD1801) 
31. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents and 
immune-modulating agents (such as systemic corticosteroids, interleukins, interferons); 
32. Allergy to the clinical trial material or its components; 
33. Received any experimental medications within 30 days prior to Screening; 
34. 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: 500 mg or 1000 mg administered as tablets twice daily with food  
Placebo: Administered as tablets twice daily with food 
 
Reference therapy, dose and mode of administration:    N/A 
Duration of treatment: Up to 18 weeks 
Criteria for Evaluation: 
 
Efficacy Evaluation  
 
Efficacy endpoints: 
 
The primary endpoint for this study is the change in serum alkaline phosphatase (ALP) between 
Baseline and Week 6. 
 
Secondary endpoints will include: 
 
1. 
Change in serum ALP between Baseline and Weeks 12 or 18, dependent upon the length of 
continuous treatment, compared to the placebo response during Period 1; 
2. 
Change in serum ALP between a new baseline at Week 6 and the final value at Weeks 12 for 
those subjects who received placebo during Period 1, compared to their initial 6-week placebo 
response; 
3. 
Change in serum ALP between a new baseline at Week 6 and the final value at Weeks 12 for 
those subjects who received placebo during Period 1, compared to the similar change in the 
500 mg and 1,000 mg treatment groups; 
4. 
Change in serum ALP between a new baseline at Week 12 and the final value at Weeks 18 for all 
subjects following the randomized withdrawal; 
5. 
Proportion of patients who achieve ALP of <1.5 x ULN; 
6. 
Proportion of patients who achieve a 50% decrease in ALP; 
7. 
The proportion of patients who normalize ALP; 
8. 
Change in AST/ALT ratio; 


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
STUDY SYNOPSIS (continued) 
 
 
Page 7 
Name of sponsor company: HighTide BioPharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate (HTD1801) 
9. 
Change in serum bilirubin; 
10. In subjects with IBD who have elevated FC, change in FC compared to Baseline at Weeks 6 and 
12, and the proportion of subjects who normalize FC at Weeks 6 and 12; 
11. For subjects who have elevated CRP at Baseline (for all subjects as well as only IBD subset): 
change from Baseline in CRP at Weeks 6 and 12, and normalization of CRP at Weeks 6 and 12; 
12. For subjects with IBD who have Partial Mayo Score above 0: Change from Baseline in Mayo 
scores at Weeks 6 and 12. 
Efficacy analysis: 
 
The mITT population will be used for the analysis of all efficacy endpoints. The primary efficacy 
variable is the change in ALP from Baseline to Week 6 in the initial double-blind parallel group period. 
Changes in ALP from Baseline will be summarized by treatment group, visit and treatment period using 
descriptive statistics. A mixed model repeated measures (MMRM) will be fit to the data and the model 
will include fixed factors for treatment, visit and treatment by visit interaction, a random factor for 
subject, and Baseline value as a covariate. An unstructured covariance matrix will be used to model the 
repeated assessment over time. Denominator degrees of freedom will be adjusted using 
Kenward-Roger’s method. Sensitivity analyses will be described in the statistical analysis plan (SAP). 
Treatment comparisons will be made at each visit and each treatment period, with the primary 
comparison at Week 6. No imputation of missing data is necessary for the MMRM analysis of the 
primary endpoint.  A similar MMRM analysis will be performed for the randomized withdrawal period. 
Analysis for the randomized withdrawal period will be conducted for all subjects and separately for 
responders based on pre-specified responder criteria.  For the dose-controlled treatment period, a one 
sample t-test will be used to evaluate the change in ALP from Week 6 to Week 12 for the subjects who 
were previously randomized to placebo during the first period. 
 
The secondary efficacy variables of the proportion of subjects whose ALP values normalize, the 
proportion of subjects whose ALP values decrease below 1.5 x ULN, and the proportion of subjects who 
achieve a 50% decrease in ALP from Baseline will be calculated at end of treatment using a last 
observation carried forward for any missing data. Frequencies and percentages will be calculated by 
treatment group and by visit. Any adjustments for multiplicity will be described in the SAP. Treatment 
comparisons will be made at Week 6 (or LOCF) using Fisher’s exact test. A similar analysis will be 
performed for the randomized withdrawal period. For the dose-controlled extension period, a one sample 
exact test will be used to evaluate the proportion of subjects achieving each of the secondary endpoints 
at Week 12 for the subjects who were randomized to placebo during the double-blind period. The 
secondary efficacy variables of change from Baseline in AST/ALT ratio, bilirubin, C-reactive protein 
and fecal calprotectin will be analyzed using a MMRM similar to that described above for the primary 
efficacy variable. 


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
STUDY SYNOPSIS (continued) 
 
 
Page 8 
 
Safety Evaluation  
 
Safety Endpoints: 
Adverse events and changes in clinical laboratory assessments will be used to evaluate safety and 
tolerability. 
 
Safety Analysis: 
Safety data will be summarized using descriptive analysis. 
 
PK/PD Evaluation 
 
Pharmacokinetic Endpoints: 
1. Apparent clearance (CL/F) of UDCA and BBR; 
2. Apparent volume of distribution at steady state (Vss/F) for UDCA and BBR; 
3. Additional single-dose and steady-state non-compartmental exposure metrics (e.g., Cmax, AUC0-12, 
AUC0-inf). 
 
Population Pharmacokinetic Analysis: 
 
Population PK models for the components of HTD1801 will be developed and validated using a 
nonlinear mixed-effects model (NONMEM) approach. Selection of the appropriate model will be based 
on hypothesis testing and graphical analysis of residual error (goodness of fit).  Target parameters for 
each component include apparent clearance (CL/F) and apparent volume of distribution at steady state 
(Vss/F). Covariate relationships will be evaluated and incorporated into the model as indicated by the 
data.  Covariates for evaluation will include, but will not be limited to, vital signs (e.g., body size), 
demographics (e.g., sex, age, race) and organ function / disease biomarkers (e.g., bilirubin and alkaline 
phosphatase).  The models will be validated using likelihood profiles, bootstrap analysis, and visual 
predictive check. 
 
Concentration vs. time profiles will be simulated for each subject based on that subject’s individual-
specific (post-hoc) parameter estimates. Individual single-dose and steady-state non-compartmental 
metrics will be calculated from these simulated data.  Metrics for UDCA will be reported with and 
without baseline correction. 
 
Pharmacokinetic/Pharmacodynamic Analysis 
 
An exploratory exposure-response analysis will be performed to evaluate the relationship between 
exposure metrics (e.g., AUC, Cmax) for UDCA, BBR, and UDCA+BBR and change from baseline in 
serum ALP.  The analysis will evaluate the effect of covariates including disease state (e.g., baseline 
ALP; IBD with elevated FC; elevated CRP). 
 
An exploratory exposure-response analysis will be performed to evaluate the relationship between 
exposure, adverse events (AE) of interest, and serious adverse events (SAE).  The relationship between 
exposure and AE or SAE occurrence will be evaluated graphically and, where indicated, statistically. 
 


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
STUDY SYNOPSIS (continued) 
 
 
Page 9 
Name of sponsor company: HighTide BioPharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate (HTD1801) 
Study Design:  The entire study is randomized and double blind, with a concurrent placebo control 
except in Period 2.  Randomization will be stratified based on presence of IBD. 
 
Period 1: Placebo and dose controlled (6 weeks) 
Each subject will be randomized to one of three groups: a) placebo twice daily with food; b) 500 mg of 
HTD1801 twice daily with food; or c) 1000 mg of HTD1801 twice daily with food. 
 
Period 2: Dose-controlled extension (6 weeks) 
Subjects previously randomized to 500 mg BID will continue receiving 500 mg. 
Subjects previously randomized to 1000 mg BID will continue receiving 1000 mg. 
Subjects previously randomized to PBO BID will be randomized to receive either 500 mg or 1000 mg. 
 
Period 3: Randomized withdrawal (6 weeks) 
All subjects will be randomized to either remain on the treatment assigned in Period 2 or to placebo 
(PBO). 
 


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
 
 
Page 10 
Figure 1. Study Design 
 
Screening 
Baseline/ 
Randomization/ 
Dosing 
Initial Dosing Period 
Dose-controlled Extension 
Randomized Withdrawal 
Follow-up 
Days -28 to -1 
Day 0/1 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Week 14 
Week 16 
Week 18 
Week 22 
 
 
 
 
 
 
 
 
 
 
 
  
500 mg BID 
  
 
  
500 mg BID 
  
  
  
500 mg BID 
  
R 
  
 
 
 
  
 
 
 
 
 
 
 
  
PBO BID 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
1000 mg BID 
  
R 
  
1000 mg BID 
  
  
  
1000 mg BID 
  
R 
  
 
 
 
  
 
 
 
 
 
 
 
  
PBO BID 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
500 mg BID 
  
 
  
 
 
 
  
500 mg BID 
  
R 
  
 
 
 
  
 
 
 
  
 
 
 
  
PBO BID 
  
 
  
PBO BID 
  
R 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
1000 mg BID 
  
 
 
 
 
 
  
1000 mg BID 
  
R 
  
 
 
 
 
 
 
 
 
 
 
 
  
PBO BID 
  


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
 
 
Page 11 
Figure 1PK. Pharmacokinetic Substudy Design 
 
 
 
 


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
 
 
Page 12 
Table 1. 
Schedule of Time and Events 
 
 
Screening 
Baseline/ 
Rand/ Dosing 
Initial Dosing Period 
Dose-controlled Extension 
Randomized Withdrawal 
Follow-
up 
 
Days -28 
to -1 
Day 0/1 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 Week 12 
Week 14 Week 16 Week 18 Week 22 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic Visits 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
G6PD 
X 
 
 
 
 
 
 
 
 
 
 
 
IgG4 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine drug test 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis B, C 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant meds 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Physical examination 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Ht., Wt., Vitals 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECG 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Pregnancy testing  
X 
X 
 
 
 
 
 
 
 
 
X 
 
Partial Mayo Score 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
CBC, CMP **, Lipids 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
INR 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Mayo Risk Score 
 
X 
 
 
 
 
 
 
 
 
 
 
C-reactive protein * 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Fecal calprotectin * 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Randomization 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Dosing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK sampling*** 
 
X 
 
 
X 
 
 
 
 
 
 
 
Dosing diary *** 
 
 
 
 
X 
 
 
 
 
 
 
 
Adverse event monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone contact 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Discharge 
 
 
 
 
 
 
 
 
 
 
X 
 
* 
IBD subset only 
**  Including GGT 
*** PK substudy only 


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
 
 
Page 13 
Table 1PK. 
Pharmacokinetic Sampling Schedule 
 
 
Timepoint 
 
Baseline 
Week 6 
Pre-dose 
X 
X 
+1 hour post-dose 
X 
X 
+2 hours post-dose 
X 
X 
+3 hours post-dose 
X 
X 
+4 hours post-dose 
X 
X 
+6 hours post-dose 
X 
X 
+8 hours post-dose 
X 
X 


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
 
 
Page 14 
TABLE OF CONTENTS 
 
Page 
 
STUDY SYNOPSIS ....................................................................................................................................................... 3 
LIST OF TABLES ....................................................................................................................................................... 17 
LIST OF FIGURES ...................................................................................................................................................... 17 
LIST OF APPENDICES .............................................................................................................................................. 18 
LIST OF ABBREVIATIONS ...................................................................................................................................... 19 
1.0 
INTRODUCTION ................................................................................................................................ 20 
1.1 
BACKGROUND .................................................................................................................................... 20 
1.1.1 
Primary Sclerosing Cholangitis ........................................................................................... 20 
1.1.2 
Nonclinical Studies .............................................................................................................. 22 
1.2 
STUDY RATIONALE ........................................................................................................................... 23 
1.3 
DOSE RATIONALE .............................................................................................................................. 23 
2.0 
OBJECTIVES ....................................................................................................................................... 24 
3.0 
STUDY DESIGN .................................................................................................................................. 25 
3.1 
BASIC DESIGN CHARACTERISTICS ............................................................................................... 25 
3.2 
STUDY POPULATION ......................................................................................................................... 26 
3.2.1 
Inclusion Criteria ................................................................................................................. 26 
3.2.2 
Exclusion Criteria ................................................................................................................ 27 
3.3 
ENDPOINTS .......................................................................................................................................... 30 
3.3.1 
Efficacy ................................................................................................................................ 30 
3.3.2 
Safety ................................................................................................................................... 32 
3.3.3 
Pharmacokinetic Endpoints ................................................................................................. 32 
3.4 
RANDOMIZATION AND BLINDING ................................................................................................ 32 
3.5 
REPLACEMENT OF DROPOUTS ....................................................................................................... 33 
4.0 
DRUGS AND DOSAGES ..................................................................................................................... 34 
4.1 
IDENTIFICATION AND DESCRIPTION OF INVESTIGATIONAL PRODUCT ............................. 34 
4.1.1 
Investigational Product ........................................................................................................ 34 
4.1.2 
Labeling ............................................................................................................................... 34 
4.2 
DOSING INSTRUCTIONS AND SCHEDULE .................................................................................... 34 
4.3 
HANDLING OF INVESTIGATIONAL PRODUCT ............................................................................ 35 
4.4 
COMPLIANCE WITH INVESTIGATIONAL PRODUCT .................................................................. 35 
4.5 
CONCOMITANT MEDICATIONS ...................................................................................................... 35 
4.6 
PROHIBITED CONCOMITANT MEDICATIONS ............................................................................. 35 
5.0 
EXPERIMENTAL PROCEDURES ................................................................................................... 37 
5.1 
PROCEDURES, MEASUREMENTS AND EVALUATIONS ............................................................. 37 
5.1.1 
Screening (Days -28 to 0) .................................................................................................... 37 
5.1.2 
Baseline (immediately prior to dosing) ................................................................................ 38 
5.1.3 
Double-Blind Treatment Period - Weeks 2, 4, and 6 ........................................................... 40 
5.1.4 
Dose-controlled Extension Period - Weeks 8, 10, and 12 ................................................... 42 
Delet
Delet
D
D
D
Delet
Delet
Delet
Delet
D
D
Delet
Delet
Delet
Delet
Delet
Delet
Delet
D
D
D
D


CONFIDENTIAL 
 
HighTide Biopharma Pty., Ltd. 
 
HTD1801 
Clinical Protocol 
IND 136137 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
 
Page 15 
5.1.5 
Random Withdrawal Period, Weeks 14, 16, and 18 ............................................................ 43 
5.1.6 
Study Discharge ................................................................................................................... 44 
5.1.7 
Follow-up Period (Week 22) ............................................................................................... 45 
6.0 
PROCEDURES FOR HANDLING ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS ................................................................................................................................................ 46 
6.1 
DEFINITION OF AN ADVERSE EVENT ........................................................................................... 46 
6.2 
DEFINITION OF A SERIOUS ADVERSE EVENT ............................................................................ 48 
6.3 
RECORDING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ...................................... 49 
6.4 
ASSESSMENT OF INTENSITY ........................................................................................................... 49 
6.5 
ASSESSMENT OF CAUSALITY ......................................................................................................... 50 
6.6 
EXPECTEDNESS OF SERIOUS ADVERSE EVENTS ....................................................................... 51 
6.7 
REPORTING OF SERIOUS ADVERSE EVENTS .............................................................................. 51 
6.8 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................ 52 
6.9 
LIVER ADVERSE EVENTS ................................................................................................................. 53 
6.10 
PREGNANCY ........................................................................................................................................ 54 
7.0 
STUDY OR SITE TERMINATION AND SUBJECT DISCONTINUATION ............................... 55 
7.1 
ADVERSE EVENT STOPPING RULES .............................................................................................. 55 
7.2 
NONCOMPLIANCE .............................................................................................................................. 55 
7.3 
WITHDRAWAL OF CONSENT ........................................................................................................... 56 
7.4 
PREMATURE STUDY OR SITE TERMINATION ............................................................................. 56 
8.0 
DATA COLLECTION AND PROCESSING AND STATISTICAL ANALYSIS ......................... 58 
8.1 
DATA COLLECTION AND PROCESSING ........................................................................................ 58 
8.2 
STATISTICAL ANALYSIS .................................................................................................................. 59 
8.2.1 
General Overview ................................................................................................................ 59 
8.2.2 
Populations of Interest ......................................................................................................... 59 
8.2.3 
Efficacy Analysis ................................................................................................................. 59 
8.2.4 
Safety Analysis .................................................................................................................... 60 
8.2.5 
Pharmacokinetic Analysis .................................................................................................... 61 
8.2.6 
Pharmacokinetic/Pharmacodynamic Analysis ..................................................................... 61 
8.2.7 
Sample Size .......................................................................................................................... 62 
9.0 
STUDY ADMINISTRATION ............................................................................................................. 63 
9.1 
INFORMED CONSENT AND AUTHORIZATION FOR USE AND DISCLOSURE OF 
PROTECTED HEALTH INFORMATION ........................................................................................... 63 
9.2 
STUDY DOCUMENTATION ............................................................................................................... 63 
9.2.1 
Investigator Information ...................................................................................................... 63 
9.2.2 
Investigator’s Study Files .................................................................................................... 63 
9.2.3 
Case Report Forms and Source Documentation .................................................................. 64 
9.2.4 
Retention of Study Documents ............................................................................................ 64 
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9.3 
CONFIDENTIALITY ............................................................................................................................ 64 
9.3.1 
Data ...................................................................................................................................... 64 
9.3.2 
Subject Anonymity .............................................................................................................. 65 
9.4 
PROTOCOL COMPLIANCE ................................................................................................................ 65 
9.5 
STUDY MONITOR FUNCTIONS AND RESPONSIBILITY ............................................................. 66 
9.6 
GENERAL INFORMATION ................................................................................................................. 66 
10.0 
REFERENCES ..................................................................................................................................... 67 
APPENDICES .............................................................................................................................................................. 72 
 
