Clinical trial NCT03381287
Conditions: Hypercholesterolemia
Sponsor: HighTide Biopharma Pty Ltd
Start date: 2018-04-13; Completion date: 2018-12-31
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a randomized, double-blind, placebo-controlled, multicenter, multiple ascending dose (MAD) study to evaluate the safety and tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of HTD1801 in overweight to obese adults with hypercholesterolemia. There were 3 cohorts of dose levels as 500, 1000 and 2000 mg/day, with 16 subjects planned for each cohort randomized 3:1 to receive either HTD1801 or Placebo.

Detailed description:

Arms: arm 1: Subjects received 500 mg/day HTD1801 arm 2: Subjects received 1000 mg/day HTD1801 arm 3: Subjects received 2000 mg/day HTD1801 arm 4: None
Interventions: intervention 1: HTD1801 Tablets, 500 mg intervention 2: HTD1801 Tablets, 1000 mg intervention 3: HTD1801 Tablets, 2000 mg intervention 4: Placebo to match 500 mg HTD1801 intervention 5: Placebo to match 1000 mg HTD1801 intervention 6: Placebo to match 2000 mg HTD1801
Intervention descriptions: intervention 1: 500 mg/day (250 mg BID) intervention 2: 1000 mg/day (500 mg BID) intervention 3: 2000 mg/day (1000 mg BID) intervention 4: 2 tablets/day (1 tablet BID) intervention 5: 4 tablets/day (2 tablet BID) intervention 6: 8 tablets/day (4 tablet BID)

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
HTD1801 Tablets   
 
 CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.  
Page 1 of 50 
 
 
 
CONFIDENTIAL 
 
CLINICAL TRIAL PROTOCOL 
 
A Randomized, Double Blind, Placebo Controlled, Multicenter, Multiple Ascending 
Dose Study to Evaluate the Safety and Tolerability of HTD1801 in Adults with 
Hypercholesterolemia 
 
 
Protocol Number: 1801.PCT004 
Version number: 2.0 
Date of issue: 19 January 2018 
 
 
Sponsor: 
HighTide Biopharma Pty Ltd 
1 Melissa Street 
Mount Waverley, Vic 3149 
Australia
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
___________________________________________________________
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22 July 2019
Page 2 of 51
This document is confidential.
2


CONFIDENTIAL 
 
   Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia    
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                    HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 2 of 50 
Sponsor Protocol Approval 
 
Steven E. Linberg, Ph.D. 
Chief Product Development Officer 
HighTide Biopharma Pty., Ltd. 
 
 
 
 
Signature 
 
Date 
 
 
 
 
Chong Ho, Ph.D. 
Director 
HighTide Biopharma Pty Ltd 
 
 
 
 
Signature 
 
Date 
 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
___________________________________________________________
_________________________________________________________________________________
____________________________________________________________________
22 July 2019
Page 3 of 51
This document is confidential.
3


CONFIDENTIAL 
 
   Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia    
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                    HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 3 of 50 
Document History 
 
Version 
Revision Date 
Revision Description 
1.0 
12 Dec 2017 
Initial Release 
2.0 
19 Jan 2018 
Amendment 1 
 
 
 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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22 July 2019
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This document is confidential.
4


CONFIDENTIAL 
 
   Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia    
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                    HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 4 of 50 
STUDY SUMMARY 
Protocol Title  
A Randomized, Double Blind, Placebo Controlled, Multicenter, Multiple Ascending Dose 
Study to Evaluate the Safety and Tolerability of HTD1801 in Adults with 
Hypercholesterolemia 
Primary Objective 
and Endpoints 
The primary objective for this study is to assess the safety and tolerability of multiple 
ascending dose levels of HTD1801 in participants with hypercholesterolemia. Safety 
assessments will occur throughout the duration of the trial, including monitoring of adverse 
events (AEs), clinical laboratory tests, vital signs measurements, electrocardiogram, and 
physical examinations. 
Secondary 
Objectives and 
Endpoints 
There are four secondary pharmacokinetic (PK) and pharmacodynamic (PD) objectives for 
this study. 
1. To assess the PK profile of HTD1801 after repeat doses as assessed by derived PK 
parameters including but not limited to:  
• 
Plasma half-life of HTD1801 components (t1/2).  
• 
Maximum plasma concentration of HTD1801 components (Cmax). 
• 
Minimum plasma concentration of HTD1801 components (Cmin). 
• 
Time to Cmax (Tmax). 
• 
Time to Cmin (Tmin). 
2. To determine the effects of HTD1801 on lipid metabolism: 
• 
Fasting lipid metabolism and atherogenic biomarkers as assessed by actual values 
and change from baseline of:  
o 
Low-density lipoprotein-C (LDL-C) 
o 
Non-high-density lipoprotein-C (non-HDL-C).  
o 
Total cholesterol, high-density lipoprotein-C (HDL-C), and the ratio of total 
cholesterol to HDL-C. 
o 
Apolipoprotein B (ApoB) and A-1 (ApoA1). 
o 
Triglycerides and free fatty acid (FFA). 
o 
C-reactive protein (CRP) measured using a high-sensitivity assay. 
o 
Lipoprotein(a) (Lp(a)). 
3. To determine the effects of HTD1801 on glucose metabolism: 
• Glycosylated hemoglobin (HbA1c) levels. 
• Markers of fasting glucose metabolism as assessed by actual values and change from 
baseline of: 
o 
Fasting plasma glucose (FPG).  
o 
Fasting serum insulin.  
o 
C-peptide 
4. To determine the effects of HTD1801 on biomarkers of liver function 
• Actual values and change from baseline in alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST). 
Phase of 
Development 
Phase 1b/2a 
Number of 
Participants 
This trial will enroll 48 participants in three planned dose escalation cohorts. Participants who 
withdraw from the trial for reasons other than safety and tolerability, may be replaced after 
discussion between the Investigator and Sponsor. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
___________________________________________________________
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____________________________________________________________________
22 July 2019
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5