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LIST OF TABLES 
 
Page 
 
Table 1. 
Schedule of Time and Events ................................................................................................................. 12 
Table 1PK. Pharmacokinetic Sampling Schedule ..................................................................................................... 13 
Table 2. 
Comparison of HTD1801 Clinical Dose with FDA Approved UDCA Dose and Recommended BBR Cl 
Dose ........................................................................................................................................................ 23 
Table 3. 
Prohibited Medications ........................................................................................................................... 36 
Table 4. 
Classification of AEs by Intensitya ......................................................................................................... 50 
Table 5. 
Assessment of Causality of AEs ............................................................................................................. 51 
Table 6. 
Timeline for Reporting SAEs ................................................................................................................. 52 
 
 
 
 
LIST OF FIGURES 
 
 
Figure 1. 
Study Design ........................................................................................................................................... 10 
Figure 1PK. Pharmacokinetic Substudy Design ......................................................................................................... 11 
 
 
 
 
 
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LIST OF APPENDICES 
 
 
Appendix A  Protection of Human Subjects (International Council for Harmonisation E6, Section 4.8) 
Appendix B  Requisite Documents for Approval of Study Site 
Appendix C  Responsibilities and Obligations  of Investigators and Sponsors 
Appendix D  Partial Mayo Score Questionnaire 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
 
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BBR 
berberine 
BBR·Cl 
berberine chloride 
BDL 
bile duct ligation 
BID 
twice daily 
CBC 
complete blood count 
CMP 
comprehensive metabolic panel 
CRF 
case report form 
DILI 
drug induced liver injury 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ERCP 
endoscopic retrograde cholangiopancreatography 
FDA 
Food and Drug Administration 
IBD 
inflammatory bowel disease 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IgG4 
Immunoglobulin G4 
IP 
investigational product 
IRB 
institutional review board 
MCRP 
magnetic resonance cholangiopancreatography 
mITT 
modified intent-to-treat 
PBC 
primary biliary cirrhosis  
PBO 
placebo 
PSC 
Primary Sclerosing Cholangitis 
SAE 
serious adverse event 
SPM 
study procedures manual 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 
 
 


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1.0 
INTRODUCTION 
HTD1801 is a novel salt formed between berberine (BBR) and ursodeoxycholic acid 
(UDCA) with a stoichiometry of 1:1, and is currently being developed as an oral 
treatment of primary sclerosing cholangitis (PSC). HTD1801 is expected to dissociate 
into berberine chloride (BBR·Cl) and UDCA after oral administration. Both UDCA 
and BBR have demonstrated efficacy in the treatment of cholestatic disease. 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 PSC by assessing 
effects of alkaline phosphatase (ALP) over 6 weeks.   
1.1 
BACKGROUND 
1.1.1 
Primary Sclerosing Cholangitis 
Primary sclerosing cholangitis (PSC) is a chronic, progressive liver disease 
characterized by inflammation and fibrosis of the intra- and/or extra-hepatic bile ducts, 
which leads to the formation of multifocal bile duct strictures. This cholestatic disease 
leads to fibrosis and ultimately liver failure, cirrhosis and an increased risk of 
malignancy.[1, 2]  Today, nearly 50,000 patients in the United States suffer from PSC, 
and the median life expectancy after diagnosis of PSC is 12 to 18 years without liver 
transplantation.[3]  PSC is more common in men than in women (2:1), and can occur at 
any age with a peak incidence around forty years of age.[4] 
Currently, no effective therapy has been approved for the treatment of PSC.[1]  UDCA 
is a secondary bile acid produced by intestinal bacteria as a metabolic by-product, 
which is approved by the Food and Drug Administration (FDA) in the United States 
for the treatment of primary biliary cirrhosis (PBC) (NDA 020675).[5] UDCA has been 
shown to significantly improve biochemical parameters, delay progression of the 
disease and prevent the need for liver transplantation in patients with PBC.[6, 7]  The 
possible mechanisms of action for UDCA’s efficacy in the treatment of chronic 
cholestasis include, but are not limited to, the following:[8] 
• 
Improvement of hydrophilicity index in the circulating bile acid pool; 
• 
Stimulation of hepatobiliary and ductular secretion; 


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• 
Cytoprotection against bile acid and cytokine-induced injury; 
• 
Immunomodulation and anti-inflammatory effects. 
Based on the pharmacological properties summarized above, UDCA has been 
investigated as a potential therapeutic agent for the treatment of patients with PSC. 
UDCA treatment leads to significant improvements in liver biochemistry, including 
serum ALP, aspartate transaminase (AST), and bilirubin. However, a meta-analysis 
failed to show that UDCA reduced mortality, hepatic decompensation, need for liver 
transplantation or liver histological deterioration compared with placebo.[9, 10]  Tabibian 
et al., pointed out that UDCA monotherapy may not be sufficient for the treatment of 
PSC and a combination therapy should be considered.[11]  An analogue of UDCA, 
2,4-norursodeoxycholic acid (nor-URDA) with a similar mechanism of action of 
UDCA has demonstrated improvements in rodent models of cholestasis[3] Nor-UDCA 
has also been evaluated in a recently completed phase 2 clinical trial in 159 patients 
with PSC.[12] 
BBR is an isoquinoline alkaloid found in many different plants, with a long history of 
use in traditional Chinese medicine.[13, 14]  BBR·Cl is an approved antiseptic drug in 
China, Japan, and Taiwan. In the United States and Australia, BBR is widely used in 
various dietary supplements for a number of advertised health benefits and is 
grandfathered under the Dietary Supplement Health and Education Act (DSHEA) in 
the United States.[15]  The reported multi-spectrum activity of BBR, including 
immunomodulation, anti-inflammation, anti-apoptosis and anti-infection, suggests that 
BBR has the potential to treat chronic cholestatic liver diseases. Studies show BBR’s 
ability to inhibit the toxic effect of lipopolysaccharide (LPS) and normalize intestinal 
permeability. Therefore, it is reasonable to believe that BBR may have beneficial 
effects in the treatment of PSC. 
ALP level has been used as a biomarker in clinical trials of PSC for the past two decades 
and the reduction of ALP has been used as primary endpoint in over 40% of clinical 
studies.[6, 16-18]  ALP was the primary variable used in the FDA's approval of 
OCALIVA.  Recently, several observational studies have further supported the use of 
ALP as a surrogate marker for transplant-free survival.[19-22]  In a phase 2 clinical trial 
of nor-UDCA in PSC patients, change in serum ALP levels during treatment is used as 
the primary outcome measure.[23]  In a preclinical study by these researchers in a 
common bile duct ligation induced mice model of cholestasis, the ALP levels were 


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reduced by approximately 30% after 7-day treatment of nor-UDCA post 3 days of bile 
duct ligation (BDL).[24]  This study will evaluate HTD1801 in adult subjects with PSC 
by assessing effects of ALP over 6 weeks.    
1.1.2 
Nonclinical Studies 
HighTide conducted an efficacy study of HTD1801 in rats subjected to BDL. HTD1801 
at doses of 50 mg/kg and 150 mg/kg reduced ALP levels by 23.8% and 25.1% 
respectively, increased super oxide dismutase activity, and reduced malondialdehyde 
levels significantly, providing mechanistic evidence for the action of HTD1801 in the 
treatment of PSC. In addition, both doses ameliorated hepatocellular necrosis, reduced 
inflammation in the portal area, and inhibited bile duct proliferation, providing 
additional evidence of the potential for therapeutic effects of HTD1801 in PSC. 
A second pharmacology study was conducted to evaluate the effects of HTD1801 on 
intestinal microbiota modification in a high-fat diet-induced hamster model of 
metabolic disorder. Recent clinical observations and animal findings have suggested 
an abundance of christensenellanceae[25] and decreased parabacteroides[26, 27] have a 
role in the etiopathogenesis of PSC.  
The nonclinical toxicity profiles of both UDCA and BBR have been extensively 
studied. A full ICH M3 battery of nonclinical studies was performed with UDCA in 
support of NDA 20675. The toxicity profile of berberine was assessed in a battery on 
nonclinical studies conducted and/or reviewed by the National Toxicology program. 
These studies include single dose oral studies in mice and rats, in vitro and in vivo 
genotoxicity studies, as well as reproductive and developmental toxicity studies in mice 
and rats.[28-32]  The pharmacokinetic and toxicity profile of HTD1801 has been 
evaluated in both rats and dogs.  HighTide conducted toxicology studies of up to 
2-weeks in rats (non-GLP) and up to 13-weeks in dogs (GLP).  The results of these 
studies show that combined administration of UDCA and berberine as HTD1801 
results in pharmacokinetic and toxicity profiles similar to that of the individual 
components UDCA and BBR. In addition, the 13-week GLP dog study provided data 
to qualify the toxicity profile of berberine in nonrodents and the safety of the 
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1.2 
STUDY RATIONALE 
This study is a dose ranging, proof-of-concept study with a PK substudy that follows 
the completion of a single ascending dose study in healthy volunteers. 
1.3 
DOSE RATIONALE 
UDCA was FDA approved at a dose of 13-15 mg/kg/day, which is roughly 1,000 mg 
UDCA per day. BBR is widely used in dietary supplements in the United States at a 
recommended dose of 17 to 33 mg/kg/day, which is roughly 1 to 2 g/day. As shown in 
Table 2, the UDCA and BBR·Cl content of HTD1801 are comparable to that already 
shown to be safe clinically. 
Table 2. 
Comparison of HTD1801 Clinical Dose with FDA Approved 
UDCA Dose and Recommended BBR Cl Dose  
Compound 
FDA Approved Clinical Dose (UDCA) / 
Dose used in dietary supplements (BBR-
Cl) 
HTD1801 Clinical Dose 
(33 mg/kg/day; 2000 mg/day)c 
UDCAa 
13-15 mg/kg/day (780-900 mg/day)b 
18 mg/kg/day (1078 mg/day) 
BBR Cla 
17-33 mg/kg/day (1000-2000 mg/day) 
17 mg/kg/day (1022 mg/day) 
a: 
mg/kg doses calculated assuming a 60-kg adult 
b: Safety at doses up to 25 mg/kg/day is supported by the published literature for PBC patients [33]  
c: 
HTD1801 dose of 2000 mg/day is equivalent to 1022 mg/day BBR Cl and 1078 mg/day of UDCA. 
 
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2.0 
OBJECTIVES 
The primary objective of this proof-of-concept study is to evaluate the effects of 
HTD1801 on ALP in adult subjects with PSC.  
The secondary objectives of this study are to evaluate the effects of HTD1801 on 
concurrent disease activity of inflammatory bowel disease (IBD), and on the safety and 
tolerability of HTD1801 over 18 weeks in adult subjects with PSC.  
Pharmacokinetic (PK) and pharmacodynamics (PD) objectives include: 
• 
Develop and validate population PK models for the components of HTD1801: 
berberine (BBR) and ursodeoxycholic acid (UDCA); 
• 
Calculate individual single-dose and steady-state exposure metrics based on 
non-compartmental analysis methods in adult patients with PSC; 
• 
Evaluate exposure-response models for efficacy; 
• 
Evaluate the relationship between exposure, adverse events, and serious adverse 
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3.0 
STUDY DESIGN 
3.1 
BASIC DESIGN CHARACTERISTICS 
This proof-of-concept study with a PK substudy will be conducted in three randomized, 
double-blind treatment periods in adult patients with PSC.   The study design consists 
of an initial randomized, double-blind, placebo- and dose-controlled, parallel group 
period, followed by a dose-controlled extension period, followed by a 
placebo-controlled randomized withdrawal period.   
• 
In the 1st period, subjects will be randomized to receive twice-daily doses of 
500 mg, 1000 mg, or matching placebo for 6 weeks.  The primary analysis will 
be based on this initial 6 week randomized, double-blind, placebo- and 
dose-controlled, parallel group period. 
• 
Following the completion of that initial double-blinded, placebo- and 
dose-controlled parallel group period, subjects will be eligible to enroll in a 
6-week extension period in which subjects previously randomized to 500 mg or 
1,000 mg twice-daily (BID) will continue for 6 more weeks at that previous dose, 
while subjects previously randomized to placebo will be re-randomized to receive 
6 weeks of either 500 mg or 1,000 mg BID.   The study will remain double-blind. 
• 
Following the completion of the 6-week experimental treatment extension, all 
subjects will be re-randomized to either continue on the active treatment they 
received in Period 2, or be assigned to placebo.  The plan is for 50% of the 
subjects to remain on the experimental treatment at the previous dose and 50% 
will receive placebo. 
 
 


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3.2 
STUDY POPULATION 
Up to 90 patients with PSC will be enrolled as subjects. Eligibility will be established 
by the investigator on the basis of the inclusion and exclusion criteria.  Approximately 
36 subjects enrolled at selected sites will undergo additional blood draws for PK/PD 
analysis. 
3.2.1 
Inclusion Criteria  
To be considered eligible to participate in this study, a subject must meet the inclusion 
criteria listed below:  
1. 
Male or female between 18 and 75 years of age; 
2. 
Have a clinical diagnosis of PSC as evident by chronic cholestasis of more than 
six months duration with either a consistent magnetic resonance 
cholangiopancreatography 
(MRCP) 
or 
endoscopic 
retrograde 
cholangiopancreatography (ERCP) showing sclerosing cholangitis; 
3. 
If subjects have Inflammatory Bowel Disease (IBD) they will be eligible to 
participate. If a subject has IBD, documented evidence of IBD must have been 
evident by prior endoscopy or in previous medical records for ≥6 months. In 
addition, subjects may only enter the study with a Partial Mayo Score of 0-4, 
inclusively.  Subjects who are on treatment are allowed, provided they are stable 
for 3 months if taking:  
i. 
5-amino salicylic acid drugs, 
ii. 
azathioprine, 
iii. 
6-mercaptopurine, or methotrexate  
iv. 
biologics; 
4. 
Have a serum ALP ≥1.5 × upper limit of normal (ULN); 
5. 
Females of child-bearing potential and males participating in the study must 
either agree to use at least 2 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 3 months after stopping 


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study drug. Females who are postmenopausal must have appropriate 
documentation; 
6. 
Be able to understand and sign a written informed consent form (ICF); 
7. 
Subjects receiving allowed concomitant medications need to be on stable 
therapy for 28 days prior to the Baseline visit, with the exception of UDCA, 
which should be stable for at least 6 weeks prior to the Baseline visit. 
3.2.2 
Exclusion Criteria 
To be eligible for entry into the study, the subject must not meet any of the exclusion 
criteria listed below: 
1. 
Presence of documented secondary sclerosing cholangitis (such as ischemic 
cholangitis, recurrent pancreatitis, intraductal stone disease, severe bacterial 
cholangitis, surgical or blunt abdominal trauma, recurrent pyogenic cholangitis, 
choledocholithiasis, toxic sclerosing cholangitis due to chemical agents, or any 
other cause of secondary sclerosing cholangitis) on prior clinical investigations; 
2. 
Small duct PSC; 
3. 
Presence of percutaneous drain or bile duct stent; 
4. 
History of cholangiocarcinoma or clinical suspicion of new dominant stricture 
within 1 year by MRCP/ERCP or clinical judgement.  Presence of dominant 
stricture without ERCP evidence of cholangiocarcinoma is acceptable if stable 
for ≥ 1 year.; 
5. 
Ascending cholangitis within 60 days prior to Screening; 
6. 
Concomitant overlap syndrome with autoimmune hepatitis (AIH) as diagnosed 
by AST or ALT > 5x ULN, AND 
i. 
positive smooth muscle antibody and/or liver-kidney microsomal 
antibody (LKM), or 
ii. 
IgG >ULN, or 
iii. 
Biopsy suggestive for AIH 


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7. 
Concomitant overlap syndrome with primary biliary cholangitis (PBC) as 
diagnosed by either:  
i. 
positive AMA or 
ii. 
biopsy suggestive for PBC 
8. 
History of alcohol or substance abuse or dependence; 
9. 
Prior or planned liver transplantation; 
10. 
Presence of alternative causes of chronic liver disease, including alcoholic liver 
disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, autoimmune 
hepatitis; 
11. 
Platelet count below 125,000/mm3, albumin below 3.0 g/dL, International 
Normalized Ratio (INR) > 1.2, or a history of ascites, or encephalopathy, or 
history of esophageal variceal bleeding; 
12. 
Anticoagulant therapy, with the exception of acetylsalicylic acid; 
13. 
Severe active IBD or flare in colitis activity within the last 90 days requiring 
intensification of therapy beyond baseline treatment;  
14. 
Use of oral prednisone/prednisolone > 10 mg/day; 
15. 
Hospitalization for colitis within 90 days; 
16. 
AST > 5 x ULN; 
17. 
ALT > 5 x ULN; 
18. 
Total bilirubin > 1.2 x ULN.  If total bilirubin result at screening is > ULN 
but ≤ 1.2 x ULN, a confirmatory total bilirubin should be collected after 21 
days.  If the confirmatory total bilirubin remains ≤ 1.2 x ULN, and all other 
eligibility criteria continue to be met, the subject will be eligible.; 
19. 
Evidence of Gilbert’s Syndrome; 
20. 
Immunoglobulin G4 (IgG4) > 2 × ULN at screening or evidence of IgG4-related 
sclerosing cholangitis; 


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21. 
Estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m2, 
calculated by the local laboratory; 
22. 
Hemoglobin < 10 g/dL for males or females; 
23. 
Hepatitis B surface antigen positive; 
24. 
Hepatitis C antibody positive; 
25. 
Human immunodeficiency virus (HIV)-1 or HIV-2 infection; 
26. 
Glucose-6-phosphate dehydrogenase (G6PD) deficiency. 
27. 
History of malignancy within the past 2 years or ongoing malignancy other than 
basal cell carcinoma, or resected noninvasive cutaneous squamous cell 
carcinoma; 
28. 
Active, serious infections that require parenteral antibiotic or antifungal therapy 
within 30 days prior to Screening; 
29. 
Major surgical procedure within 30 days of Screening or prior organ 
transplantation; 
30. 
Females who are pregnant or breastfeeding; 
31. 
Current or anticipated treatment with radiation therapy, cytotoxic 
chemotherapeutic agents and immune-modulating agents (such as systemic 
corticosteroids, interleukins, interferons); 
32. 
Allergy to the clinical trial material or its components; 
33. 
Received any experimental medications within 30 days prior to Screening; 
34. 
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. 


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3.3 
ENDPOINTS 
3.3.1 
Efficacy 
3.3.1.1 
Primary Endpoint 
The primary endpoint for this study is the change in serum alkaline phosphatase 
between Baseline and Week 6. 


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3.3.1.2 
Secondary Endpoints 
The secondary endpoints of this study include the following: 
1. 
Change in serum ALP between Baseline and Weeks 12 or 18, dependent upon 
the length of continuous treatment, compared to the placebo response during 
Period 1; 
2. 
Change in serum ALP between a new baseline at Week 6 and the final value at 
Weeks 12 for those subjects who received placebo during Period 1, compared to 
their initial 6-week placebo response; 
3. 
Change in serum ALP between a new baseline at Week 6 and the final value at 
Weeks 12 for those subjects who received placebo during Period 1, compared to 
the similar change in the 500 mg and 1,000 mg treatment groups; 
4. 
Change in serum ALP between a new baseline at Week 12 and the final value at 
Weeks 18 for all subjects following the randomized withdrawal; 
5. 
Proportion of patients who achieve ALP of <1.5 x ULN; 
6. 
Proportion of patients who achieve a 50% decrease in ALP; 
7. 
The proportion of patients who normalize ALP; 
8. 
Change in AST/ALT ratio; 
9. 
Change in serum bilirubin; 
10. In subjects with IBD who have elevated fecal calprotectin (FC), change in FC 
compared to Baseline at Weeks 6 and 12, and the proportion of subjects who 
normalize FC at Weeks 6 and 12; 
11. For subjects who have elevated CRP at Baseline (for all subjects In the IBD 
subset): change from Baseline in CRP at Weeks 6 and 12, and normalization of 
CRP at Weeks 6 and 12.   
12. For subjects with IBD who have Partial Mayo score above 0: Change from 
Baseline in Mayo scores at Weeks 6 and 12. 


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3.3.2 
Safety  
Safety endpoints to be used in this study will include:  
1. 
Proportion of subjects with a treatment-emergent adverse event (TEAE) or a 
clinically significant laboratory abnormality (overall and of any given type); 
2. 
Proportion of subjects who discontinue due to an adverse event (AE) (either 
treatment-emergent or clinically significant laboratory abnormality). 
3.3.3 
Pharmacokinetic Endpoints 
1. 
Apparent clearance (CL/F) of UDCA and BBR; 
2. 
Apparent volume of distribution at steady state (Vss/F) for UDCA and BBR; 
3. 
Additional single-dose and steady-state non-compartmental exposure metrics 
(e.g., Cmax, AUC0-12, AUC0-inf). 
3.4 
RANDOMIZATION AND BLINDING 
Period 1: Placebo- and dose-controlled, parallel-group period 
Subjects will be enrolled in equal numbers to one of the initial three treatment groups, 
those being placebo BID, HTD1801 500 mg BID, or HTD1801 1,000 mg BID, during 
the initial 6-week, double-blind, placebo- and dose-controlled, parallel-group period.  
Randomization will be centrally controlled, stratified according to a co-existing 
diagnosis of IBD, and subjects will be assigned a pre-packaged and numbered 
treatment.  
Period 2: Dose-controlled extension 
Following their completion of Period 1, subjects will enroll in a 6-week extension 
period in which subjects previously randomized to 500 mg or 1,000 mg BID will 
continue for 6 more weeks at that previous dose, while subjects previously randomized 
to placebo will be randomly assigned to receive 6 weeks of either 500 mg or 1,000 mg 
BID.    


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Period 3: Randomized withdrawal 
Following their completion of Period 2, subjects will enroll in a 6-week randomized 
withdrawal period in which all subjects will be randomly assigned to either continue 
on the active treatment they received in Period 2, or be assigned to placebo.  The plan 
is for 50% of the subjects to remain on the experimental treatment at the previous dose, 
and 50% will receive placebo.    
All subjects and study personnel (other than an unblinded statistician who will develop 
the randomization number list, and an unblinded EDC designer will load the 
randomization number list into the EDC system) will remain blinded as to the treatment 
administered throughout the study.  All study test article will be provided in matching 
white tablets, four to a bottle, two bottles to be administered each day, one in the 
morning and one in the evening.  A 45-day supply will be provided to each subject at 
each visit to cover the next 6-week period with an additional 3-days of coverage to 
provide for possible scheduling conflicts.     
In this double-blind study, if a medical emergency occurs and a decision about a 
subject’s condition requires knowledge of the treatment assignment in order to properly 
treat the subject, the study blind may be broken for that specific subject only.  Ideally, 
this decision to break the blind for this one subject should only be made after 
consultation with the Medical Monitor or Sponsor Representative. 
Any broken blind must be clearly justified and explained by a note in the subject's 
source documents.   
3.5 
REPLACEMENT OF DROPOUTS 
Subjects who do not complete study assessments through Week 6 of the initial double-
blind period are eligible to be replaced at the Sponsor's discretion. 


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4.0 
DRUGS AND DOSAGES 
4.1 
IDENTIFICATION AND DESCRIPTION OF INVESTIGATIONAL PRODUCT 
4.1.1 
Investigational Product 
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. HTD1801 is expected 
to dissociate into BBR·Cl and UDCA after oral administration.  
4.1.2 
Labeling 
The study medication and placebo will be supplied by HighTide and packaged into 
white polyethylene bottles, induction--sealed with aluminum foil and a polyethylene 
bottle gap. Each bottle will contain 4 tablets and be affixed with a single-panel label 
that will describe the following information: protocol number, study medication, dose, 
kit number, sponsor name, instructions for storage between 35.6°F and 46.4°F (2°C 
and 8°C), and includes the statement “Caution: New Drug - Limited by or United States 
law to investigational use.”  
A 3-month supply of bottles will be placed into kits packaged for weekly use, and each 
patient will receive the appropriate number of kits to provide supplies until their next 
scheduled visit to the investigational site. Each kit will bear a label describing the 
following information: study medication, dose, kit number, protocol number, 
instructions for storage between 35.6°F and 46.4°F (2°C and 8°C), instructions for use, 
the sponsor name, and the includes the statement “Caution: New Drug - Limited by 
United States law to investigational use.”   
4.2 
DOSING INSTRUCTIONS AND SCHEDULE 
Subjects are instructed to take the entire contents of one bottle of study medication each 
morning and each evening with water and food.  Each bottle will contain four identical 
white tablets.  Subjects should retain the empty bottles and return them to the study site 
on their next visit along with any unused study medication.  


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4.3 
HANDLING OF INVESTIGATIONAL PRODUCT 
The Investigator will be fully responsible for the security, accessibility and storage of 
the test articles while they are at the investigational site.  The Investigator is also 
responsible for the education of study staff in the correct administration of the test 
articles. 
4.4 
COMPLIANCE WITH INVESTIGATIONAL PRODUCT 
Subjects will be queried about their compliance and the number of full and empty study 
medication bottles will be captured on the CRF. 
4.5 
CONCOMITANT MEDICATIONS 
Any non-prohibited concomitant medications are to be continued during the study at 
the same dosage strength and frequency, and should not be taken within 1 hr prior to 
dosing or up to 6 hrs following dosing.  Changes to concomitant medications are not to 
be made unless medically necessary. The need for the change must be documented, 
e.g., in response to an AE.  
Patients should be cautioned about the use of glucose lowering drugs.  The berberine 
component of HTD1801 is reported to lower blood glucose and may potentially cause 
hypoglycemia in patient taking other glucose lowering drugs at the same time.  Patients 
who take glucose lowering drugs should be already aware of the most common 
symptoms of low blood sugar (dizziness, sweating, unusual hunger, shakiness, and a 
very rapid heartbeat) and should know how to react; in all these cases, however, 
patients should report these events to the Investigator. 
4.6 
PROHIBITED CONCOMITANT MEDICATIONS 
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.  These 
exclusions are primarily due to the currently unknown drug interaction profile of the 
berberine component of HTD1801.  Medications known to be strong inhibitors of 
P-glycoprotein (P-gp), CYP3A4, and CYP2D6, and p-gp substrates with a narrow 
therapeutic index are excluded, as shown in Table 3 below: 


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Table 3. 
Prohibited Medications 
P-glycoprotein 
CYP3A4 
CYP2D6 
clarithromycin 
clarithromycin 
bupropion 
amiodarone 
telithromycin 
fluoxetine 
erythromycin 
nefazodone 
fluoxamine 
ketoconazole 
itraconazole 
quinidine 
quinidine 
ketoconazole 
terbinafine 
saquinavir 
atazanavir 
 
verapamil 
darunavir 
 
 
indinavir 
 
digitalis 
lopinavir 
 
lovastatin 
nelfinavir 
 
sildenafil 
ritonavir 
 
 
saquinavir 
 
 
tipranavir 
 
 
chloramphenicol 
 
 
cobicistat 
 
 
grapefruit juice 
 
Source: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLa
beling/ucm093664.htm#table3-2 
 
 
 
 


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5.0 
EXPERIMENTAL PROCEDURES 
5.1 
PROCEDURES, MEASUREMENTS AND EVALUATIONS 
Study procedures are summarized across all study visits as indicated in the Study 
Design (Figure 1), Pharmacokinetic Substudy Design (Figure 1PK), and the Schedule 
of Time and Events (Table 1). 
Throughout the study, blood and urine samples will be collected in a fasting state.  
Study medication should be taken with water and food. 
5.1.1 
Screening (Days -28 to 0) 
Prior to any clinical procedures and evaluations, written signed informed consent must 
be obtained. Subjects who are currently taking UDCA, or who have taken UDCA 
during the past 6 weeks, must have been receiving a stable dosage regimen for at least 
6 weeks before Baseline measurements can be taken (see Section 5.1.2 below).  
Screening is to occur no more than 28 days before the Baseline visit. Potential subjects 
who do not meet all eligibility criteria at Screening will be allowed to rescreen once.  
If a potential subject fails to meet eligibility criteria upon rescreen, he or she will remain 
ineligible for the study. 
During Screening, the following procedures must be conducted and assessments 
obtained.  The information will be collected in a source document templates provided 
by the Sponsor.  Local laboratories may be used for all blood and urine samples 
collected for purposes of Screening.   
• 
Informed consent 
• 
Confirm eligibility criteria 
• 
Demographic information 
• 
Medical History 
• 
Physical Examination 
• 
Weight, height 
• 
Vital signs 
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• 
Prior and concomitant medications 
• 
Glucose-6-phosphate dehydrogenase (G6PD) 
• 
Electrocardiogram, 12 lead (ECG) 
• 
Urine drug test 
• 
HIV, and Hepatitis B, C 
• 
Pregnancy test (urine or serum) 
• 
Complete Blood Count (CBC),  
• 
Comprehensive Metabolic Panel (CMP) that includes ALP, AST, ALT, bilirubin 
If total bilirubin result at Screening is > ULN but ≤ 1.2 x ULN, a 
confirmatory total bilirubin should be collected after 21 days.  If the 
confirmatory total bilirubin remains ≤ 1.2 x ULN, and all other eligibility 
criteria continue to be met, the subject will be eligible. 
• 
INR 
• 
Serum IgG4 if no evidence of IgG4-related sclerosing cholangitis. 
• 
Partial Mayo Score (see Appendix D) 
Subjects will be instructed to stop all prohibited medications (see Section 4.6) prior to 
beginning Baseline procedures. 
5.1.2 
Baseline (immediately prior to dosing) 
Potential subjects who have successfully completed all of the Screening procedures and 
have met all the eligibility criteria (see Sections 3.2.1 and 3.2.2) will be eligible for 
enrollment in the study. Prior to randomization, potential subjects will undergo the 
following Baseline procedures and assessments: 
• 
An update of Medical History information 
• 
Physical examination and vital signs 
• 
An update of prior and concomitant medications 
• 
ECG 
• 
Confirmation of non-pregnant status for females 


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If the potential subject continues to satisfy the Inclusion/Exclusion criteria based upon 
these procedures and assessments stated above, those data will become part of the 
Baseline.  Those potential subjects may be randomized and officially become subjects 
in the study.  Subjects who have been taking UDCA will be instructed to 
discontinue UDCA prior to the Baseline visit.  Subjects will again be instructed to 
avoid any use of the prohibited medications listed in Section 4.6 for the entire duration 
of the study, or until formally instructed otherwise.   
Patients should also be cautioned about the use of glucose lowering drugs.  The 
berberine component of HTD1801 is reported to lower blood glucose and may 
potentially cause hypoglycemia in patient taking other glucose lowering drugs at the 
same time.  Patients who take glucose lowering drugs should be already aware of the 
most common symptoms of low blood sugar (dizziness, sweating, unusual hunger, 
shakiness, and a very rapid heartbeat) and should know how to react; in all these cases, 
however, patients should report these events to the Investigator. 
Prior to dosing on Visit 2, the following additional Baseline procedures and 
assessments are to be conducted at the investigational site.  All clinical laboratory 
samples are to be sent to the designated central laboratory for analysis.  These Baseline 
central laboratory data will not be used to determine eligibility in the study as the newly 
enrolled subject has already been randomized.  The additional pre-dose Baseline 
procedures are to include: 
• 
CBC 
• 
INR 
• 
CMP that includes ALP, AST, ALT, bilirubin 
• 
Standard serum lipid panel 
• 
Partial Mayo Score 
• 
Mayo Risk Score 
• 
Plasma C-reactive protein(CRP) (only in patients with IBD) 
• 
Stool sample for fecal calprotectin (FC) (only in patients with IBD).  The stool 
sample testing may be completed separately from the site visit. 


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For subjects participating in the PK substudy, additional blood samples for PK analysis 
will be collected, processed, and sent to the designated central laboratory.  PK samples 
will be collected at the following timepoints (see Table 1PK): 
• 
Pre-dose 
• 
1, 2, 3, 4, 6, and 8 hours post-dose 
Subjects participating in the PK substudy will be required to maintain a dosing diary. 
The date and time of each dose of study medication taken on the last 3 days prior to the 
Week 6 visit must be recorded, and the diary must be brought back to the site at the 
Week 6 clinic visit. 
Following the successful completion of all Baseline procedures, the subject will 
self-administer the first dose of the study medication, consisting of 4 tablets, under the 
supervision of study personnel.  The subject will be provided an entire 6-week supply 
of study medication consisting of a total of 90 dosage units, each containing 4 tables.  
The subject will be instructed to swallow the contents of one dosage unit containing 
4 tablets in the morning, and one dosage unit containing 4 tablets in the evening, each 
day until they return to the investigational site 6 weeks later for the next visit.  Subjects 
will be instructed to contact the investigational site immediately if any problems or 
concerns arise.  
5.1.3 
Double-Blind Treatment Period - Weeks 2, 4, and 6  
During the double-blind treatment period, the following procedures and assessments 
will be conducted on Weeks 2 and 4:  
• 
Subjects are required to provide blood samples for CBC, CMP, and Lipids.  This 
will not require a visit to the study site and will involve local sample collection. 
• 
Subjects will be contacted by the Investigator, or one of their staff, to discuss the 
occurrence of any AEs, any new or changes in concomitant medications, 
adherence to the treatment schedule, and compliance with the requirement to visit 
a pre-specified clinical laboratory for CBC, CMP, and Lipids.  Any new 
medications that are being taken are, by default, to be considered as being 
necessitated by an AE.  If necessary, subjects may be asked to visit the 
investigational site, at the Investigator's discretion.  


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• 
It is recognized that some investigational sites may require subjects to come to 
the clinic for these visits and related activities. 
During the double-blind treatment period, the following procedures and assessments 
will be conducted during the visit to the investigational site on Weeks 6:  
• 
Prior and concomitant medications will be reviewed and any changes will be 
recorded on the appropriate eCRF page.  Generally, any new medications that are 
being taken are, by default, to be considered as being necessitated by an AE.  
Rarely, a previously unmentioned prior medication may be disclosed, and that 
eCRF page should be updated. 
• 
A physical examination including vital signs will be conducted and any findings 
that represent clinical deteriorations from Baseline are to be recorded as Adverse 
Events. 
• 
An ECG is to be recorded.  Any findings that represent clinical deteriorations 
from Baseline are to be recorded as an AE. 
• 
Blood samples for CBC, INR, CMP, and Lipids panel are to be collected and sent 
to the designated central laboratory. Any subsequent findings that represent 
clinical deteriorations from Baseline are to be recorded as an AE. 
• 
Partial Mayo Score. 
• 
Subjects with IBD will provide a blood sample for C-reactive protein. 
• 
Subjects with IBD will also complete a test for fecal calprotectin.  (The stool 
sample testing may be completed separately from the site visit.) 
• 
The subject is to be queried for any changes to existing AEs, or any additional 
AEs that may have occurred during the intervening period. 
After the Week 6 visit, all subjects are eligible to enroll into the 6-week Dose-controlled 
Extension Period of the study.  Subjects who do not wish to continue may choose to 
discontinue and should be handled according to the information listed in Sections 5.1.6 
and Section 7.0. 
For subjects participating in the PK substudy and continuing into the Dose-controlled 
Extension Period, the subject will be instructed not to take the morning dose of study 
medication at home on the day of the Week 6 visit.  The morning dose will be taken in 


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the clinic, the dosing diary will be collected, and additional blood samples for PK 
analysis will be collected, processed, and sent to the designated central laboratory.  PK 
samples will be collected at the following timepoints on Week 6 (see Table 1PK): 
• 
Pre-dose (taken in clinic) 
• 
1, 2, 3, 4, 6, and 8 hours post-dose 
PK samples will not be collected during the Week 6 visit for subjects who withdraw 
from the study prior to beginning the Dose-controlled Extension Period. 
5.1.4 
Dose-controlled Extension Period - Weeks 8, 10, and 12  
During the dose-controlled extension period, the following procedures and assessments 
will be conducted at Weeks 8 and 10:  
• 
Subjects are required to provide blood samples for CBC, CMP, and Lipids.  This 
will not require a visit to the study site and will involve local sample collection. 
• 
Subjects will be contacted by the Investigator, or one of their staff, to discuss the 
occurrence of any AEs, any new or changes in concomitant medications, 
adherence to the treatment schedule, and compliance with the requirement to visit 
a pre-specified clinical laboratory for CBC, CMP, and Lipids.  Any new 
medications that are being taken are, by default, to be considered as being 
necessitated by an AE.  If necessary, subjects may be asked to visit the 
investigational site, at the Investigator's discretion.  
• 
It is recognized that some investigational sites may require subjects to come to 
the clinic for these visits and related activities. 
During the dose-controlled extension period, the following procedures and assessments 
will be conducted during the visit to the investigational site on Weeks 12:  
• 
Prior and concomitant medications will be reviewed and any changes will be 
recorded on the appropriate eCRF page.  Generally, any new medications that are 
being taken are, by default, to be considered as being necessitated by an Adverse 
Event.  Rarely, a previously unmentioned prior medication may be disclosed, and 
that eCRF page should be updated. 