CONFIDENTIAL 
 
   Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia    
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                    HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 5 of 50 
Inclusion Criteria  
 Participants meeting all the following criteria will be eligible to participate in this trial: 
1. Have given written informed consent 
2. Males or females aged 18 to 70 years old at the time of first dosing 
3. Satisfy the following: 
Females: Non-pregnant and non-lactating; surgically sterile, post-menopausal, or 
abstinent; or if engaged in sexual relations of childbearing potential, participant 
agrees to use two acceptable methods of contraception for 4 weeks prior to the 
treatment period, for the 4 weeks of the Treatment Period, and for at least 2 weeks 
after the last dose of study drug. One of the methods must be an appropriate 
hormonal contraceptive (stable for at least 4 weeks prior to treatment), and the other 
method can be an acceptable method of barrier contraception, e.g., a condom for the 
male partner.  
Males: Surgically sterile or abstinent; or if engaged in sexual relations of 
childbearing potential, the participant and his partner must agree to use an 
acceptable contraceptive method during the 4 weeks of the Treatment Period and for 
2 weeks after the last dose of study drug. 
4. Have a body mass index (BMI) of >25.0 and ≤ 45.0 kg/m2 at Screening  
5. Have a documented history of hypercholesterolemia, defined as LDL-C ≥ 2.59 
mmol/L.  
Exclusion Criteria 
Participants meeting any of the following criteria will be excluded from this trial: 
1. The use of any anti-dyslipidemia agent within 28 days prior to dosing 
2. History of a total cholesterol ≥ 10.35 mmol/L or triglyceride ≥ 11.3 mmol/L 
3. History of a clinically significant cardiac arrhythmia or clinically significant abnormal 
ECG results at Screening 
4. Significant peripheral or coronary vascular disease 
5. Clinically significant abnormal blood pressure at Screening or Baseline, defined as 
supine blood pressure ≥160/100 mmHg, or ≤ 90/60 mmHg 
6. Primary hypothyroidism (thyroid stimulating hormone [TSH] > upper limit or normal 
[ULN] and free T4 < lower limit of normal [LLN]), primary subclinical 
hypothyroidism (screening TSH > ULN and free T4 within normal limits [WNL]), or 
secondary hypothyroidism (screening TSH < LLN and free T4< LLN) at Screening 
7. Glucose-6-phosphate dehydrogenase (G6PD) deficiency 
8. History of unstable proliferative retinopathy or maculopathy and/or severe 
neuropathy, in particular autonomic neuropathy, as judged by the Investigator 
9. Malignancy within 5 years, except for curatively treated basal cell, squamous cell 
carcinoma of the skin or carcinoma in-situ of the cervix 
10. Known history of, or positive test for, human immunodeficiency virus (HIV), 
hepatitis C, or chronic hepatitis B 
11. Active infection that is currently producing symptoms or in which the causative 
organism of the disease is rapidly reproducing 
12. Current or recent history (verbal report) in last 6 months of drug or alcohol abuse, or 
consumption of more than 30 g of alcohol (3 standard drinks) per day (for male and 
female participants) within 4 weeks prior to Screening, or positive urine drug screen 
for drugs of abuse  
13. Clinically significant abnormalities identified during physical examination or from 
the participant’s medical history such as: 
a. 
Any history of cardiac insufficiency defined as New York Heart Association 
(NYHA) Class II to IV  
b. Angina pectoris within the last 6 months 
c. 
Acute myocardial infarction at any time 
d. Major surgery within the last 3 months 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
___________________________________________________________
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____________________________________________________________________
22 July 2019
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6


CONFIDENTIAL 
 
   Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia    
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                    HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 6 of 50 
e. 
Stroke 
14. Treatment with any agent that decreases body weight, actively enrolled in a weight 
loss program or following a special diet  
15. Gastrointestinal conditions that involve malabsorption or inflammation (e.g., 
ulcerative colitis, Crohn’s disease), and recent or past bariatric surgery of any kind  
16. Current or recent use of prohibited medications 
17. Current outpatient insulin use, or history of outpatient insulin use for more than 2 
weeks in the last year 
18. Whole blood donation or significant blood loss within 30 days prior to screening or 
Plasma donation within 14 days prior to the first study drug administration 
19. User of any nicotine containing products within the past 6 months 
20. Unwillingness to comply with study procedures, including follow-up, as specified by 
this protocol, or unwillingness to cooperate fully with the Investigator 
21. Participation in an investigational drug trial within 30 days prior to dosing or 10 
half-lives within the last dose of said investigational drug, whichever is longer 
22. The presence of any other conditions, which, in the opinion of the Investigator would 
make the participant unsuitable for inclusion, or could interfere with the participant 
participating in or completing the trial. 
Summary of Study 
Design 
This is a randomized, double-blind, placebo-controlled, multicenter, multiple ascending dose 
(MAD) study to evaluate the safety and tolerability, PK, and PD profiles of HTD1801 in 
overweight to obese adults with hypercholesterolemia. Two study drugs will be administered: 
(1) the investigational product HTD1801 and (2) matching placebo.  
There are three planned dose escalation cohorts. Each cohort will consist of 16 participants 
randomized 3:1 to receive either HTD1801 or placebo. The cohorts will be enrolled 
sequentially, but may overlap (the next cohort can begin during the Follow-up Period of the 
prior cohort). The decision to move to the next dose level will be based on safety findings and 
will not be dependent on establishing preliminary efficacy findings. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
___________________________________________________________
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____________________________________________________________________
22 July 2019
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CONFIDENTIAL 
 
   Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia    
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                    HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 7 of 50 
Summary of Study 
Procedures 
The trial will consist of the following:  
• 
Screening Period, including a 4-week anti-dyslipidemia treatment washout if 
applicable  
• 
Treatment Period (Days 1-28) consisting of an initial inpatient visit, an outpatient 
period, and a second inpatient visit 
• 
Follow-up Period 
 