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• 
A physical examination including vital signs will be conducted and any findings 
that represent clinical deteriorations from Baseline are to be recorded as Adverse 
Events. 
• 
An ECG is to be recorded.  Any findings that represent clinical deteriorations 
from Baseline are to be recorded as an AE. 
• 
Blood samples for CBC, INR, CMP, and Lipids panel are to be collected and sent 
to the designated central laboratory. Any subsequent findings that represent 
clinical deteriorations from Baseline are to be recorded as an AE. 
• 
Partial Mayo Score. 
• 
Subjects with IBD will provide a blood sample for C-reactive protein. 
• 
Subjects with IBD will also complete a test for fecal calprotectin.  (The stool 
sample testing may be completed separately from the site visit.) 
• 
The subject is to be queried for any changes to existing AEs, or any additional 
AEs that may have occurred during the intervening period. 
After the Week 12 visit, all subjects are eligible to enroll into the 6-week Randomized 
Withdrawal Period of the study.  Subjects who do not wish to continue may choose to 
discontinue and should be handled according to the information listed in Sections 5.1.6 
and Section 7.0.    
5.1.5 
Random Withdrawal Period, Weeks 14, 16, and 18  
During the random withdrawal period, the following procedures and assessments will 
be conducted on Weeks 14 and 16:  
• 
Subjects are required to provide blood samples for CBC, CMP, and Lipids.  This 
will not require a visit to the study site and will involve local sample collection. 
• 
Subjects will be contacted by the Investigator, or one of their staff, to discuss the 
occurrence of any AEs, any new or changes in concomitant medications, 
adherence to the treatment schedule, and compliance with the requirement to visit 
a pre-specified clinical laboratory for CBC, CMP, and Lipids.  Any new 
medications that are being taken are, by default, to be considered as being 
necessitated by an AE.  If necessary, subjects may be asked to visit the 
investigational site, at the Investigator's discretion.  


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• 
It is recognized that some investigational sites may require subjects to come to 
the clinic for these visits and related activities. 
During the random withdrawal period, the following procedures and assessments will 
be conducted during the visit to the investigational site on Weeks 18:  
• 
Prior and concomitant medications will be reviewed and any changes will be 
recorded on the appropriate eCRF page.  Generally, any new medications that are 
being taken are, by default, to be considered as being necessitated by an Adverse 
Event.  Rarely, a previously unmentioned prior medication may be disclosed, and 
that eCRF page should be updated. 
• 
A physical examination including vital signs will be conducted and any findings 
that represent clinical deteriorations from Baseline are to be recorded as Adverse 
Events. 
• 
An ECG is to be recorded.  Any findings that represent clinical deteriorations 
from Baseline are to be recorded as an AE. 
• 
Blood samples for CBC, INR, CMP, and Lipids panel are to be collected and sent 
to the designated central laboratory. Any subsequent findings that represent 
clinical deteriorations from Baseline are to be recorded as an AE. 
• 
Partial Mayo Score. 
• 
Subjects with IBD will provide a blood sample for C-reactive protein. 
• 
Subjects with IBD will also complete a test for fecal calprotectin.  (The stool 
sample testing may be completed separately from the site visit.) 
• 
The subject is to be queried for any changes to existing AEs, or any additional 
AEs that may have occurred during the intervening period. 
5.1.6 
Study Discharge  
Following the successful completion of all procedures at the Week 18 visit, all subjects 
are to undergo discharge procedures.  This will include instructions to the subject to 
contact the investigational site immediately if any problems or concerns arise during 
the next 4 weeks of follow-up. Female subjects will complete a pregnancy test.  
Pregnancy is not to be recorded as an Adverse Event. 


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5.1.7 
Follow-up Period (Week 22) 
Subjects will undergo follow-up evaluations 4 weeks after the last dose of study drug. 
The follow-up can be via phone, providing the patient has no health concerns related 
to the study. The subject may be asked to return to the investigational site if the 
Investigator thinks it is advisable for safety reasons.  The following assessments will 
be conducted by phone or other contact at Week 22: 
• 
AE monitoring  
• 
Concomitant medications (query for any possible relationship to an AE) 
Following the completion of the follow-up procedures, the subject is officially 
discharged from the study. 


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6.0 
PROCEDURES FOR HANDLING ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS 
6.1 
DEFINITION OF AN ADVERSE EVENT 
The following definition of adverse event (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. 
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. 


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• 
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 preexisting disease or condition (present 
or detected before enrollment) that does not worsen overall 
• 
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 
AEs may include pre-treatment or post-treatment events that occur as a result of 
protocol-mandated procedures (e.g., invasive procedures, modification of the subject’s 
previous therapeutic regimen).  
AEs 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 study staff 
will note all AEs mentioned by the subject at Baseline and during administration of the 
investigational product. All clinical complaints volunteered by or elicited from the 
subject during the study will be recorded on the appropriate page of the electronic case 
report form (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 
annual report or more frequently if requested by the regulatory agency. SAEs require 
special reporting in addition to documentation in the eCRF as described in Section 6.7.   


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6.2 
DEFINITION OF A SERIOUS ADVERSE EVENT 
In this study, a serious adverse event 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. 
• 
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. 
• 
An 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 


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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).  
6.3 
RECORDING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
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 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. 
6.4 
ASSESSMENT OF INTENSITY 
The investigator will assess the intensity for each AE and SAE reported during the 
study on the basis of his or her clinical judgement.  The classifications in Table 4 should 
be used in assigning intensity of each AE recorded in the case report form. 
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Table 4. 
Classification of AEs by Intensitya 
Intensity 
Definition 
Mild AE 
(Grade 1) 
An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities 
Moderate AE 
(Grade 2) 
An event that is sufficiently discomforting to the extent of interfering with 
normal everyday activities 
Severe AE 
(Grade 3) 
An event that prevents the subject from performing normal everyday 
activities 
Life-threatening or 
disabling AE (Grade 
4) 
An event that, at the time of occurrence, put the subject at risk of death or 
resulted in a persistent or significantly disability or incapacity 
Death related to AE 
(Grade 5) 
An event that resulted in death 
AE = adverse event   
a From Common Terminology Criteria for Adverse Events, version 4.0 
 
 
Any AE that changes in intensity 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, 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 6.1. 
6.5 
ASSESSMENT OF CAUSALITY 
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 


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one of the criteria 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. 
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.  
AE = adverse event. 
 
 
6.6 
EXPECTEDNESS OF SERIOUS ADVERSE EVENTS 
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. 
6.7 
REPORTING OF SERIOUS ADVERSE EVENTS 
1. 
Any SAE occurring after the subject signs the informed consent form and the 
investigational product has been administered, as described in Section 6.1, must 
be reported to the Medical Monitor 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 
competed 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 
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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 
SAE = serious adverse event. 
 
 
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 pharmacovigilance within the designated time 
frames. If additional information to complete the SAE report is needed, the investigator 
will not wait before notifying the safety department of the SAE. The SAE report will 
be updated by the investigator when additional information is received.  
6.8 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
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. 


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The appropriate SAE report will be updated once the SAE resolves, stabilizes, or is 
otherwise explained or until the subject is lost to follow-up. The investigator will also 
ensure that updates include any supplemental data that may explain causality of the 
SAE(s). 
New or updated information will be recorded on a copy of the initial SAE report form; 
all incorrect data should be marked out (by a single line), initialed, and dated by the 
investigator or designee, with the new information clearly recorded. The updated SAE 
report form will then be signed and dated by the investigator and resubmitted to the 
pharmacovigilance department as outlined in Table 6.  
6.9 
LIVER ADVERSE EVENTS 
The following algorithm will be used to monitor for drug-induced liver injury (DILI): 
If isolated transaminase (AST or ALT) elevations are observed, defined as: Normal 
bilirubin and absence of clinical hepatitis, AND 
1. 
ALT or AST  5 times the ULN if normal at baseline, OR 
2. 
ALT or AST  3 times the baseline or ≥ 400 U/L if abnormal at baseline 
Then  
1. 
Repeat liver profile (ALT, AST, bilirubin and PT/INR) within 2 to 3 days, AND  
2. 
Monitor the patient with laboratory testing and physical examination 2 to 3 times 
per week as per the “close observation” definition in the DILI guidance 
(https://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf). 
If any ONE of the following criteria is met: 
- Transaminases (ALT or AST ≥ 3 x baseline) AND bilirubin (total bilruibin 
> 2 x ULN), OR 
- Cholestatic markers (ALP or GGT > 2 x baseline), OR 
- Isolated ALT/AST ≥ 8x ULN or 600 U/L in the presence of normal CPK and 
LDH and not secondary to cholangitis, OR 
- INR increase > 1.5 refractory to vitamin K administration 


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OR: if any ONE of the following criteria is met for total bilirubin unrelated to 
hemolysis: 
1. 
Doubling of total bilirubin  
- OR: any increase in total bilirubin if there are symptoms of clinical hepatitis 
(e.g., vomiting, nausea, right upper quadrant pain), 
- OR: there are immunological reactions (rash or >5% eosinophilia), 
Then  
1. 
study medication must be interrupted, and   
2. 
a drug-induced liver injury workup must be initiated for alternate etiologies; 
3. 
repeat a liver profile (ALT, AST, total bilirubin, direct bilirubin, ALP) and 
PT/INR within 48 to 72 hours;  
4. 
monitor the patient with further laboratory testing and physical examination 2 to 
3 times per week as per the “close observation” definition in the DILI guidance 
(https://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf.  
5. 
If a subject lives in a remote area, they can be tested locally and the results 
communicated to the investigator promptly.  
Rechallenge  
1. 
Only if a firm alternate etiology is identified AND liver tests have returned to 
baseline (a rechallenge may be considered)  
2. 
If cholangitis is the etiology – diagnosis must be firmly established according to 
the protocol definition before a rechallenge is considered 
Rechallenge is not recommended if it is determined that the subject has had a drug 
induced liver injury.  
6.10 
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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7.0 
STUDY OR SITE TERMINATION AND SUBJECT DISCONTINUATION 
7.1 
ADVERSE EVENT STOPPING RULES 
If a subject experiences an AE that, in the judgment of the investigator, the sponsor, or 
the medical monitor, presents an unacceptable consequence or risk to the subject, the 
subject may be discontinued from the study.  
If a participant develops cholangitis or an inflammatory bowel disease (IBD) flare 
twice during the trial, then the patient should be discontinued from study drug, but 
maintained in the study for safety follow-up.   
• 
Cholangitis is defined as cholestasis and systemic inﬂammation demonstrated by 
clinical signs or blood test results in addition to biliary manifestations 
demonstrated by imaging. 
• 
Inflammatory bowel disease flare-ups are defined as unexpectedly frequent 
and/or urgent bowel movements, diarrhea, bloody stools or abdominal pain, not 
requiring systemic immunosupression with a corticosteroid or a biological agent. 
If a participant develops a dominant stricture or an IBD flare requiring new or increased 
of immunosupressive therapy (systemic corticosteroids or biologics), then the patient 
should be discontinued from study drug, but maintained in the study for safety 
follow-up. 
• 
A dominant stricture is defined as intervention due to symptoms, compelling 
imaging results, or a prominent increase in liver biochemical markers. 
7.2 
NONCOMPLIANCE 
After the investigator, the medical monitor, or study monitor consult (and the sponsor 
if appropriate), a subject may be discontinued from the study for the following 
administrative reasons: 
• 
Failure to receive study medication or treatment as mandated by the instructions 
provided in Section 4.0 
• 
Failure to comply with protocol requirements 
• 
Unauthorized, subject-initiated changes in dosing regimen 


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7.3 
WITHDRAWAL OF CONSENT 
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.  Subjects will be encouraged to complete the study; however, they may 
voluntarily withdraw at any time. The investigator will provide a written explanation 
of the reason for discontinuation in a source document and this information will be 
recorded on the appropriate eCRF page. Subjects will be specifically queried to 
determine whether or not withdrawal of consent might have been due to an adverse 
event.  If a subject withdraws before completion, every effort should be made to 
complete the assessments scheduled during the follow-up period [termination/end of 
study visit]. A subject may be removed from the study for the reasons described in 
Section 7.1 through Section 7.3. 
7.4 
PREMATURE STUDY OR SITE TERMINATION 
If the sponsor, investigator, medical monitor, study monitor, or appropriate regulatory 
officials discover conditions arising during the study that indicate that the study should 
be halted or that the site should be terminated, this action may be taken after appropriate 
consultation among the sponsor, investigator, medical monitor, and study monitor.  The 
Common Terminology Criteria for Adverse Events (CTCAE) will be used to for the 
assessment of trial stopping criteria.  
The study trial will be stopped if: 
• 
Three patients develop the same Grade 3 CTCAE  
• 
OR: Two patients develop any Grade 4 CTCAE  
• 
OR: One patient develops a Grade 5 CTCAE 
Additional conditions that may warrant termination of the study include, but are not 
limited to, the following: 
• 
The discovery of an unexpected, serious, or unacceptable risk to the subjects 
enrolled in the study 
• 
A decision on the part of the sponsor to suspend or discontinue testing, evaluation, 
or development of the product 


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A study conducted at a single site in a multicenter study may also warrant termination 
under the following conditions: 
• 
Failure of the investigator to enroll subjects into the study at an acceptable rate 
• 
Failure of the investigator to comply with pertinent regulations of appropriate 
regulatory authorities 
• 
Submission of knowingly false information from the site to the sponsor, study 
monitor, or appropriate regulatory authority 
• 
Insufficient adherence to protocol requirements 
Study termination and follow-up will comply with the conditions set forth in 
International Council for Harmonisation E6, Guideline for Good Clinical Practice, 
Sections 4.12, 4.13, 5.20, and 5.21. 


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8.0 
DATA COLLECTION AND PROCESSING AND STATISTICAL ANALYSIS 
8.1 
DATA COLLECTION AND PROCESSING  
Electronic case report forms (eCRFs) will be used to capture study assessments and 
data. The study coordinator or other delegated study staff will enter data from source 
documents into the eCRFs. All eCRFs will be reviewed and source-verified by the 
study monitor during periodic site visits, and the study monitor will ensure that all data 
in the eCRF are correct and complete. Before or between visits, the medical monitor or 
study monitor may conduct a preliminary medical review of the eCRFs. Once the 
eCRFs are completed and source-verified, the investigator must electronically sign all 
required eCRF pages, verifying the accuracy of all data contained in the eCRFs. 
Training will be provided for the electronic data capture (EDC) system. All study staff 
using the EDC system must have the necessary education, training, and experience or 
any combination of these. The investigator will be responsible for documenting 
employee education, training, and previous experience that pertain to the EDC system 
for all site staff using the EDC system.  
The investigator must maintain adequate security of the EDC system, including 
documentation that all users have been trained on the appropriate standard operating 
procedure and a list of authorized users. To ensure all data entries can be tracked, all 
personnel responsible for data entry must obtain a unique user identification (user ID) 
and password before any data can be entered in the eCRFs. Authorized study staff will 
be assigned a unique user ID only after receiving standard operating procedure training.  
If electronic data systems other than those provided and maintained by the sponsor are 
used for documentation and data capture, the investigator must ensure that the systems 
are validated and that data are backed up as described in Section 9.2. 


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8.2 
STATISTICAL ANALYSIS 
8.2.1 
General Overview 
The data will be summarized in tables by treatment period and treatment group, as 
appropriate, showing the number of subjects with nonmissing data (n), mean, standard 
deviation, median, minimum, and maximum for continuous data and showing counts 
and percentage for categorical data. Data will also be listed as deemed appropriate. All 
statistical analyses will be performed and data appendices will be created by using SAS 
version 9.4 or later. 
All statistical tests will be two-sided with an alpha (α) level of 0.05. 
8.2.2 
Populations of Interest 
The modified Intent-to-treat population (mITT) will consist of all randomized subjects 
who receive at least one dose of study drug and who have at least one post-dose efficacy 
assessment. 
The safety population will include randomized subjects who receive at least one dose 
of study drug. 
8.2.3 
Efficacy Analysis 
The mITT population will be used for the analysis of all efficacy endpoints. No alpha 
adjustments for multiplicity will be made for the analysis of efficacy endpoints for this 
proof of concept study. 
The primary efficacy variable is the change in ALP from Baseline to Week 6 in the 
double-blind parallel group period. Changes in ALP from Baseline will be summarized 
by treatment group and visit using descriptive statistics. A mixed model repeated 
measures (MMRM) will be fit to the data and the model will include fixed factors for 
treatment, randomization strata of IBD diagnosis, visit and treatment by visit 
interaction, and Baseline value as a covariate. An unstructured covariance matrix will 
be used to model the repeated assessment over time. Denominator degrees of freedom 
will be adjusted using Kenward-Roger’s method. Sensitivity analyses will be described 
in the statistical analysis plan (SAP). Treatment comparisons will be made at each visit, 


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with the primary comparison at Week 6. No imputation of missing data is necessary 
for the MMRM analysis of the primary endpoint.  A similar MMRM analysis will be 
performed for the randomized withdrawal period. Analysis for the randomized 
withdrawal period will be conducted for all subjects and separately for responders 
based on pre-specified responder criteria. For the dose-controlled treatment period, a 
one sample t-test will be used to evaluate the change in ALP from Week 6 to Week 12 
for the subjects who were previously randomized to placebo during the first period.    
The secondary efficacy variables of the proportion of subjects who normalize ALP, the 
proportion of subjects who achieve ALP of < 1.5 x ULN and the proportion of subjects 
who achieve a 50% decrease in ALP from Baseline will be calculated at the end of 
treatment using a last observation carried forward for any missing data. Frequencies 
and percentages will be calculated by treatment group and by visit. Any adjustments 
for multiplicity will be discussed in the SAP. Treatment comparisons will be made at 
Week 6 (or LOCF) using Fisher’s exact test. A similar analysis will be performed for 
the randomized withdrawal period. For the dose-controlled extension period, a one 
sample exact test will be used to evaluate the proportion of subjects achieving each of 
the secondary endpoints at Week 12 for the subjects who were randomized to placebo 
during the first double-blind period. The secondary efficacy variables of change from 
Baseline in AST/ALT ratio, bilirubin, and IgG4 will be analyzed using a MMRM 
similar to that described above for the primary efficacy variable. 
Further details of the efficacy analyses will be provided in a separate statistical analysis 
plan. 
8.2.4 
Safety Analysis 
The safety population will be used for all safety analyses. AE data will be listed 
individually, and the incidence of adverse events will be summarized by system organ 
class and preferred terms within a system organ class for each treatment group. When 
calculating the incidence of AEs, each AE will be counted only once for a given subject 
within a specified system organ class, preferred term. If the same AEvent occurs on 
multiple occasions for a subject, the occurrence with the highest severity and 
relationship to study drug will be reported. If two or more AEs are reported as a unit, 
the individual terms will be reported as separate events. 