Screening Period 
All participants must be consented prior to any study-related activities. Screening assessments 
will include demographics, medical history, physical exam, vital signs, ECG; as well as 
laboratory assessments including hematology, lipid profile, clinical chemistry, virus screen, 
G6PD, urinalysis, drug and alcohol screen, and pregnancy tests. All Inclusion and Exclusion 
criteria must be met prior to the 1st dose of study medication. Eligible participants who are 
currently taking anti-dyslipidemia agents will need to discontinue those agents for at least 28 
days prior to further participation in the trial.   
Visit 1  
Participants will undergo baseline measurement of lipid metabolism, liver function, and 
glucose metabolism biomarkers. PK samples will be collected for the determination of 
berberine and UDCA. 
Participants will be treated with the first dose of study drug (active or placebo). The study 
drug will be administered with a 240-mL glass of water immediately following the morning 
meal. Only one dose will be administered on Day 1. Participants will remain in-house for at 
least 24 hours of safety and PK monitoring following study drug administration. On Day 2, 
twice per day study drug dosing will begin immediately after morning and evening meals. 
Participants will be discharged on Day 2 after PK and safety assessments, if they are 
considered stable by the Investigator. Prior to discharge, participants will be given dietary 
counseling to prepare them for the outpatient period, as well as instructions to continue taking 
the study drug twice daily following the morning and evening meals. Participants will be 
instructed to return to the investigational site with their study drug prior to the morning dosing 
that will occur on Study Day 14. 
Outpatient Period 
Participants will continue to take the study drug twice daily following the morning and 
evening meals during the entire Outpatient Period. There will be one outpatient visit during 
that time, intended to occur on Day 14, to provide samples for clinical laboratory assessments, 
safety assessments; and glucose metabolism, lipid metabolism and liver function biomarker 
assessments.  
Visit 2 
Participants will return to the study site on Day 27 ± 3, and the next day will undergo fasting 
measurements of glucose metabolism, lipid metabolism and liver function biomarkers. PK 
samples will be collected for the determination of berberine and UDCA. 
Participants will remain in-house for approximately 36 hours.  Participants will be discharged 
approximately on Day 29 after PK and safety assessments, if they are considered stable by the 
Investigator. 
Follow-up Visit 
A safety Follow-up phone call will occur on Day 42. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
___________________________________________________________
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22 July 2019
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8


CONFIDENTIAL 
 
   Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia    
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                    HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 8 of 50 
Treatments 
This trial includes three planned dose escalation cohorts. The doses of HTD1801 (active or 
placebo) to be administered are summarized in the table below. 
    Table 1. Planned Dose Escalation Cohorts 
Cohort 
Number 
Number of 
Participants Planned 
Dose Regimen   
1  
12 
HTD1801: 500 mg/day (250 mg bid) 
4 
Placebo: 2 tablets/day (1 tablet bid) 
2 
12 
HTD1801: 1000 mg/day (500 mg bid) 
4 
Placebo: 4 tablets/day (2 tablets bid) 
3 
12 
HTD1801: 2000 mg/day (1000 mg bid) 
4 
Placebo: 8 tablets/day (4 tablets bid) 
 
Dose escalation criteria will be applied on a per cohort basis and is distinct from early study 
termination criteria. All dose escalation and stopping decisions will be made following a 
discussion between the Sponsor and the Investigator. Dose escalations may be stopped at any 
time by the Sponsor or the Investigator.   
Route of 
Administration 
Oral 
Duration of 
Participation 
The trial is expected to take approximately 10 weeks for each participant from Screening 
through Follow-up. 
Sample Size 
Determination 
The sample size of 16 participants per cohort, with 12 receiving HTD1801 and 4 receiving 
placebo, was empirically determined and consistent with typical sample sizes used for similar 
studies to assess robust data for safety and PK. 
Statistical Methods 
Safety and tolerability of the study drugs will be assessed by collection and review of AEs, 
laboratory parameters, and vital signs. Safety analysis will also involve examination of the 
descriptive statistics and individual participant listings for any effects of study treatment on 
clinical tolerability and safety. 
 
Safety analyses will be detailed in a statistical analysis plan (SAP).  Pharmacokinetic 
assessments will be summarized using descriptive statistics.  Assessments for other secondary 
objectives will be analyzed using descriptive and comparative statistical methods. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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22 July 2019
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CONFIDENTIAL 
 
          Phase 1a/2b Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
HTD1801 Tablets   
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 9 of 50 
 
Table 2.  SCHEDULE OF TIME AND EVENTS 
 
Study Period► 
Screening 
Visit 1 
Outpatient Period 
Visit 2 
Follow-up 
Study Day► 
-28 to -1 
BSLN 
1 
2 
3-13 
14 (clinic) 
15-26 
27 
28 
29 
42 
EVENT▼ 
Informed consent 
X 
  
  
  
  
 
  
 
  
  
  
Demographics 
X 
 
  
  
  
 
  
 
  
  
  
Medical history 
X 
X 
  
  
  
 
  
 
  
  
  
Physical examination 
X 
X 
 
 
 
X 
 
X 
 
 
 
Eligibility criteria 
X 
X 
  
  
  
 
  
 
  
  
  
Ht., Wt., Vital signs 
X 
X 
X 
X  
  
X 
  
X 
 X 
X  
  
Urine drug /Alcohol breath test 
X 
 
X  
  
  
X 
 
X 
  
  
  
Pregnancy test  
X 
X 
 
  
  
X 
  
X 
  
  
   
G6PD 
X 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
 
 
X 
 
 
X 
 
 
Clinical Chemistry 
X 
X 
 
 
 
X 
 
 
X 
 
 
Lipid Profile 
X 
X 
 
 
 
X 
 
 
X 
 
 
ApoA1, ApoB, Lp(a) and FFA 
 
X 
 
 
 
X 
 
 
X 
 
 
Urinalysis 
X 
X 
  
  
  
X 
 
 
X 
  
  
HIV, Hepatitis B, C 
X 
  
  
  
  
 