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Changes in vital signs, hematology, and clinical chemistry parameters from Baseline 
to the end of the study will be examined. Treatment-emergent changes from normal 
values to abnormal values in key laboratory parameters will be identified. 
8.2.5 
Pharmacokinetic Analysis 
Population PK models for the components of HTD1801 (UDCA and BBR) will be 
developed and validated using a nonlinear mixed-effects model (NONMEM) approach. 
The model for UDCA will include endogenous UDCA. The error model will include 
between-subject variability and residual error between observed and predicted 
concentration (using NONMEM’s FOCE method).  Selection of the appropriate model 
will be based on hypothesis testing using the likelihood ratio test and graphical analysis 
of residual error (goodness of fit).  Target parameters for each component include 
apparent clearance (CL/F) and apparent volume of distribution at steady state (Vss/F). 
Covariate relationships between PK parameters and individual characteristics will be 
evaluated and incorporated into the model as indicated by the data.  Covariates for 
evaluation will include, but will not be limited to, vital signs (e.g.,, body size), 
demographics (e.g., sex, age, race) and organ function / disease biomarkers (e.g., 
bilirubin and alkaline phosphatase).  The models will be validated using likelihood 
profiles, bootstrap analysis, and visual predictive check. 
Concentration vs. time profiles will be simulated for each subject based on that 
subject’s individual-specific (post-hoc) parameter estimates. Individual single-dose 
and steady-state non-compartmental metrics will be calculated from this simulated data 
(e.g., Cmax, AUC0-12, AUC0-inf).  Metrics for UDCA will be reported with and without 
baseline correction. 
8.2.6 
Pharmacokinetic/Pharmacodynamic Analysis 
An exploratory exposure-response analysis will be performed to evaluate the 
relationship between exposure metrics (e.g., AUC, Cmax) for UDCA, BBR, and 
UDCA+BBR and change from baseline in serum ALP.  The analysis will evaluate the 
effect of covariates including disease state (e.g., baseline ALP; IBD with elevated FC; 
elevated CRP). 
An exploratory exposure-response analysis will be performed to evaluate the 
relationship between exposure, adverse events (AE) of interest, and serious adverse 


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events (SAE). The relationship between exposure and AE or SAE occurrence will be 
evaluated graphically and, where indicated, statistically. 
8.2.7 
Sample Size 
Results from published clinical trials of PSC patients including Zhu et al., 2015 and 
Fickert et al., 2017 were reviewed.[10, 34] These publications were used along with 
consideration of inclusion and exclusion criteria for this study to estimate mean 
baseline ALP and  to estimate variability.  Total sample size was chosen based on 
balancing  consideration of business costs, time to enroll subjects with this rare disease 
and the mean change which could be detected given the mean baseline and variability 
assumptions. The standard deviation for change from baseline in ALP was assumed to 
be 200. A total of 90 subjects, 30 subjects per group is sufficient to detect a mean 
difference from placebo within a dose group of 147 with 80% power at an alpha of 
0.05. Assuming a mean baseline ALP of 450, this equates to a 32.7% reduction. This 
study whould be adequate to determine if there is a positive signal in ALP during 
HTD1801 treatment.  
No formal sample size analysis was performed for the PK substudy.  Thirty-six (36) 
subjects providing up to 504 pharmacokinetic samples is considered sufficient to 
characterize CL/F and Vss/F of UDCA and BBR in this study population. 
 
 


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9.0 
STUDY ADMINISTRATION 
9.1 
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 period 
evaluations. One copy of the signed informed consent form 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 informed consent form and authorization 
for use and disclosure of protected health information, which is prepared by the 
investigator or the study 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 informed consent form must 
contain the 20 elements of informed consent described in International Council for 
Harmonisation 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.  
9.2 
STUDY DOCUMENTATION 
9.2.1 
Investigator Information 
Investigator information is included in the study procedures manual, which is updated 
as needed. 
9.2.2 
Investigator’s Study Files 
Documentation about the investigator and 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 investigational 
product, biological samples, and the laboratory, the study procedures manual and study 
logs, eCRFs, records of monitoring activities, and correspondence between sponsor or 
study monitor and the investigator.  


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9.2.3 
Case Report Forms and Source Documentation 
The investigator must make study data accessible to the site 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 site by the site 
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 on computer disc after study closure to be kept in the investigator’s study files.  
9.2.4 
Retention of Study Documents 
According to International Council for Harmonisation 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 the another investigator 
at the institution where the study was conducted. 
Audit trails for electronic document 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. 
9.3 
CONFIDENTIALITY 
9.3.1 
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 


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(with the exception of information required by law or regulations to be disclosed to the 
IRB/IEC, the subject, or the appropriate regulatory authority).  
9.3.2 
Subject Anonymity 
The anonymity of participating subjects must be maintained. Subjects will be identified 
by an assigned subject number on eCRFs and other documents retrieved from the site 
or sent to the study monitor, sponsor, regulatory agencies, central laboratories, or 
blinded reviewers. Documents that identify the subject (e.g., the signed informed 
consent form) 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. 
9.4 
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 informed consent form, the revised informed 
consent form prepared by the investigator must also be approved by the sponsor, study 
monitor, and the IRB/IEC before implementation. 
Departures from the protocol are allowed only in situations that eliminate an immediate 
risk to a subject and that are deemed crucial for the safety and well-being of that subject. 
The investigator or the attending physician also will contact the medical monitor as 
soon as possible in the case of such a departure. These departures do not require 
preapproval 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.  


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9.5 
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 
International Council for Harmonisation E6, Section 5.18.4. 
9.6 
GENERAL INFORMATION 
The investigator should refer to the Investigator’s Brochure, study procedures manual, 
and any other information provided about this investigational product and details of the 
procedures to be followed during this study. 
 


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10.0 
REFERENCES 
1. 
Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al. 
Diagnosis and management of primary sclerosing cholangitis. Hepatology 
2010;51(2):660-678. 
2. 
Weismuller TJ, Wedemeyer J, Kubicka S, Strassburg CP, Manns MP. The 
challenges in primary sclerosing cholangitis--aetiopathogenesis, autoimmunity, 
management and malignancy. J Hepatol 2008;48 Suppl 1:S38-S57. 
3. 
Ali AH, Carey EJ, Lindor KD. Current research on the treatment of primary 
sclerosing cholangitis. Intractable Rare Dis Res 2015;4(1):1-6. 
4. 
Bambha K, Kim WR, Talwalkar J, Torgerson H, Benson JT, Therneau TM, 
et al. Incidence, clinical spectrum, and outcomes of primary sclerosing 
cholangitis in a United States community. Gastroenterology 2003;125(5):1364-
1369. 
5. 
FDA. Review Package for UDCA (Application Number 020675).   Accessed 
September 15, 2017 Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/20675a.cfm. 
6. 
Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler 
AS, et al. High-dose ursodeoxycholic acid for the treatment of primary 
sclerosing cholangitis. Hepatology 2009;50(3):808-814. 
7. 
Levy C, Lindor KD. Treatment Options for Primary Biliary Cirrhosis and 
Primary 
Sclerosing 
Cholangitis. 
Curr 
Treat 
Options 
Gastroenterol 
2003;6(2):93-103. 
8. 
Poupon R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents 
for cholestatic liver diseases: an overview of their mechanisms of action. Clin 
Res Hepatol Gastroenterol 2012;36 Suppl 1:S3-S12. 
9. 
Poropat G, Giljaca V, Stimac D, Gluud C. Bile acids for primary sclerosing 
cholangitis. Cochrane Database Syst Rev 2011;(1):CD003626. 


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10. 
Zhu GQ, Shi KQ, Huang GQ, Wang LR, Lin YQ, Braddock M, et al. A network 
meta-analysis of the efficacy and side effects of UDCA-based therapies for 
primary sclerosing cholangitis. Oncotarget 2015;6(29):26757-26769. 
11. 
Tabibian JH, O'Hara SP, Trussoni CE, Tietz PS, Splinter PL, Mounajjed T, 
et al. Absence of the intestinal microbiota exacerbates hepatobiliary disease in 
a 
murine 
model 
of 
primary 
sclerosing 
cholangitis. 
Hepatology 
2016;63(1):185-196. 
12. 
Dr. Falk Pharma GmbH. Norursodeoxycholic acid in the treatment of primary 
sclerosing cholangitis (NUC-3). ClinicalTrials.gov Website.   Accessed 
November 5, 2015 Available at: 
https://clinicaltrials.gov/ct2/show/NCT01755507. 
13. 
Kumar A, Ekavali, Chopra K, Mukherjee M, Pottabathini R, Dhull DK. Current 
knowledge and pharmacological profile of berberine: An update. Eur J 
Pharmacol 2015;761:288-297. 
14. 
Caliceti C, Franco P, Spinozzi S, Roda A, Cicero AF. Berberine: New Insights 
from Pharmacological Aspects to Clinical Evidences in the Management of 
Metabolic Disorders. Curr Med Chem 2016;23(14):1460-1476. 
15. 
Council for Responsible Nutrition. CRN List of Dietary Ingredients 
"grandfathered" under DSHEA.   Acessed September 18, 2017 Available at: 
https://www.fda.gov/ohrms/dockets/dockets/05p0305/05p-0305-cr00001-04-
Council-For-Responsible-Nutrition-vol1.pdf. 
16. 
Olsson R, Boberg KM, de Muckadell OS, Lindgren S, Hultcrantz R, Folvik G, 
et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-
year 
multicenter, 
randomized, 
controlled 
study. 
Gastroenterology 
2005;129(5):1464-1472. 
17. 
Olsson R, Broome U, Danielsson A, Hagerstrand I, Jarnerot G, Loof L, et al. 
Colchicine treatment of primary sclerosing cholangitis. Gastroenterology 
1995;108(4):1199-2203. 


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18. 
Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary 
Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med 
1997;336(10):691-695. 
19. 
Stanich PP, Bjornsson E, Gossard AA, Enders F, Jorgensen R, Lindor KD. 
Alkaline phosphatase normalization is associated with better prognosis in 
primary sclerosing cholangitis. Dig Liver Dis 2011;43(4):309-313. 
20. 
Al Mamari S, Djordjevic J, Halliday JS, Chapman RW. Improvement of serum 
alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and 
reduced risk of cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 
2013;58(2):329-334. 
21. 
Lindstrom L, Hultcrantz R, Boberg KM, Friis-Liby I, Bergquist A. Association 
between reduced levels of alkaline phosphatase and survival times of patients 
with 
primary 
sclerosing 
cholangitis. 
Clin 
Gastroenterol 
Hepatol 
2013;11(7):841-846. 
22. 
Rupp C, Rossler A, Halibasic E, Sauer P, Weiss KH, Friedrich K, et al. 
Reduction in alkaline phosphatase is associated with longer survival in primary 
sclerosing cholangitis, independent of dominant stenosis. Aliment Pharmacol 
Ther 2014;40(11-12):1292-301. 
23. 
Halilbasic E, Fuchs C, Hofer H, Paumgartner G, Trauner M. Therapy of 
Primary Sclerosing Cholangitis--Today and Tomorrow. Dig Dis 2015;33 Suppl 
2:149-163. 
24. 
Fickert P, Pollheimer MJ, Silbert D, Moustafa T, Halilbasic E, Krones E, et al. 
Differential effects of norUDCA and UDCA in obstructive cholestasis in mice. 
J Hepatol 2013;58(6):1201-1208. 
25. 
Tremlett H, Fadrosh DW, Faruqi AA, Zhu F, Hart J, Roalstad S, et al. Gut 
microbiota in early pediatric multiple sclerosis: a case-control study. Eur J 
Neurol 2016;23(8):1308-1321. 


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26. 
De Cruz P, Kang S, Wagner J, Buckley M, Sim WH, Prideaux L, et al. 
Association between specific mucosa-associated microbiota in Crohn's disease 
at the time of resection and subsequent disease recurrence: a pilot study. J 
Gastroenterol Hepatol 2015;30(2):268-278. 
27. 
Noor SO, Ridgway K, Scovell L, Kemsley EK, Lund EK, Jamieson C, et al. 
Ulcerative colitis and irritable bowel patients exhibit distinct abnormalities of 
the gut microbiota. BMC Gastroenterol 2010;10:134. 
28. 
National Toxicology P. Toxicology and carcinogenesis studies of goldenseal 
root powder (Hydrastis Canadensis) in F344/N rats and B6C3F1 mice (feed 
studies). Natl Toxicol Program Tech Rep Ser 2010;(562):1-188. 
29. 
National Toxicology Program, U.S. Department of Health and Human Services. 
Final Study Report: Developmental toxicity evaluation for berberine chloride 
dihydrate (CAS No. 5956-60-5) administered in the feed to Swiss (CD-1)  
mice 
on 
gestational 
Days 
6 
through 
17. 
 
Available 
at: 
https://ntp.niehs.nih.gov/testing/types/dev/abstracts/ter99002/ter99002.html; 
Report date: 14 April 2003, Updated 22 July 2016. 
30. 
National Toxicology Program, U.S. Department of Health and Human Services. 
Final Study Report: Developmental toxicity research evaluation of berberine 
chloride dihydrate (Cas No. 5956-60-5) administered by Gavage to Swiss 
(CD-1®) mice on gestational Days 6 through 16.  Available at: 
https://ntp.niehs.nih.gov/testing/types/dev/abstracts/ter20103/index.html; 
Report date: 26 February 2003, Updated 27 June 2014. 
31. 
National Toxicology Program, U.S. Department of Health and Human Services. 
Final Study Report: Developmental toxicity research evaluation for berberine 
chloride dihydrate (Cas No. 5956-60-5) administered by gavage to 
Sprague-Dawley (CD®) rats on gestational Days 6 through 19.  Available at: 
https://ntp.niehs.nih.gov/testing/types/dev/abstracts/ter20102/index.html; 
Report date: 23 October 2002, Updated 27 June 2014. 


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32. 
National Toxicology Program, U.S. Department of Health and Human Services. 
Final Study Report: Developmental toxicity evaluation for berberine chloride 
dihydrate (CAS No. 5956-60-5) administered in the feed to Sprague Dawley 
(CD) 
rats 
on 
gestational 
Days 
6 
through 
20. 
 
Available 
at: 
https://ntp.niehs.nih.gov/testing/types/dev/abstracts/ter98008/ter98008.html; 
Report date: 14 April 2003, Updated 22 July 2016. 
33. 
Angulo P, Dickson ER, Therneau TM, Jorgensen RA, Smith C, DeSotel CK, 
et al. Comparison of three doses of ursodeoxycholic acid in the treatment of 
primary biliary cirrhosis: a randomized trial. J Hepatol 1999;30(5):830-835. 
34. 
Fickert P, Hirschfield GM, Denk G, Marschall H-U, Altorjay I, Färkkilä M, 
et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing 
cholangitis. J Hepatol 2017;(Article in press). 
 
 


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APPENDICES 


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APPENDIX A 
 
PROTECTION OF HUMAN SUBJECTS 
(INTERNATIONAL COUNCIL FOR HARMONISATION E6, SECTION 4.8) 


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PROTECTION OF HUMAN SUBJECTS 
(International Council for Harmonisation E6, Section 4.8) 
Informed consent must be obtained from every subject before he or she enters a study. It must be 
given freely and not under duress. Consent must be documented by the subject or the subject’s 
legally acceptable representative signing an IRB/IEC-approved consent form. When minors are 
involved, a parent or guardian should sign the consent form. If the minor is an adolescent (12 to 
16-18 years of age, dependent on region, as specified in ICH E11, Clinical Investigation of 
Medicinal Products in the Pediatric Population), his or her signature should also be included. 
Subjects who do not speak English must be presented with a consent form written in a language 
that they understand. A copy of the signed consent form must be given and made available to 
sponsor and representatives of the appropriate regulatory authority upon request. If, for any reason, 
subject risk is increased as the study progresses, a revised IRB/IEC-approved consent form must 
be signed by the subject. 
Nothing in these regulations is intended to limit the authority of a physician to provide emergency 
medical care to the extent the physician is permitted to do so under applicable federal, state, or 
local laws. Only in the case of a life-threatening incident may an investigational agent be used 
without prior signed consent. In such an emergency situation, separate certifications must be 
written by both a physician not participating in the study and the investigator. The certifications, 
along with the protocol and informed consent form, must be sent to the IRB/IEC within 5 working 
days. In this situation, the investigator may not administer any subsequent investigational product 
to that subject until informed consent and IRB/IEC approval are obtained. 
BASIC ELEMENTS OF INFORMED CONSENT 
Every informed consent form must include explanations of each of the following 22 elements: 
• The fact that the trial involves research 
• The purpose of the trial 
• The trial treatment(s) and the probability for random assignment to each treatment 
• The trial procedures to be followed, including all invasive procedures 


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• The subject’s responsibilities 
• Those aspects of the trial that are experimental 
• The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an 
embryo, fetus, or nursing infant 
• The reasonably expected benefits (When there is no intended clinical benefit to the subject, the 
subject should be made aware of this.) 
• The alternative procedure(s) or course(s) of treatment that may be available to the subject, as 
well as their important potential benefits and risks 
• The compensation or treatment available to the subject in the event of a trial-related injury 
• The anticipated prorated payment, if any, to the subject for participating in the trial 
• The anticipated expenses, if any, to the subject for participating in the trial 
• The fact that the subject’s participation in the trial is voluntary and that the subject may refuse 
to participate or withdraw from the trial, at any time, without penalty or loss of benefits to 
which the subject is otherwise entitled 
• That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be 
granted direct access to the subject’s original medical records for verification of study 
procedures or data, without violating the confidentiality of the subject, to the extent permitted 
by applicable laws and regulations and that, by signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access 
• That the records identifying the subject will be kept confidential and, to the extent permitted 
by the applicable laws or regulations, will not be made publicly available; and if the results of 
the trial are published, the subject’s identity will remain confidential 
• That the subject or the subject’s legally acceptable representative will be informed in a timely 
manner if information becomes available that may be relevant to the subject’s willingness to 
continue participation in the trial 


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• The person(s) to contact for further information about the trial and the rights of trial subjects, 
and whom to contact in the event of a trial-related injury 
• The foreseeable circumstances or reasons under which the subject’s participation in the trial 
may be terminated 
• The expected duration of the subject’s participation in the trial 
• The approximate number of subjects involved in the trial 
• The consequences of a subject’s decision to withdraw from the research and the procedure for 
orderly termination of participation by the subject 
• That the trial will be included on ClinicalTrials.gov as required by United States law, and, if 
applicable, the appropriate study database of another regulatory agency (e.g., the Health 
Canada Clinical Trial Database, EudraCT). 
Nothing is intended to limit the authority of a physician to provide emergency medical care to the 
extent the physician is permitted to do so under applicable federal, state, or local laws. 
The informed consent requirements are not intended to preempt any applicable federal, state, or 
local laws that require additional information to be disclosed in order that informed consent be 
legally effective. Some states require further action on the investigator’s part concerning subject 
consent. 
 


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APPENDIX B 
 
REQUISITE DOCUMENTS FOR APPROVAL OF STUDY SITE 


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REQUISITE DOCUMENTS FOR APPROVAL OF STUDY SITE 
Investigational product will be provided to the investigators after they have submitted the 
following documents to the sponsor or study monitor (if applicable): 
• Signed statement of investigator (if required by the regulatory agency) 
• Institutional review board (IRB) or independent ethics committee (IEC) composition 
• Document indicating IRB or IEC approval of the final protocol and amendment(s) if applicable 
(to include name, address, and chairperson of the IRB or IEC) 
• Document indicating IRB or IEC approval of the final and revised informed consent form if 
applicable (to include name, address, and chairperson of the IRB or IEC) 
• Blank copy of the IRB or IEC-approved final and revised informed consent form 
• Signed investigator’s study agreement and confidentiality disclosure agreement 
• Laboratory certification or accreditation and normal ranges for tests that are performed in the 
laboratory for study assessments 
• Curricula vitae for the investigator and subinvestigator(s) listed on the Form FDA 1572 of the 
study. 
• Financial disclosure for the investigator and subinvestigator(s) listed on the Form FDA 1572 
of the study. 
 


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APPENDIX C 
 
RESPONSIBILITIES AND OBLIGATIONS  
OF INVESTIGATORS AND SPONSORS 


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RESPONSIBILITIES AND OBLIGATIONS OF INVESTIGATORS AND SPONSORS 
For non–treatment protocols (e.g., separate follow-up protocol, observational protocol), some of 
the following may not be applicable. 
1.0 
SPONSOR 
The following sections describe the responsibilities and obligation of the sponsor or 
designee. 
1.1 
Conduct a site selection visit or study initiation visit to: 
1.1.1 
Establish the acceptability of the facility and record the visit in a written report (i.e., 
memorandum or form). 
1.1.2 
Discuss with the investigator the proposed study and supply him or her with draft 
electronic case report forms (eCRFs), the Investigator’s Brochure, and the draft protocol 
for his or her review and approval. 
1.1.3 
Discuss with the investigator the regulatory requirements with respect to informed 
consent, institutional review board/independent ethics committee (IRB or IEC) approval 
of the trial, the protocol, protocol amendments, and changes to the informed consent 
form. 
1.1.4 
Discuss with the investigator the timing of interim and final reports to the study monitor 
and his or her obligation to supply the study monitor with copies of all study-related 
documents (including IRB or IEC approval, IRB or IEC charter or equivalent, 
membership and qualifications, protocol amendments, informed consent forms, and 
consent changes), eCRFs, eCRF changes, and all pertinent correspondence to and from 
the IRB or IEC. 
1.2 
Conduct periodic on-site visit(s) to: 
1.2.1 
Ensure adherence to the protocol. 
1.2.2 
Review eCRFs and source documents for accuracy and completeness of information. 


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1.2.3 
Examine pharmacy records for documentation of quantity and date of receipt of 
investigational drug, dispensation and accountability data for product administration to 
each subject, loss of materials, contamination, and unused supplies. 
1.2.4 
Record and report (summarize) observations on the progress of the trial and continued 
acceptability of the facilities, and prepare an on-site visit report. 
1.2.5 
Review investigator files for required documents (e.g., protocols; protocol amendments; 
Investigator’s Brochure; study procedures manual; IRB or IEC approval of protocols, 
amendments, and informed consent form; IRB or IEC charter and membership; and 
communications to and from the IRB/IEC and the study monitor). 
2.0 
INVESTIGATOR 
2.1 
Institutional review board or independent ethics committee 
The investigator must assure the study monitor that the IRB or IEC: 
2.1.1 
Meets International Council for Harmonisation (ICH) guidelines as defined in ICH E6 
Section 3, Institutional Review Board/Independent Ethics Committee 
2.1.2 
Has the authority delegated by the parent institution and found in the IRB or IEC by-laws, 
operation guidelines, or charter to approve or disapprove clinical studies and protocols, 
including the informed consent form and other documents (e.g., protocol amendments 
and information to be supplied to subjects concerning informed consent) 
2.1.3 
Complies with proper personnel make-up of the board 
2.1.4 
Convenes meetings using acceptable rules of order for making decisions, recording such 
decisions, and implementing them 
2.1.5 
Maintains files that contain (a) documentation of its decisions, such as are found in IRB 
or IEC minutes and correspondence, (b) written guidelines or by-laws governing IRB or 
IEC functions, (c) protocol, (d) protocol amendments, (e) approved informed consent 
document and information to be supplied to the subject, and (f) correspondence between 
the IRB or IEC and investigator (e.g., consent changes, protocol amendments) 


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2.2 
Informed consent of human subjects 
The investigator must assure the study monitor that the informed consent form for a 
subject: 
2.2.1 
Meets ICH guidelines as defined in ICH E6, Section 4.8, Informed Consent of Trial 
subjects 
2.2.2 
Has been approved by the IRB or IEC, including (when required) information to be given 
to the subject about the trial in which he or she is enrolled 
2.2.3 
Includes the basic elements and any additional elements of informed consent that are 
appropriate 
2.2.4 
Has been signed by both the subject (or the subject’s legally acceptable representative), 
the investigator, and a witness, and a copy has been given to the subject 
2.2.5 
Is provided, if necessary, to the subject in the “short form” informed consent form 
(presented orally to the subject or the subject's legally acceptable representative, with a 
witness listening) with written information as an alternative 
2.2.6 
Allows for assent to be obtained for minor children as required by the IRB or IEC 
2.3 
Storage and dispensing of product supplies 
The investigator (or the investigator’s pharmacist) must assure the study monitor that: 
2.3.1 
Adequate and accurate written records show receipt and disposition of all product 
supplies, including dates, serial or lot numbers, quantities received, and each quantity 
dispensed, administered, or used, with identification of each subject.  
2.3.2 
Purpose and reasons are given in written records for product disposal (e.g., the amount 
contaminated, broken, or lost) and the quantity that was returned to the sponsor. 
 
 


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2.4 
Case report forms 
The investigator must assure the study monitor that: 
2.4.1 
The completed eCRF accurately reflects the hospital records for each subject. 
2.4.2 
The eCRFs and hospital records will be accessible to the study monitor during on-site 
visits. 
2.5 
Files and records 
The investigator must ensure the quality, integrity, and content of his or her files, which 
will be subject to audit by the study monitor and the appropriate regulatory authority 
inspectors. The files must contain, as minimum the following: 
• 
Investigator’s Brochure 
• 
Investigator’s obligations, including the following: 
1. 21 Code of Federal Regulations (CFR) Part 312.50, General Responsibilities of 
Sponsors  
2. 21 CFR Part 312.60, General Responsibilities of Investigators 
3. 21 CFR Part 50, Protection of Human Subjects 
4. 21 CFR Part 56, Institutional Review Boards 
- ICH, E6, Guideline for Good Clinical Practice 
• 
IRB or IEC-approved protocol and protocol amendments 
• 
Blank eCRFs (and amendments to eCRF) 
• 
Study procedures manual and amended pages 
• 
Statement of investigator forms (copy of signed Form FDA 1572 and a copy of each revised 
form if required by the regulatory agency) as well as current curricula vitae and 
bibliography for each investigator and subinvestigator 


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• 
IRB or IEC document, including the following: 
5. IRB or IEC charter membership and qualifications of each member 
6. IRB or IEC letter of approval of protocol and amendments 
7. IRB or IEC letter of approval of informed consent form and amendments 
8. Investigator’s annual report to the IRB or IEC 
9. IRB or IEC annual re-approval of protocol  
10. Reports to IRB or IEC of deaths and serious adverse events (SAEs) 
11. Notification to IRB of study completion and investigator’s final report 
12. IRB approval of advertisements for subject recruitment (if applicable) 
- All additional correspondence with the IRB/IEC 
• 
IRB/IEC - approved informed consent document (all versions) and information to be 
supplied to the subject 
• 
Study staff signature log 
• 
Subject accountability records, including the following: 
13. Subject screening log 
14. Medical exceptions log 
15. Site status report 
16. Subject identification code list 
17. Original signed informed consent form 
18. A note stating the location of the eCRFs and data clarification requests 
- Copies of completed eCRF transmittal logs  
• 
Investigation product records, including the following: 
19. Receipt, date and quantity, and batch or lot number  
20. Disposition dates and quantity administered to each subject 
21. Inventory records 
- All correspondence related to the investigational product 


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• 
SAE/safety reports 
- Copies of signed SAE reports 
- All SAE correspondence, including MedWatch and Form FDA 3500A 
• 
Biological sample inventory forms and correspondence with the analytical laboratory 
• 
Monitoring activities 
22. Monitoring log (should include all visits [i.e., site initiation, periodic, and termination 
visits]) 
23. Telephone contact reports 
24. Site initiation visit reports 
• 
General Correspondence 
25. All correspondence between the study monitor, sponsor, and the site 
26. All correspondence between site staff about the protocol 
Documents and records must be retained by the investigator for at least 2 years after 
the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or for at least 2 years 
after the formal discontinuation of clinical development of the investigational product.


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Page 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX D 
 
PARTIAL MAYO SCORE QUESTIONNAIRE 
 
 


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Page 2 
 
HTD1801.PCT003 Partial Mayo Score Questionnaire v1.0 
IRB approved date: 
 
HTD1801.PCT003 Study 
Partial Mayo Score Questionnaire 
 
Subject #: _________    
Subject Initials: _________ 
 
Date of visit: _______________________ 
 
Visit Name:  Screening 
Baseline  
Week 6 
     Week 12          Week 18 
 
Patients will fill out the first two questions, and the physician will fill out the last question. 
 
Patients: please select an option below based on stool frequency in the past 3 days. 
 
1. Stool Frequency 
□  Normal number of stools for patient 
□  1 to 2 stools per day more than normal 
□  3 to 4 stools more than normal 
□  ≥ 5 stools more than normal 
 
Patients: please select an option below based on rectal bleeding in the past 3 days. 
 
2. Rectal Bleeding 
□  No blood seen 
□  Streaks of blood with stool less than half of the time 
□  Obvious blood with stool most of the time 
□  Blood alone passes 
 
 
 
 
Physicians: Please select an option below: 
 
3. Physician’s Global Assessment: 
□  Normal 
□  Mild disease 
□  Moderate disease 
□  Severe disease 
 
 
 
Site staff: To calculate the total score, either enter the responses onto the Partial Mayo Score EDC 
page of the appropriate visit OR manually calculate the sum using the response values noted above 
and record total score on the visit worksheet. 
 
 
 
 
Study coordinator or PI initials:_________________________________Date__________ 
= 0 
= 1 
= 2 
= 3 
= 0 
= 1 
= 2 
= 3 
= 0 
= 1 
= 2 
= 3 

SAP_001.pdf: 
HighTide Biopharma Pty. Ltd. 
HTD1801.PCT003 
Statistical Analysis Plan 
Final Version 1 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
A Proof-of-Concept and Dose-Ranging Study Investigating the 
Efficacy and Safety of HTD1801 in Adult Subjects with Primary 
Sclerosing Cholangitis (PSC) 
 
 
Phase: 
2 
 
 
Protocol No.: 
HTD1801.PCT003 
 
 
Protocol Date(s): 
Protocol Versions 1.4, 07 January 2019 
 
 
Analysis Plan Version and 
Date: 
Final Version 1, 31 Aug 2020 
 
 
Prepared By: 
Zack Scott 
PharPoint Research, Inc. 
5003 S. Miami Blvd. 
Suite 100 
Durham, NC 27703 
 
 
 
Prepared For: 
HighTide Biopharma Pty. Ltd. 
1 Melissa Street  
Mount Waverley, Vic 3149 
Australia 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION
Q HIGHTIDE 
2


HighTide Biopharma Pty. Ltd. 
HTD1801.PCT003 
Statistical Analysis Plan 
Final Version 1 
 
 
 
CONFIDENTIAL 
Page 2 
31AUG2020 
 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL 
 
This Statistical Analysis Plan has been prepared in accordance with team reviewers’ specifications.   
 
Prepared by: 
 
 
 
 
 
Zack Scott, MS 
Manager, Biostatistics 
PharPoint Research, Inc. 
 
Date 
 
Review:  
 
 
 
 
 
 
 
 
Amy Flynt, PhD 
Senior Director, Consulting Operations, Biostatistics 
PharPoint Research, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
On behalf of HighTide Biopharma Pty. Ltd. (HighTide): 
Cathryn Bennett, B.N., R.N., C.C.R.A. 
VP, Clinical Operations 
HighTide 
 
Date 
(
DocuSigned by: 
I M
;;~tt 
l(J 
Signer Name: Zack Scott 
L 
Signing Reason: I am the author of this document 
Signing Time: 31-Aug-2020 117:44 EDT 
B0732999AA74463F9272293C562B38A0 
r ::ignedby 
l(J 
Signer Name: Amy Flynt 
L 
Signing Reason: I have reviewed this document 
Signing Time: 31-Aug-2020 119:30 EDT 
AQ813g4CCQ7844~C87C4gaQB~7e~A84~ 
r ::i:: 
l(J 
Signer Name: Cathryn Bennett 
L 
Signing Reason: I approve this document 
Signing Time: 31-Aug-2020 114:37 PDT 
F735F155A5B6407E9B93FEE2AB2466C2 
3


HighTide Biopharma Pty. Ltd. 
HTD1801.PCT003 
Statistical Analysis Plan 
Final Version 1 
CONFIDENTIAL 
Page 3 
31AUG2020 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL .............................................. 2 
TABLE OF CONTENTS ................................................................................................................. 3 
1.
INTRODUCTION....................................................................................................................5
1.1. 
STUDY OVERVIEW .......................................................................................................... 5 
1.2. 
SCHEDULE OF EVENTS .................................................................................................. 7 
1.3. 
GLOSSARY OF ABBREVIATIONS ................................................................................ 9 
2. 
OBJECTIVES ......................................................................................................................... 10 
3.
GENERAL STATISTICAL CONSIDERATIONS ............................................................. 10 
3.1. 
SAMPLE SIZE AND POWER ......................................................................................... 10 
3.2. 
RANDOMIZATION AND BLINDING ........................................................................... 10 
3.3. 
HANDLING OF DATA .................................................................................................... 12 
3.3.1. Strata and Covariates ................................................................................................... 12 
3.3.2. Examination of Subject Subsets ................................................................................... 12 
3.3.3. Multiple Testing and Comparisons .............................................................................. 12 
3.3.4. Missing Data .................................................................................................................. 12 
3.3.5. Imputation of Incomplete Dates ................................................................................... 12 
3.3.6. Presentations by Study Visit ......................................................................................... 13 
3.3.7. Definitions and Terminology ........................................................................................ 14 
3.4. 
TIMING OF ANALYSES ................................................................................................. 15 
4. 
ANALYSIS POPULATIONS ................................................................................................ 15 
4.1. 
MODIFIED INTENT-TO-TREAT POPULATION ...................................................... 15 
4.2. 
SAFETY POPULATION .................................................................................................. 16 
5. 
STATISTICAL METHODS .................................................................................................. 16 
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5.1. 
SUBJECT DISPOSITION, DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS, AND EXPOSURE .................................................................................. 17 
5.2. 
EFFICACY ANALYSIS ................................................................................................... 18 
5.2.1. Primary Efficacy Endpoint........................................................................................... 18 
5.2.2. Primary Efficacy Analysis ............................................................................................ 18 
5.2.3. Additional Analyses of the Primary Endpoint ............................................................ 18 
5.2.4. Secondary Efficacy Endpoints ..................................................................................... 18 
5.2.5. Secondary Efficacy Analysis ......................................................................................... 19 
5.3. 
SAFETY ............................................................................................................................. 20 
5.3.1. Adverse Events .............................................................................................................. 20 
5.3.2. Clinical Laboratory Assessments, Vital Signs, Height, and Weight ......................... 21 
5.3.3. Concomitant Medications ............................................................................................. 21 
6. 
PROTOCOL DEVIATIONS ................................................................................................. 21 
7.
CHANGES IN THE PLANNED ANALYSES ..................................................................... 21 
8.
PROGRAMMING CONVENTIONS ................................................................................... 23 
 