  
 
  
  
  
TSH and Free T4 
X 
  
  
  
  
 
  
 
  
  
  
LDH 
 
X 
 
 
 
X 
 
 
X 
 
 
ECG 
X 
X 
X 
  
  
X 
 
X 
X 
 
  
Concomitant medications 
X 
X 
X 
X  
  
X 
 
X 
X  
X  
 
Dietary counseling 
X 
 
 
X 
  
X 
 
 
 
 
 
C-reactive protein 
  
X 
 
 
  
X 
 
 
X 
 
 
Liver function biomarkers 
  
X 
 
 
  
X 
 
 
X 
 
 
Glucose metabolism biomarkers 
 
X 
 
 
  
X 
 
 
X 
 
 
Study Drug Dosing 
  
  
q.am 
 bid 
 bid 
 bid 
 bid 
 bid 
 q.am 
 
  
PK Sampling 
  
X 
X 
X 
  
 
 
 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
___________________________________________________________
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22 July 2019
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CONFIDENTIAL 
 
      
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
                   HTD1801 Tablets 
19 January 2018   
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
 CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.  
Page 10 of 50 
Table 3.  Pharmacokinetic Sampling Schedule 
hours pre (-) and post (+) treatment 
Baseline 
Day 1 
Day 28 
no drug 
q.am 
q.am 
-18 
X 
 
 
-12 
X 
 
 
-6 
X 
 
 
 0 (pre-dose) 
 
X 
X 
+0.25 (post dose) 
 
X 
X 
+0.50 
 
X 
X 
+1 
 
X 
X 
+2 
 
X 
X 
+3 
 
X 
X 
+4 
 
X 
X 
+8 
 
X 
X 
+12 
 
X 
X 
+24 
 
X 
X 
 
 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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22 July 2019
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 11 of 50 
 
TABLE OF CONTENTS 
STUDY SUMMARY ..................................................................................................................... 4 
LIST OF ABBREVIATIONS ....................................................................................................... 14 
1. 
INTRODUCTION ............................................................................................................ 16 
1.1 
Background ................................................................................................................. 16 
1.2 
Rationale for the Proposed Study ................................................................................ 18 
1.3 
Summary of Pre-Clinical /Clinical Studies ................................................................. 18 
1.3.1 
Pre-Clinical Studies in Animal Models ......................................................... 18 
1.3.2 
Clinical Studies in Humans ............................................................................ 20 
1.4 
Rationale for Treatment and Dose .............................................................................. 20 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 21 
2.1 
Primary Objectives ...................................................................................................... 21 
2.2 
Secondary Objectives .................................................................................................. 21 
2.3 
Rationale for Study Endpoints .................................................................................... 22 
3. 
STUDY POPULATION ................................................................................................... 23 
3.1 
Inclusion Criteria ......................................................................................................... 23 
3.2 
Exclusion Criteria........................................................................................................ 23 
4. 
STUDY DESIGN AND PROCEDURES ......................................................................... 25 
4.1 
Study Design ............................................................................................................... 25 
4.2 
Study Procedures ......................................................................................................... 26 
4.2.1 
Screening Period ............................................................................................ 26 
4.2.2 
Visit 1 (Baseline and Dosing) ........................................................................ 27 
4.2.3 
Outpatient Period (with one Outpatient Visit) ............................................... 28 
4.2.4 
Visit 2 (Final Assessments) ........................................................................... 29 
4.2.5 
Follow-up ....................................................................................................... 30 
4.3 
Dose Escalation, Study Discontinuation and Stopping Criteria.................................. 30 
4.3.1 
Dose Escalation Algorithm ............................................................................ 30 
4.3.2 
Dose Escalation Stopping Criteria ................................................................. 30 
4.3.3 
Criteria for Early Termination of the Study ................................................... 31 
4.3.4 
Criteria for Early Termination of Individual Participants.............................. 31 
4.4 
Prohibited Medications ............................................................................................... 32 
4.5 
Contraception .............................................................................................................. 32 
4.6 
Dietary Counseling...................................................................................................... 33 
5. 
STUDY MATERIALS ..................................................................................................... 35 
5.1 
Investigational Products .............................................................................................. 35 
HighTide Biopharma Pty Ltd 
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Final
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 12 of 50 
 
5.1.1 
HTD1801 ....................................................................................................... 35 
5.1.2 
Placebo ........................................................................................................... 35 
5.2 
Packaging, and Labeling of Investigational Products ................................................. 35 
5.3 
Storage and Drug Accountability of Investigational Products .................................... 35 
6. 
ADVERSE EVENTS ........................................................................................................ 36 
6.1 
Definitions ................................................................................................................... 36 
6.1.1 
Adverse Event ................................................................................................ 36 
6.1.2 
Treatment Emergent Adverse Event .............................................................. 36 
6.1.3 
Clinical Laboratory Event .............................................................................. 36 
6.1.4 
Serious Adverse Event (SAE) ........................................................................ 36 
6.1.5 
Severity of AEs .............................................................................................. 37 
6.1.6 
Causality of AEs ............................................................................................ 37 
6.2 
Recording and Reporting Procedures.......................................................................... 38 
6.2.1 
Collection and Recording of AEs .................................................................. 38 
6.2.2 
Collection and Reporting of SAEs ................................................................. 38 
6.3 
Anticipated Adverse Events ........................................................................................ 39 
6.4 
Follow-up of Adverse Events and Serious Adverse Events........................................ 39 
6.5 
Safety Monitoring Committee .................................................................................... 40 
7. 
DATA HANDLING AND MANAGEMENT .................................................................. 41 
7.1 
Data Management ....................................................................................................... 41 
7.2 
CRFs (Electronic)........................................................................................................ 41 
7.2.1 
Clinical Data Management Workflow ........................................................... 41 
7.2.2 
Data Entry of Electronic Case Report Forms ................................................ 42 
7.2.3 
Corrections to Electronic Case Report Forms ............................................... 42 
7.2.4 
Investigator Approval of Electronic Case Report Form Data ........................ 42 
7.3 
Retention of Documents .............................................................................................. 42 
8. 
STATISTICAL METHODS ............................................................................................. 43 
8.1 
Statistical and Analytical Plans ................................................................................... 43 
8.2 
Sample Size Calculation ............................................................................................. 43 
8.3 
Analysis Population .................................................................................................... 43 
9. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................ 44 
9.1 
Monitoring .................................................................................................................. 44 
9.2 
Protocol Deviations ..................................................................................................... 44 
10. 
ETHICAL ASPECTS OF THE STUDY .......................................................................... 45 
10.1 
Institutional Review Board and/or Independent Ethics Committee ............................ 45 
10.2 
Informed Consent ........................................................................................................ 45 
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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10.3 
Participant Confidentiality .......................................................................................... 46 
11. 
PUBLICATION, DISCLOSURE, AND CLINICAL TRIAL REGISTRATION 
POLICY ............................................................................................................................ 47 
12. 
REFERENCES .................................................................................................................. 48 
13. 
APPENDICES .................................................................................................................. 49 
13.1 
Principal Investigator Compliance Statements ........................................................... 49 
 
LIST OF IN-TEXT TABLES 
Table 1. Planned Dose Escalation Cohorts ..................................................................................... 8 
Table 2.  SCHEDULE OF TIME AND EVENTS .......................................................................... 9 
Table 3.  Pharmacokinetic Sampling Schedule ............................................................................. 10 
Table 4. Planned Dose Escalation Cohorts ................................................................................... 30 
Table 5. Prohibited Medications ................................................................................................... 32 
  
LIST OF IN-TEXT FIGURES 
Figure 4-1 Overall Study Design Schematic ................................................................................. 26 
 
 
 
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACC 
American College of Cardiology 
AE 
Adverse event 
AHA 
American Heart Association 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
ApoA1 
Apolipoprotein A-1 
ApoB 
Apolipoprotein B 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BBR 
Berberine 
bid or b.i.d. 
Twice per day 
BMI 
Body mass index 
BMR 
Basal metabolic rate 
BSLN 
Baseline 
BUN 
Blood urea nitrogen 
CDM 
Clinical data management 
Cmax 
Maximum concentration  
CRF 
Case report form 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CVD 
Cardiovascular Disease 
DDE 
Drug Dictionary Enhanced (WHO DDE) 
DMP 
Data management plan 
ECG  
Electrocardiogram 
eCRF 
Electronic CRF 
ED50 
Median Effective Dose 
FFA 
Free Fatty Acid 
FPG 
Fasting plasma glucose 
FPFV 
First participant first visit 
FSH 
Follicle Stimulating Hormone 
G6PD 
Glucose-6-Phosphate Dehydrogenase 
GCP 
Good Clinical Practice 
HbA1C 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL-C 
High Density Lipoprotein Cholesterol 
HED 
Human Equivalent Dose 
HIV 
Human immunodeficiency virus 
HREC 
Human Research Ethics Committee 
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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IB 
Investigator’s brochure 
ICH 
International Council on Harmonization 
IP 
Investigational Product 
IV 
Intravenous 
kg 
Kilogram 
lb 
Pound 
LDL-C 
Low Density Lipoprotein Cholesterol 
LLN 
Lower Limit of Normal 
Lp(a) 
Lipoprotein(a) 
LPLV 
Last Participant Last Visit 
mg 
Milligram 
NYHA 
New York Heart Association 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PPP 
Pharmaceutical Packaging Professionals (IP logistics contractor) 
q.am 
Once in the morning. 
QD or q.d. 
Once per day 
RBC 
Red Blood Cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SMC 
Safety Monitoring Committee 
SOE 
Schedule of events 
t½ 
half-life 
T2DM 
Type 2 diabetes mellitus 
TEAE 
Treatment emergent adverse event 
TG 
Triglycerides 
Tmax 
Time to maximum serum concentration 
TSH 
Thyroid-stimulating hormone 
UDCA 
Ursodeoxycholic acid 
ULN 
Upper limit of normal 
US 
United States  
USP 
Unites States Pharmacopeia 
WHO 
World Health Organization 
WNL 
Within Normal Limits 
 
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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Page 16 of 50 
 
1. INTRODUCTION 
1.1 
Background 
Hyperlipidemia, is defined as the elevation of fasting levels of total cholesterol or low-density 
lipoprotein cholesterol (LDL-C), which may or may not be associated with elevated levels of 
triglycerides [Mitchell et al. 2016; Nelson 2103]. While some patients present with familial 
hyperlipidemia associated with hereditary factors, hyperlipidemia is most often an acquired 
condition [Nelson 2013]. In a 2009 survey of primary care physicians, hyperlipidemia was the 
second most common chronic condition (first was hypertension) observed in primary care 
[Nelson 2013]. Patients with hyperlipidemia are commonly diagnosed with other comorbid 
conditions including cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and 
non-alcoholic fatty liver disease (NAFLD) [Mitchell 2016; Nelson 2013; NCEP 2002]. Of 
these, CVD is the leading cause of death in the United States (US) [Nelson 2013].  
Reducing LDL-C is the primary treatment goal for patients with hyperlipidemia [NCEP 2002]. 
LDL-C consists of a single lipoprotein (apolipoprotein B [ApoB]) and typically makes up 
approximately 60-70% of total serum cholesterol [NCEP 2002]. Comprehensive treatment 
guidance has been provided by the National Cholesterol Education Program (NCEP)- Expert 
Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult 
Treatment Panel [ATP] III). In 2013, an update was issued, however, the guidance provided by 
the American College of Cardiology (ACC) and American Heart Association (AHA) 
(convened as the ATP IV expert panel) was strictly focused on treatment strategies to reduce 
atherosclerotic CVD. Therefore, the more comprehensive ATP III recommendations are 
referenced here. While cholesterol levels <2.59 mmol/L are considered “optimal” these levels 
are also not considered attainable in all patients, in part due to the cost associated with treatment 
to target levels on a population wide scale [NCEP 2002]. Therefore, the ATP III panel adopted 
the following tiered recommendation based on the number of preexisting risk factors for CVD: 
• Multiple (2+) risk factors → target LDL-C <3.36 mmol/L achieved through lifestyle 
modification (baseline LDL-C 3.36-4.11 mmol/L) or lifestyle modification and 
medication (baseline LDL-C ≥4.14 mmol/L). 
• 0-1 risk factors → target LDL-C <4.14 mmol/L (<3.36 mmol/L is preferred) achieved 
primarily through lifestyle modification. Medication should be considered for patients 
with LDL-C ≥4.91 mmol/L after lifestyle changes. 
However, treatment targets are not met in most (61.8-93.8%) patients at high risk for CVD 
[Mitchell et al. 2016]. Hyperlipidemia patients with existing CVD or diabetes were the least 
likely to reach treatment goals [Mitchell et al. 2016]. 
There are currently three classes of drugs commonly used to treat elevated LDL-C levels:  
Statins.  Statins are the first-line therapy for patients with elevated LDL-C and act by inhibiting 
HMG CoA reductase to block cholesterol synthesis. They have been shown to have clinical 
benefits including lowering LDL-C levels, reducing atherosclerosis, reducing triglyceride 
levels, and anti-inflammatory effects [NCEP 2002]. Statins are generally well tolerated, but are 
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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Page 17 of 50 
 