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1.
INTRODUCTION
This document describes the statistical methods and data presentations to be used in the summary 
and analysis of data from Protocol HTD1801.PCT003. Background information is provided for the 
overall study design and objectives.  The reader is referred to the study protocol and case report 
forms (CRFs) for details of study conduct and data collection. 
1.1. 
STUDY OVERVIEW 
Protocol HTD1801.PCT003 is a Phase 2, randomized, double-blind study which consists of a 
placebo- and dose-controlled parallel group period, a dose-controlled extension period, and a 
placebo-controlled randomized withdrawal period with the intent of comparing multiple doses of 
investigational product (HTD1801) to placebo. Approximately 60 patients with Primary Sclerosing 
Cholangitis (PSC) will be enrolled as subjects. Upon confirmation of eligibility, subjects will be 
randomized in Period 1 in a 1:1:1 ratio, stratified by inflammatory bowel disease (IBD) diagnosis 
and ursodiol (UDCA) status, to one of the following treatment arms: 
•
Treatment Arm 1: HTD1801 500 mg twice daily (BID)
•
Treatment Arm 2: HTD1801 1000 mg BID
•
Treatment Arm 3: Placebo BID.
Subjects will receive the treatment to which they are randomly assigned for 6 weeks during the first 
period.  
In response to the COVID-19 pandemic, enrollment into the study was prematurely stopped on 25th 
March 2020.  This impacted 3 subjects who had been randomized but had not yet initiated dosing. 
There may be additional restrictions associated with COVID-19 that may impact sites’ ability to 
schedule subjects for in-clinic visits and thus, complete all protocol-required assessments.  These 
will be noted as protocol deviations related to COVID-19 should they occur.  These measures were 
put into place following the issuance of the FDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Pandemic (March 2020 and April 2020). 
See Section 3.2 for additional details on Period 1 randomization. 
Following the completion of the first period, subjects are eligible to enroll in Period 2 which is a 6-
week extension period. During this period, subjects who were previously randomized to 500 mg or 
1000 mg BID in Period 1 will continue to receive the same dose. Subjects who were previously 
randomized to placebo will be randomized in a 1:1 ratio to receive 6 weeks of either 500 mg or 
1000 mg BID. This period will continue to be double-blind.  
Following the completion of Period 2, the 6-week treatment extension period, all subjects will be 
randomized in a 1:1 ratio to either continue on the active treatment they received in the second 
period or be assigned to placebo.  
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An independent Data and Safety Monitoring Board (DSMB) will provide additional safety 
oversight.  
 
 
 
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1.2. 
SCHEDULE OF EVENTS 
  
 
Screening Baseline 
Initial Dosing Period 
Dose-controlled Extension 
Randomized Withdrawal 
Follow-
up 
Visit Day 
-28 to -1 
0 
Week 2 
Week 4 
Week 6 
Week 8 
Week 
10 
Week 
12 
Week 
14 
Week 16 Week 18 Week 22 
Procedures 
Clinic visits 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
G6PD 
X 
 
 
 
 
 
 
 
 
 
 
 
IgG4 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine drug test 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis B, C 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant meds 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Physical examination 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height/Weight/Vitals 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECG 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Pregnancy testing 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Partial Mayo Score * 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
CBC, CMP**, Lipids 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
INR 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
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Screening Baseline 
Initial Dosing Period 
Dose-controlled Extension 
Randomized Withdrawal 
Follow-
up 
Visit Day 
-28 to -1 
0 
Week 2 
Week 4 
Week 6 
Week 8 
Week 
10 
Week 
12 
Week 
14 
Week 16 Week 18 Week 22 
Mayo Risk Score 
 
X 
 
 
 
 
 
 
 
 
 
 
C-reactive protein * 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Fecal calprotectin * 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Randomization 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Dosing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event 
monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone contact 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Discharge 
 
 
 
 
 
 
 
 
 
 
X 
 
*     IBD subset only 
**   Including GGT 
 
 
  
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1.3. 
GLOSSARY OF ABBREVIATIONS 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA Analysis of Covariance 
AST 
Aspartate Aminotransferase 
BID 
twice daily 
BMI 
Body Mass Index 
CRF 
case report form 
CRP 
C-reactive Protein 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
ET 
Early Termination 
FAS 
full analysis set 
FC 
Fecal Calprotectin 
GGT 
Gamma-Glutamyl Transferase 
IBD 
Inflammatory Bowel Disease 
ITT 
Intent-to-treat population 
IxRS 
interactive web/voice response system 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat population 
MMRM 
Mixed Model with Repeated Measures 
PP 
per protocol 
PSC 
Primary Sclerosing Cholangitis 
PT 
Preferred Term 
SAE 
serious adverse event 
SD 
standard deviation 
SOC 
System Organ Classification 
TEAE 
treatment emergent adverse events 
UDCA 
ursodeoxycholic acid 
WHO 
World Health Organization 
 
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2. 
OBJECTIVES 
Primary Objective: 
 
The primary objective of this proof-of-concept study is to evaluate the effects of HTD1801 on 
serum alkaline phosphatase (ALP) levels in adult subjects with PSC. 
 
Secondary Objective: 
 
The secondary objectives of this study are to evaluate: 
• 
the effects on concurrent disease activity of IBD, and  
• 
the safety (inclusive of adverse events, serology, and vital signs) and  
• 
the tolerability of HTD1801 over 18 weeks in adult subjects with PSC.  
3. 
GENERAL STATISTICAL CONSIDERATIONS 
3.1. 
SAMPLE SIZE AND POWER 
Results from published clinical trials of PSC patients including Zhu et al., 2015 and Fickert et al., 
2017 were reviewed. These publications were used along with consideration of inclusion and 
exclusion criteria for this study to estimate mean Baseline ALP and to estimate variability. Total 
sample size was chosen based on balancing consideration of business costs, time to enroll subjects 
with this rare disease and the mean change which could be detected given the mean Baseline and 
variability assumptions. The standard deviation for change from Baseline in ALP was assumed to be 
200. A total of 90 subjects, 30 subjects per group, is sufficient to detect a mean difference from 
placebo within a dose group of 147 with 80% power at an alpha of 0.05. Assuming a mean Baseline 
ALP of 450, this equates to a 32.7% reduction. This study should be adequate to determine if there 
is a positive signal in ALP during HTD1801 treatment. 
 
While the sample size was originally planned to be 90 subjects, in view of the protracted period 
necessary to enroll subjects into the study, a strategy session in the fall of 2018 with external 
consultants advised that the study would be adequately powered by enrolling approximately 60 
subjects.  Specifically, it was determined that a total of 63 subjects, 21 subjects per group, would be 
sufficient to detect a mean difference of 180 for each dose group vs. placebo with 80% power for a 
two-sided t-test with alpha of 0.05. A protocol amendment was deemed unnecessary. 
 
 
3.2. 
RANDOMIZATION AND BLINDING 
 
Period 1: Placebo- and dose-controlled, parallel-group period 
Subjects will be enrolled in equal numbers to one of the initial three treatment groups (placebo BID, 
HTD1801 500 mg BID, HTD1801 1000 mg BID) during the initial 6-week, double-blind, placebo- 
and dose-controlled, parallel-group period. Randomization will be centrally controlled, stratified 
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according to a co-existing diagnosis of IBD and UDCA status, and subjects will be assigned a pre-
packaged and numbered treatment. 
Subjects who were currently taking ursodeoxycholic acid (UDCA), or who had taken UDCA 
during the 6 weeks prior to randomization were to have completed a 6-week washout period before 
Baseline measurements per Protocol Version 1.2 dated 01 February 2018. The UDCA restriction 
was modified in Protocol Version 1.3 dated 12 June 2018 since only one subject had been enrolled 
in the earlier version of the protocol. Subjects on UDCA were eligible as long as the dose of 
UDCA was stable for at least 6 weeks prior to the Baseline visit. 
Following the strategy session in the fall of 2018, an unblinded individual from the CRO, Cato 
Research, was tasked with determining whether the number of subjects taking UDCA was evenly 
distributed among the three study groups.  This was found not to be so, with one dose cohort 
having no subjects who had previously been taking UDCA.  While at the onset of the study, Period 
1 randomization was stratified only by IBD diagnosis, this discovery spurred the inclusion of 
UDCA status as a stratification factor in an attempt to ensure even distribution between treatment 
groups for the primary analysis. UDCA status was therefore retroactively applied as a stratification 
factor to those 42 subjects who had already been randomized to Period 1, and gaps in these new 
strata were subsequently filled by 17 subjects enrolling from that point forward, with new 
randomization blocks prospectively added.   
 
This new manual randomization process was initiated in November 2019. The autogenerated 
randomization process in the web-response system was too time consuming and costly to 
implement.  This is managed by Dr. Philip Lavin (Boston Biostatistics Research Foundation, Inc.) 
in conjunction with an unblinded data base administrator, William Scott (Cato Research Limited). 
The additional stratification factor of UDCA status will be included in the modeling. 
 
Period 2: Dose-controlled extension 
Following their completion of Period 1, subjects will enroll in a 6-week extension period in which 
subjects previously randomized to 500 mg or 1000 mg BID will continue for 6 more weeks at that 
previous dose, while subjects previously randomized to placebo will be randomly assigned to receive 
6 weeks of either 500 mg or 1000 mg BID. 
 
Period 3: Randomized withdrawal 
Following their completion of Period 2, subjects will enroll into a 6-week randomized withdrawal 
period in which all subjects will be randomly assigned in a 1 to 1 ratio to either continue on the active 
treatment they received in Period 2, or be assigned to placebo so that 50% of the subjects remain on 
the experimental treatment at the previous dose, and 50% will receive placebo. 
 
All subjects and study personnel will remain blinded as to the treatment administered throughout the 
study with the exception of an unblinded statistician who will develop the randomization list with 
the expanded strata and an unblinded EDC designer who will load the completed randomizations 
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into the EDC system. All study test drug will be provided in matching white tablets, four to a bottle, 
two bottles to be administered each day, one in the morning and one in the evening. A 45-day supply 
will be provided to each subject at each visit to cover the next 6-week period with an additional 3 
days of coverage to provide for possible scheduling conflicts. 
 
In this double-blind study, if a medical emergency occurs and a decision about a subject’s condition 
requires knowledge of the treatment assignment in order to properly treat the subject, the study blind 
may be broken for that specific subject only. Ideally, the decision to break the blind for this one 
subject should only be made after consultation with the Medical Monitor or Sponsor Representative. 
 
Any broken blind must be clearly justified and explained by a note in the subject’s source documents. 
 
3.3. 
HANDLING OF DATA 
3.3.1. 
Strata and Covariates 
Statistical models run for the primary endpoint as well as secondary continuous endpoints in Period 
1 will include IBD diagnosis as randomized and UDCA status when entering the study as 
covariates. Secondary continuous endpoints in Periods 2 and 3 will also include IBD diagnosis and 
UDCA status as a covariate. 
3.3.2. 
Examination of Subject Subsets 
Analysis of the primary endpoint will additionally be presented by IBD diagnosis as randomized 
and UDCA status when entering the study. 
3.3.3. 
Multiple Testing and Comparisons  
All analyses will be conducted without adjustments for multiple comparisons for this proof-of-
concept study. 
3.3.4. 
Missing Data  
Every effort will be made to obtain required data at each scheduled evaluation from all subjects 
who have been treated. Missing end dates for dosing in each period will be imputed using the first 
date of dosing in the next period if available, or the last collected visit date for the period if not. 
Missing start dates will be imputed as the earliest study drug dispensation date for the period, 
provided there is a last dose date or multiple dispensations in the period. No other imputations will 
be used for this analysis except for handling of incomplete dates. 
 
3.3.5. 
Imputation of Incomplete Dates 
An incomplete date is any date for which either the day, month, or year is unknown, but all three 
fields are not unknown.  An incomplete date occurs when the exact date an event occurred or ended 
cannot be obtained from a subject.  For many of the analyses, a complete date is necessary in order 
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to determine if the event should be included in the analysis (i.e., if the event is treatment-emergent) 
or to establish the duration of an event.  In such cases, incomplete dates will be imputed. 
For purposes of imputation, all events with an incomplete end date are assumed to have ended on or 
before the day the form was completed. In an effort to minimize bias, the project statistician will 
impute dates in a systematic but reasonable manner, as described below.  
For event start dates, if the month/year is the same as the Day 1 month/year then the date will be set 
to the date of Day 1.  In other cases, missing days will be imputed as the day component of Day 1; 
missing months/years will be imputed as the month/year of Day 1. If the end date is present, then the 
imputed start date will be set to the end date if the above imputation imputes a date after the end date.  
For event end dates, if the month/year is the same as the event start date month/year then the date 
will be set to the date of the event start date.  In other cases, missing days will be imputed as the day 
component of the event start date, or if missing, then then day component of the treatment start date; 
missing months/years will be imputed as the month/year of the event start date, or if missing then the 
months/years of the treatment start date. 
3.3.6. 
Presentations by Study Visit 
Nominal study visits as obtained from the CRF or laboratory will be utilized for summary displays 
of efficacy endpoints. Unscheduled and early termination (ET) visits will be windowed based on 
study day, according to the table below. All assessments will be presented in the listings. If 
assessments are collected multiple times within a given study visit, the result closest to the 
scheduled visit date will be used for summary presentations. If two measurements have the same 
distance to the expected date, the earlier value will be used. If a scheduled assessment and an 
unscheduled or ET assessment are collected within a given visit, the value from the scheduled 
assessment will be chosen over the value from the unscheduled assessment.  
 
Study Day 
Windowed Study Visit 
Additional Details 
2 – 20 
Week 2 
 
21 – 34 
Week 4 
 
35 – (date of 
randomization to 
Period 2) 
Week 6 
If subject is not 
randomized to 
Period 2, use study 
day 42 as upper 
limit  
(date of 
randomization to 
Period 2) + 1 – 62 
Week 8 
 
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63 - 76 
Week 10 
 
77 – (date of 
randomization to 
Period 3) 
Week 12 
If subject is not 
randomized to 
Period 3, use study 
day 84 as upper 
limit 
(date of 
randomization to 
Period 3) + 1 – 104 
Week 14 
 
105 – 118 
Week 16 
 
119 – Exit 
Week 18 
 
 
3.3.7. 
Definitions and Terminology  
Age 
The age of a subject is defined as the number of whole years between the subject’s birth date and 
the Period 1 treatment start date. 
 
Day 1 (Baseline)  
Day 1 is the earliest day that study drug is initiated in Period 1. 
 
Study Day  
Study Day is defined relative to Baseline (Day 1). Thus, the study day of an event is calculated as: 
Study Day = event date – date of Day 1 (+ 1 if event date >= date of Day 1). 
Study Visit  
Study Visit is the nominal visit as recorded on the CRF.   
 
Weeks of Exposure 
Weeks of exposure is calculated as the (Last Day on Study Drug – First Day on Study Drug + 1) / 7 
within each period. 
 
Treatment Compliance 
Treatment compliance is calculated as the Number of Days of Dosing / Expected number of days 
of dosing within each period. 
 
Baseline Value 
For purposes of analysis, the baseline value is defined as the last non-missing value obtained prior 
to initiation of study drug. 
 
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Change from Baseline  
Change from baseline for a given endpoint is defined as the Study Day X value minus the Baseline 
Value. 
 
Adverse Event (AE) 
An AE is defined as 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. All adverse events will be recorded on the Adverse Event 
CRF.  
 
Treatment-emergent Adverse Event (TEAE)  
A TEAE will be an AE that occurred during the study after the first dose of study drug or that was 
present prior to dosing and exacerbates after the first dose of study drug. Additionally, it is 
assumed that an Adverse Event which was reported to have started on Day 1 without an associated 
onset time occurred after the initiation of study drug. 
 
Concomitant Medications 
Concomitant medications are those medications taken on or after the initiation of study drug.  This 
definition includes medications started prior to the initiation of study drug but continuing 
concomitantly with study drug. 
 
Prior Medications 
Prior medications are those medications taken prior to the initiation of study drug.  
 
 
3.4. 
TIMING OF ANALYSES 
The final analysis will be completed after the last subject completes or discontinues the study and 
the resulting clinical database has been cleaned, quality checked, and locked. 
Additionally, safety oversight will be conducted throughout the study under the direction of a 
DSMB. The timing and frequency for the DSMB will be detailed in a separate DSMB charter. 
 
4. 
ANALYSIS POPULATIONS 
The populations for analysis will include the modified intent-to-treat population (mITT) and safety 
population. 
4.1. 
MODIFIED INTENT-TO-TREAT POPULATION 
The mITT population will consist of all randomized subjects who receive at least one dose of study 
drug and who have at least one post-dose efficacy assessment. Subjects in this population will be 
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analyzed according to the treatment group to which they were randomized. This population will be 
used for analyses of efficacy.  
4.2. 
SAFETY POPULATION  
 
The safety population consists of all subjects who receive at least one dose of study treatment, 
regardless of whether or not they undergo any study assessments.  Subjects in this population will 
be analyzed according to the treatment which they receive. All safety analyses will be based on this 
population. 
5. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study, with hypothesis 
testing performed for the primary and other selected efficacy endpoints. Unless stated otherwise, 
the term “descriptive statistics” refers to number of subjects (n), mean, median, standard deviation 
(SD), minimum and maximum for continuous data and frequencies and percentages for categorical 
data. Additional statistical methods include mixed model repeated measures (MMRM), Student’s t-
test (unpaired and paired), and Fisher Exact test. All data collected during the study will be 
included in data listings. Unless otherwise noted, the data will be sorted first by subject number, 
and then by Period and date within each subject number. 
 