associated with adverse effects that may not make them suitable for treating every patient. 
These effects include muscle pain or weakness (7-29% of patients), hepatic toxicity, limited 
efficacy in patients with heterozygous familial hypercholesterolemia, and increased risk of 
insulin resistance [NCEP 2002].  
Non-Statins: The second class of LDL-C lowering medications are the non-statins including 
bile acid sequestrants, niacin (also called nicotinic acid), and ezetimibe. Bile acid sequestrants 
work indirectly to lower LDL-C levels by relieving feedback inhibition on the pathway that 
converts LDL-C to bile acid [NCEP 2002]. Niacin reduces circulating LDL-C by preventing 
hepatic lipoprotein synthesis [NCEP 2002], and ezetimibe prevents cholesterol absorption 
[NCEP 2002]. However, all three compounds have limited LDL-C reducing effects when taken 
alone and can have significant gastrointestinal side effects [NCEP 2002].  
PCSK9 Inhibitors. Finally, elevated LDL-C levels can be treated using proprotein convertase 
subtilisin/kexin type 9 (PCSK9) inhibitors. This class of drugs blocks the cellular uptake and 
degradation of the LDL surface receptor on hepatocytes, which is enhanced by soluble PCSK9 
binding to the LDL receptor. In healthy individuals, the LDL receptor binds to and removes 
LDL-C from circulation via lysosomal degradation [Rosei and Salvetti 2016; Tavori et al. 
2016]. While PCSK9 inhibitors reduce LDL-C levels, they are costly, require repeated 
injections, and increase the risk of developing T2DM [Rosei and Salvetti 2016].  
Given the limitations of the current LDL-C lowering agents on the market, there is an unmet 
clinical need for LDL-C lowering agents that may benefit patients with familial 
hypercholesterolemia, patients in whom other LDL-C lowering medications are not sufficient, 
and patients who are intolerant to statins. 
The investigational product (IP), HTD1801, is a novel compound under development to treat 
hyperlipidemia, and NAFLD/non-alcoholic steatohepatitis (NASH). HTD1801 is an ionic salt 
of berberine (BBR) and ursodeoxycholic acid (UDCA) (1:1 stoichiometry). BBR and its 
derivatives are patented for use treating a wide array of conditions including cancer, 
inflammation, infectious disease, CVD, metabolic disorders, and others [Singh and Mahajan 
2013]. BBR use can be traced back to China some 3,000 years ago. BBR is approved for use as 
an antiseptic in China, Japan, and Taiwan, and marketed as a dietary supplement for managing 
diabetes and dyslipidemia in the US, Europe, and Canada. Its lipid and glucose lowering effects 
have been supported in controlled clinical trials [Lan et al. 2015; Dong et al. 2013]. Typical 
daily dosing is 0.5-1.5 g/day divided over 2-3 doses [Dong et al. 2013]. UDCA is approved to 
treat cholesterol gallstones and primary biliary cirrhosis in several markets including the US, 
Japan, and China, although its efficacy in primary biliary cirrhosis has remained somewhat 
controversial [Zhu et al. 2015]. The approved dosing regimen is 13-15 mg/kg/day divided over 
2-4 doses [UrsoForte Product Insert]. Additional composition/formulation details for HTD1801 
are provided in the Investigator’s Brochure (IB) and Section 5.1.1.  
HTD1801 has been shown to reduce LDL-C levels with a mechanism of action (MOA) that is 
distinct from statins, to improve liver function, and to normalize glucose homeostasis. Please 
refer to IB for details on MOA. The preclinical and clinical studies supporting the development 
of HTD1801 are described in more detail in the IB and below in Section 1.3. The clinical 
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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Page 18 of 50 
 
benefits of its components suggest that HTD1801 has the potential to be an integrated lipid 
management solution for patients with complex metabolic problems (e.g., NAFLD and 
T2DM). 
1.2 
Rationale for the Proposed Study 
This is a multiple ascending dose study, the safety data from which will complement the safety 
data from the single ascending dose study. The primary objective is therefore to assess the 
safety and tolerability of BBR and UDCA when administered concomitantly in the form of 
HTD1801. An additional objective is to assess the PK profile of UDCA and BBR after 
repeat-dose administration of HTD1801 in humans.  
As summarized in Section 1.3 below, HTD1801 has been shown in preclinical studies to have 
multiple activities at a cellular level, amongst which its effects on lipid metabolism, glucose 
metabolism, and liver function have been most robust. The secondary objective of this study is 
therefore to monitor for activity in these three metabolic areas as a means to inform future 
development efforts for HTD1801 in dyslipidemia. 
1.3 
Summary of Pre-Clinical /Clinical Studies 
Detailed information pertaining to the pre-clinical and ongoing clinical studies using HTD1801 
is provided in the IB. The results from the most relevant studies are summarized in the sections 
below. 
1.3.1 Pre-Clinical Studies in Animal Models 
1.3.1.1 Efficacy Study in Golden Hamsters Fed a High Fat Diet 
Syrian golden hamsters (n=8/group) were used to examine the effects of HTD1801 treatment 
on serum and liver lipid levels following consumption of a high fat diet. The hamsters were 
divided into four treatment groups: (1) normal control – normal chow, (2) model control – high 
fat diet, no treatment, (3) low dose HTD1801 – high fat diet, treated with 50 mg/kg HTD1801 
once daily (QD) for seven weeks, and (4) high dose HTD1801 – high fat diet, treated with 200 
mg/kg HTD1801 QD for seven weeks. At the end of the treatment period, the hamsters were 
sacrificed and the effects of HTD1801 treatment on serum and liver lipid profiles were assessed. 
As expected, the hamsters in model group developed significantly higher serum LDL-C and 
total cholesterol compared to the normal control group. Compared to the normal control group, 
the serum PCSK9 levels of model group significantly increased. The animals in model group 
also developed signs of impaired liver function (elevated aspartate aminotransferase [AST] and 
alanine aminotransferase [ALT]), elevated liver lipids (total cholesterol and triglycerides), and 
signs of liver inflammation compared to the normal control group. Treatment with HTD1801 
significantly reduced serum total cholesterol, triglycerides, and LDL-C, and reduced total 
cholesterol and triglycerides in the liver in a dose dependent manner. Secondary effects 
included: reducing the levels of AST and ALT; reducing serum PCSK9 levels; improving liver 
function; and reducing liver fat deposition and inflammation. 
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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1.3.1.2 Determination of the HTD1801 ED50 in Syrian Golden Hamsters 
Syrian golden hamsters (n=10/group) were used to determine the median effective dose (ED50) 
of HTD1801. The hamsters were fed a high fat diet and treated with 0, 6.25, 12.5, 25, 50, 100, 
or 200 mg/kg/day HTD1801 respectively. A normal control diet group was included as a 
normal control. HTD1801 was administered QD for 2-weeks. As expected, HTD1801 
treatment resulted in a dose dependent reduction in the elevated serum LDL-C, total cholesterol, 
and triglyceride levels caused by the high fat diet. The ED50 was calculated based the reduction 
in serum LDL-C levels and was determined to be 45 mg/kg (human equivalent dose [HED] of 
425 mg/70 kg). 
1.3.1.3 Efficacy 
Study 
in 
Rhesus 
Macaques 
with 
Naturally 
Occurring 
Hyperlipidemia/NAFLD 
Rhesus macaque is a widely used non-human primate model that closely mimics human 
physiology in the etiology, pathogenesis, and pathology of hyperlipidemia and NAFLD. The 
efficacy of HTD1801 was tested in rhesus macaques with naturally occurring 
hyperlipidemia/NAFLD over a 69-day treatment period. The macaques were fed a diet 
containing approximately 18% fat and negligible levels of cholesterol. The study consisted of 
three randomly assigned treatment groups (n=3-4/group): placebo, 15 mg/kg HTD1801 QD 
(HED of 525 mg/70 kg QD), and 30 mg/kg HTD1801 QD (HED of 1050 mg/ 70kg QD). 
Treatment with HTD1801 reduced the level of serum LDL-C from baseline in a dose dependent 
manner. The level of LDL-C in the placebo group remained unchanged throughout the 
treatment period. Following the washout, serum LDL-C levels increased to pre-treatment levels 
in the rhesus macaques receiving HTD1801. Similar trends were observed for serum total 
cholesterol, ALT, and AST levels. HTD1801 treatment also reduced liver fat content in a dose 
dependent manner, and had a significant blood glucose lowering effect in the rhesus macaques 
treated with 30 mg/kg HTD1801 compared to the placebo group. These findings suggest that 
HTD1801 may have beneficial effects on glucose metabolism. There was no effect on body 
weight or food intake. Notably, HTD1801 was well tolerated in the rhesus macaques 
throughout the 69-day treatment period. 
1.3.1.4 Good Laboratory Practice Toxicity Study in Dogs 
The safety and tolerability of HTD1801 was tested in Beagle dogs in a Good Laboratory 
Practice (GLP) study over a 3-month treatment period. HTD1801 was administered at 60, 200, 
or 600 mg/kg.  
In this study, no mortality occurred and there were no treatment-related effects on clinical 
chemistry, hematology, and ECG. Repeated oral (capsule) administration of HTD1801 to 
Beagle dogs, once daily for 91 days was tolerated at a dose of up to 200 mg/kg. The 
gastrointestinal tract was considered to be the toxicity target, which is consistent with the 
published adverse effects of BBR or UDCA in clinical practice (see the Section 6.7 in IB). The 
no-observed adverse effect level (NOAEL) was determined at 60 mg/kg under current study 
conditions in view of low incidence and/or minimal severity grade of the reversible clinical 
observations and microscopic changes observed in the 60 mg/kg group. The exposure (mean 
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
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Protocol 1801.PCT004 
19 January 2018 
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Cmax and mean AUC0-24h) of both BBR and UDCA increased with increasing dose on each 
testing day, except that the exposure of BBR for the males changed little from 60 to 200 mg/kg 
on Day 14 and Day 91. No gender differences were observed and no accumulation for UDCA 
was observed. Accumulation in BBR was noted in some to most animals of each dose. A more 
detailed summary of the results can be found in the IB.  
1.3.2 Clinical Studies in Humans 
1.3.2.1 Phase 1 Single Ascending Dose Study – Protocol No. 1801.PCT002  
HTD1801 was administered to four cohorts of health male volunteers at dosages of 0.5, 1.0, 2.0, 
and 4.0 g per day. The results of this trial showed that orally administered HTD1801 is safe and 
well tolerated in this population at up to 4.0 g per day. Inter-participant variability in PK 
parameters was generally high across all dose level cohorts. Nevertheless, plasma BBR and 
unconjugated UDCA levels increased with increasing doses of HTD1801 and dose 
proportionality was demonstrated for UDCA and BBR AUC(0-last). Cmax was approximately 
linear and approaching dose proportionality for UDCA and BBR plasma levels, for HTD1801 
dose levels of 1.0-4.0 g. A more detailed summary of these data can be found in the IB. 
1.4 
Rationale for Treatment and Dose  
The dose range for HTD1801 was intended to bracket the intended 1.5 g/day dose for humans, 
starting with 0.5 g/day, and testing up to 2 g/day or the maximum tolerated dose, whichever is 
lower. Subjects in the highest dose cohort would receive approximately 0.925 g of BBR and 
1.075 g of UDCA. There is interest in carefully investigating the safety of these upper limits 
which is why the doses to be administered to the highest dose cohort in this study are slightly 
more than the generally recommended amounts of each compound. 
In a previous SAD study, HTD1801 was administered to four cohorts of healthy male 
volunteers at dosages of 0.5, 1.0, 2.0, and 4.0 g per day. The results of this trial showed that 
orally administered HTD1801 is safe and well tolerated in health male volunteers at up to 4.0 g 
per day. 
 