The term ‘treatment group’ refers to all subjects on the same dosing regimen. Efficacy and Safety 
tables will include only treatment groups that are present in the respective period being 
summarized. Safety tables will include all treatment groups. The treatment groups will apply for 
each period: 
• 
Overall – Subjects will be summarized according to the period 1 treatment for 
demographic and screening information, or according to the actual treatment at the time of 
event or visit for safety summaries. AE summaries will use this format as well for the by 
period summaries. 
o Placebo 
o HTD1801 500 mg BID 
o HTD1801 500 mg BID 
• 
Period 1 – Subjects will be summarized according to Period 1 treatment 
o Placebo 
o HTD1801 500 mg BID 
o HTD1801 500 mg BID 
• 
Period 2 – Subjects will be summarized according to the Period 1 and Period 2 treatments 
o HTD1801 500 mg BID to HTD1801 500 mg BID 
o Placebo to HTD1801 500 mg BID 
o All HTD1801 500 mg BID (efficacy only) 
o HTD1801 1000 mg BID to HTD1801 1000 mg BID 
o Placebo to HTD1801 1000 mg BID 
o All HTD1801 1000 mg BID (efficacy only) 
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• 
Period 3 – Subjects will be summarized according to the Period 2 and Period 3 treatments 
o HTD1801 500 mg BID to HTD1801 500 mg BID 
o HTD1801 1000 mg BID to HTD1801 1000 mg BID 
o HTD1801 500 mg BID to Placebo 
o HTD1801 1000 mg BID to Placebo 
o All Active to Placebo 
All statistical tests will be two-sided with an alpha level of 0.05. 
The statistical analyses will be conducted with the SAS® System version 9.4 or higher. All analyses 
will be subject to formal verification procedures. Specifically, results will be verified utilizing 
independent programming prior to issuance of the draft statistical report. All documents will be 
verified by the lead statistician to ensure accuracy and consistency of analyses. 
5.1. 
SUBJECT DISPOSITION, DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS, AND EXPOSURE  
Subject disposition will be presented for all subjects randomized in Period 1. Subjects will be 
summarized in aggregate for the number of screen failures, the number subjects in the Safety and 
mITT populations, the number of subjects completing the study and each period, the reasons for 
early discontinuation at any point, and the number of subjects discontinuing by treatment taken 
when discontinuation occurred. Disposition and all listings will be presented for the subjects 
randomized (in Period 1). 
Demographic data and baseline characteristics including age, sex, race, height at screening, weight 
at screening, body mass index (BMI), IBD diagnosis as randomized, UDCA status when entering 
the study, and protocol version will be summarized using descriptive statistics for the Safety 
population, and will be presented by treatment group, as treated for Period 1. This information will 
be reviewed for baseline differences, but no statistical testing will be performed. 
Data on drug accountability and total amount of study drug received will be summarized by Period 
and treatment type according to treatment received in each period. Total study drug exposure 
within each period will be calculated as the sum of tablets dispensed over the duration of time a 
subject was on a given study drug within said period – the amount of that study drug returned 
within said period x the number of mg in the tablets (i.e. 0 mg for Placebo, 125 mg for 500 mg 
Arm, and 250 mg for 1000 mg Arm). Total exposure over the study period will also be summarized 
as the sum of the mg taken over all periods. 
Weeks of exposure in each period will be calculated as (date of first dose – date of last dose + 1)/7 
in the period. Study drug compliance will then be calculated as the number of tablets taken (as 
defined above) divided by the number of expected tablets to be taken in the period (weeks of 
exposure x 56) and then x 100 to convert to percentage. Weeks of exposure and study drug 
compliance will only be presented by period. 
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Medical history will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
version 20.1 preferred term (PT) and system organ classification (SOC). Subjects will be 
summarized in aggregate for the number of subjects with any medical history and the number of 
subjects by SOC and PT. Subjects with multiple histories mapping to a single SOC or PT will only 
be counted once within the SOC or PT. 
5.2. 
EFFICACY ANALYSIS 
 
5.2.1. 
Primary Efficacy Endpoint 
The primary endpoint for this study is the absolute change in ALP from Baseline to Week 6 in the 
double-blind parallel group period (Period 1).   
 
5.2.2. 
Primary Efficacy Analysis 
ALP values and absolute change from Baseline will be presented by treatment group and study 
visit within Period 1. A mixed model with repeated measures (MMRM) will be fit to the data 
testing absolute change from Baseline, and this model will include fixed effects for treatment, IBD 
diagnosis, UDCA status, visit and treatment by visit interaction, with Baseline ALP value as a 
covariate. An unstructured covariance matrix will be used to model the repeated assessments over 
time. Denominator degrees of freedom will be adjusted using Kenward-Roger’s method. Least 
Square (LS) Means and corresponding standard errors and 95% confidence intervals resulting from 
the model described will be presented at each visit. Differences in LS Means and corresponding 
two-sided 95% confidence intervals will be calculated at each Week 6 comparing each active arm 
to placebo as well as comparing the HTD1801 1000 mg BID treatment group to the HTD1801 500 
mg BID treatment group. 
 
The mean ALP will additionally be represented graphically via a line chart for all scheduled visits 
in Period 1. Each treatment group by UDCA status combination will be presented on a page, with a 
line for each subject within the group charted individually, and with one line for the overall group. 
 
5.2.3. 
Additional Analyses of the Primary Endpoint 
Subgroup analyses will be performed based on the IBD diagnosis as randomized and UDCA status 
when entering the study. For each subgroup, the ALP values and change from Baseline will be 
presented separately by treatment group and study visit within Period 1.  
 
5.2.4. 
Secondary Efficacy Endpoints 
• 
Relative change in ALP from Baseline to Week 6 
• 
Absolute change in ALP from Week 6 to Week 12  
• 
Change in ALP from Week 12 to Week 18 for all subjects following the randomized 
withdrawal 
• 
Proportion of subjects who achieve ALP of < 1.5 x ULN at the end of each period for each 
treatment group 
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• 
Proportion of subjects who achieve at least a 50% decrease in ALP at the end of each 
period for each treatment group 
• 
Proportion of subjects who normalize ALP at the end of each period for each treatment 
group 
• 
Absolute change in Gamma-Glutamyl Transferase (GGT) from Baseline to Week 6 
• 
Relative change in GGT from Baseline to Week 6 
• 
Absolute change in GGT from Week 6 to Week 12  
• 
Change in GGT from Week 12 to Week 18 for all subjects following the randomized 
withdrawal 
• 
Absolute change in serum total bilirubin at the end of each period for each treatment group 
• 
In subjects with IBD, absolute change in fecal calprotectin (FC) from Baseline to Week 6 
• 
In subjects with IBD, absolute change in FC from Week 6 to Week 12  
• 
In subjects with IBD, absolute change in FC from Week 12 to Week 18 for all subjects 
following the randomized withdrawal 
• 
In subjects with IBD who have elevated FC, the proportion of subjects who normalize FC 
at Weeks 6, 12, and 18 for each treatment group 
• 
In subjects with IBD, absolute change in C-reactive Protein (CRP) from Baseline to Week 
6 
• 
In subjects with IBD, absolute change in CRP from Week 6 to Week 12  
• 
In subjects with IBD, absolute change in CRP from Week 12 to Week 18 for all subjects 
following the randomized withdrawal 
• 
In subjects with IBD who have elevated CRP, the proportion of subjects who normalize 
CRP at Weeks 6, 12, and 18 for each treatment group 
• 
In subjects with IBD, absolute change in Mayo scores from Baseline to Week 6 
• 
In subjects with IBD, absolute change in Mayo scores from Week 6 to Week 12  
• 
In subjects with IBD, absolute change in Mayo scores from Week 12 to Week 18 for all 
subjects following the randomized withdrawal 
• 
In subjects with IBD who have Baseline Partial Mayo score above 0, absolute change in 
Mayo scores from Baseline to Week 6 
• 
In subjects with IBD who have Baseline Partial Mayo score above 0, absolute change in 
Mayo scores from Week 6 to Week 12  
• 
In subjects with IBD who have Baseline Partial Mayo score above 0, absolute change in 
Mayo scores from Week 12 to Week 18 for all subjects following the randomized 
withdrawal 
 
5.2.5. 
Secondary Efficacy Analysis 
All secondary endpoints will be summarized descriptively by treatment group and visit as defined 
for each period. Continuous endpoints will present baseline and actual value summaries and change 
from baseline (Period 1), Week 6 (Period 2), or Week 12 (Period 3) as appropriate. Proportions will 
be presented with denominators based on the number of subjects randomized to each treatment 
group. 
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The mean ALP values will additionally be represented graphically via a line chart for Period 2 and 
Period 3, with one page for each treatment group, with a line for each subject within the group 
charted individually, and with one line for the overall group. Period 2 will graph values for all 
scheduled visits from Baseline through Week 12 and Period 3 will graph values for all scheduled 
visits from Baseline through Week 18. 
Absolute change in GGT from Baseline to Week 6 will be tested using a mixed model with 
repeated measures (MMRM) analogous to the primary endpoint (Section 5.2.2). This model will 
include fixed effects for treatment, IBD diagnosis, UDCA status, visit and treatment by visit 
interaction, with Baseline GGT value as a covariate. An unstructured covariance matrix will be 
used to model the repeated assessments over time. Denominator degrees of freedom will be 
adjusted using Kenward-Roger’s method. Least Square (LS) Means and corresponding standard 
errors and 95% confidence intervals resulting from the model described will be presented at each 
visit. Differences in LS Means and corresponding two-sided 95% confidence intervals will be 
calculated at each visit comparing each active arm to placebo as well as comparing the HTD1801 
1000 mg BID treatment group to the HTD1801 500 mg BID treatment group. The primary 
comparison of these treatment groups will be at Week 6. 
Absolute change in GGT from Baseline to Week 6 will also be summarized by the subgroups as 
detailed in Section 5.2.3. 
5.3. 
SAFETY 
5.3.1. 
Adverse Events 
AEs will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) version 20.1 
preferred term (PT) and system organ classification (SOC). If a subject experiences multiple events 
that map to a single preferred term, the greatest severity grade according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be assigned to the preferred 
term for the appropriate summaries. Should an event have a missing severity or relationship, it will 
be classified as having the highest severity and/or assumed related to study medication. The overall 
occurrence of any TEAEs, TEAE related to study drug, severe TEAEs, serious TEAEs, TEAE 
leading to discontinuation of study drug, and TEAE leading to death, alongside individual counts 
of each respective TEAE. The occurrence of TEAEs will be summarized by treatment group by 
SOC, and PT based on the treatment taken at AE start date. Summaries of the total number of 
subjects receiving each treatment and the average weeks of exposure for each treatment will be 
provided for context. 
Separate summaries of each TEAE by period, TEAEs leading to the discontinuation of study, 
TEAEs related to study drug, and serious TEAEs will be generated and summarized by SOC and 
PT. The occurrence of TEAEs will be summarized by treatment group by SOC, PT, and Severity 
will also be summarized. 
All adverse events reported will be listed for individual subjects showing verbatim term, PT and 
SOC. All AEs that occurred prior to the initiation of study treatment will be excluded from the 
tables but will be included in the listings.  
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Missing onset dates will be imputed as previously outlined in Section 3.3.5 as required to 
determine treatment-emergent events. 
5.3.2. 
Clinical Laboratory Assessments, Vital Signs, Height, and Weight 
Descriptive summaries of selected (quantitative) clinical laboratory results and change from 
Baseline will be presented by time point and overall treatment groups.  Baseline will be the last 
value observed prior to dosing in Period 1. For more detail on how safety tables will be presented, 
see Section 3.3.6.  
Shift tables (low, normal, high) for change from Baseline to Week 6 in Period 1, and from Week 6 
to Week 12 in Period 2 will be presented for all appropriate clinical laboratory parameters by 
treatment group in Period 1 and Period 2 (excluding efficacy only groups).  
Descriptive summaries and change from Baseline in vital signs data, as well as height and weight, 
will be presented by time point and overall treatment groups, similar to the presentation of clinical 
laboratory assessments.  
Values for all safety variables will be listed by subject and visit (as applicable). 
5.3.3. 
Concomitant Medications 
Previous and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary Enhanced September 2017 version. Previous and concomitant medications will be 
presented in a data listing. Concomitant medications will additionally be summarized by aggregate 
treatment group. 
Missing end dates will be imputed as previously outlined in Section 3.3.5 as required to determine 
concomitant medications, and all ongoing medications will be considered concomitant. 
6. 
PROTOCOL DEVIATIONS
Possible protocol deviations will be identified and displayed in a data listing and sorted by subject, 
Period, and study day (where applicable). An additional listing of those deviations deemed Major 
during the blinded review will be provided. 
7. 
CHANGES IN THE PLANNED ANALYSES
The following secondary endpoints listed in the protocol were removed, with replacements noted in 
parenthesis. 
•
Change in serum ALP between Baseline and Weeks 12 or 18, dependent upon the
length of continuous treatment, compared to the placebo response during Period 1
(replaced with change from Week 6 to Week 12, and Week 12 to Week 18;
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endpoint will be evaluated from descriptive summaries, but no statistical testing 
will be performed) 
• Change in serum ALP between a new baseline at Week 6 and the final value at 
Weeks 12 for those subjects who received placebo during Period 1, compared to 
their initial 6-week placebo response (endpoint will be evaluated from descriptive 
summaries, but no statistical testing will be performed) 
• Change in serum ALP between a new baseline at Week 6 and the final value at 
Weeks 12 for those subjects who received placebo during Period 1, compared to 
the similar change in the 500 mg and 1,000 mg treatment groups (endpoint will be 
evaluated from descriptive summaries, but no statistical testing will be performed) 
• Change in serum ALP between a new baseline at Week 12 and the final value at 
Weeks 18 for all subjects following the randomized withdrawal (endpoint will be 
evaluated from descriptive summaries, but no statistical testing will be performed) 
• Proportion of patients who achieve ALP of <1.5 x ULN (endpoint will be evaluated 
from descriptive summaries, but no statistical testing will be performed) 
• Proportion of patients who achieve a 50% decrease in ALP (endpoint will be 
evaluated from descriptive summaries, but no statistical testing will be performed) 
• The proportion of patients who normalize ALP (endpoint will be evaluated from 
descriptive summaries, but no statistical testing will be performed) 
• Change in AST/ALT ratio (endpoint replaced with change in GGT) 
• Change in serum bilirubin (endpoint will be evaluated from descriptive summaries, 
but no statistical testing will be performed) 
• In subjects with IBD who have elevated fecal calprotectin (FC), change in FC 
compared to Baseline at Weeks 6 and 12, and the proportion of subjects who 
normalize FC at Weeks 6 and 12 (change in FC will be evaluated for all subjects 
with IBD, not just those with elevated FC; both endpoints will evaluated from 
descriptive summaries but no statistical testing will be performed) 
• For subjects who have elevated CRP at Baseline (for all subjects In the IBD 
subset): change from Baseline in CRP at Weeks 6 and 12, and normalization of 
CRP at Weeks 6 and 12 (change in CRP will be evaluated for all subjects with IBD, 
not just those with elevated CRP; both endpoints will evaluated from descriptive 
summaries but no statistical testing will be performed) 
• 
For subjects with IBD who have Partial Mayo score above 0: Change from 
Baseline in Mayo scores at Weeks 6 and 12. (For Week 12, change from Week 6 
will replace change from baseline; endpoint will evaluated from descriptive 
summaries but no statistical testing will be performed) 
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8. 
PROGRAMMING CONVENTIONS 
• 
Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in 
landscape orientation.  There should be a minimum of a 1.25” boundary on the upper (bound) 
edge, and a minimum of a 1.0” boundary on the remaining three edges.  Output should be 
printed in Courier New with a point size of 8.  Titles may be printed using a larger font (e.g., 
Arial point size 10). 
• 
Identification of analysis population: Every summary table and figure should clearly specify 
the analysis population being summarized.  Listings will be prepared for all subjects. 
• 
Group headers: In the summary tables, the group headers will identify the summary group and 
the sample size for the indicated analysis population.  Of note, the header’s sample size does 
not necessarily equal the number of subjects actually summarized within any given summary 
module; some subjects in the analysis population may have missing values and thus may not be 
summarized. 
• 
Suppression of percentages corresponding to null categories: When count data are presented as 
category frequencies and corresponding percentages, the percent should be suppressed when 
the count is zero in order to draw attention to the non-zero counts. 
• 
Presentation of sample sizes: Summary modules should indicate, in one way or another, the 
number of subjects actually contributing to the summary statistics presented in any given 
summary module.  As mentioned above, this may be less than the number of subjects in the 
analysis population due to missing data. 
• 
In the quantitative modules describing continuous variables (and thus presenting sample 
size, means, and standard deviations), the sample size should be the number of non-
missing observations.  The number of missing observations, if any, will be noted. 
• 
For categorical variables that are presented in frequency tables, the module should present 
the total count in addition to the count in each category.  Percentages should be calculated 
using this total as the denominator, and the percentage corresponding to the sum itself (that 
is, 100%) should be presented so as to indicate clearly to a reviewer the method of 
calculation.  The number of missing observations, if any, will be noted. 
• 
Sorting: Listings will be sorted by treatment group, subject number, and date, if applicable.  If 
a listing is sorted in a different manner, a footnote will indicate as such.  
• 
General formatting rules: Rounding for all variables will occur only as the last step, 
immediately prior to presentation in listings, tables, and figures.  No intermediate rounding will 
be performed on derived variables.  The standard rounding practice of rounding numbers 
ending in 0-4 down and numbers ending in 5-9 up will be employed.   
• 
Numerical Values: The presentation of numerical values will adhere to the following 
guidelines:  
• 
Raw measurements will be reported to the number of significant digits as captured 
electronically or on the CRFs.   
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• 
Standard deviations will be reported to one decimal place beyond the number of decimal 
places the original parameter is presented. 
• 
Means will be reported to the same number of significant digits as the parameter.  
• 
Calculated percentages will be reported with no decimals. 
• 
Dates will be formatted as DDMMMYYYY.  Partial dates will be presented on data listings as 
recorded on CRFs. 
• 
Time will be presented according to the 24-hour clock (HH:MM). 
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