 
 
 
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objectives 
The primary objective for this study is to assess the safety and tolerability of multiple ascending 
dose levels of HTD1801 in participants with hypercholesterolemia. Safety assessments will 
occur throughout the duration of the trial, including monitoring of adverse events (AEs), 
clinical laboratory tests, vital signs measurements, electrocardiogram, and physical 
examinations. 
2.2 
Secondary Objectives 
There are four secondary pharmacokinetic (PK)/pharmacodynamic (PD) objectives for this 
trial. 
1. To assess the PK profile of HTD1801 after repeat doses as assessed by derived PK 
parameters including but not limited to:  
• 
Plasma half-life of HTD1801 components (t1/2)  
• 
Maximum plasma concentration of HTD1801 components (Cmax) 
• 
Minimum plasma concentration of HTD1801 components (Cmin) 
• 
Time to Cmax (Tmax) 
• 
Time to Cmin (Tmin), 
2. To determine the effects of HTD1801 on lipid metabolism: 
• 
Fasting lipid metabolism and atherogenic biomarkers as assessed by actual values 
and change from baseline of:  
o 
Low-density lipoprotein-C (LDL-C) 
o 
Non-high-density lipoprotein-C (non-HDL-C)  
o 
Total cholesterol (TC), HDL-C, and TC/HDL-C ratio 
o 
Apolipoprotein B (ApoB) and A-1 (ApoA1) 
o 
Triglycerides and free fatty acid (FFA). 
o 
C- reactive protein (CRP) measured using a high-sensitivity assay 
o 
Lipoprotein(a) [Lp(a)]. 
3. To determine the effects of HTD1801 glucose metabolism: 
• 
Glycosylated hemoglobin (HbA1c) levels. 
• 
Markers of fasting glucose metabolism as assessed by actual values and change 
from baseline of: 
o 
Fasting plasma glucose (FPG).  
o 
Fasting serum insulin.  
o 
C-peptide. 
4. To determine the effects of HTD1801 on markers of liver function 
• 
Actual values and change from baseline in ALT and AST. 
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
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2.3 
Rationale for Study Endpoints 
The primary endpoints are related to assessing the safety and tolerability of multiple doses of 
HTD1801 in overweight to obese hyperlipidemic adults.   
The secondary endpoints are related to characterizing the effects of HTD1801 on dyslipidemia 
in overweight to obese participants. The participant population chosen for this trial allows 
assessment of both anti-dyslipidemia effects and improvement in insulin sensitivity. Given that 
the participants enrolled will be overweight to obese, there is expected to be a propensity 
toward development of T2DM and liver disease (NAFLD/NASH) among the study population. 
Therefore, the liver function biomarkers AST and ALT, and the glucose metabolism 
biomarkers FPG, fasting serum insulin, HbA1c and C-peptide will also be evaluated in order to 
provide insight into the effects of HTD1801 in the study population.  
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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3. STUDY POPULATION 
This trial will be performed in overweight to obese participants with hypercholesterinemia. 
3.1 
Inclusion Criteria 
Participants meeting all the following criteria will be eligible to participate in this trial: 
1. Have given written informed consent 
2. Males or females aged 18 to 70 years old at the time of first dosing 
3. Satisfy the following: 
• 
Females: Non-pregnant and non-lactating; documented surgically sterile, confirmed 
post-menopausal, or abstinent; or if engaged in sexual relations of childbearing 
potential, participant agrees to use two acceptable methods of contraception for 4 
weeks prior to the treatment period, for the 4 weeks of the Treatment Period, and for 
at least 2 weeks after the last dose of study drug. One of the methods must be an 
appropriate hormonal contraceptive (stable for at least 4 weeks prior to treatment), 
and the other method can be an acceptable method of barrier contraception, e.g., a 
condom for the male partner.  
• 
Males: Surgically sterile or abstinent; or if engaged in sexual relations of 
childbearing potential, the participant and his partner must agree to use an 
acceptable contraceptive method during the 4 weeks of the Treatment Period and for 
2 weeks after the last dose of study drug. 
4. Have a body mass index (BMI) of >25.0 and ≤ 45.0 kg/m2 at Screening  
5. Have a documented history of dyslipidemia defined as LDL-C ≥ 2.59 mmol/L. 
3.2 
Exclusion Criteria 
Participants meeting any of the following criteria will be excluded from this trial: 
1. The use of any anti-dyslipidemia agent within 28 days prior to dosing 
2. History of a total cholesterol ≥ 10.35 mmol/L or triglyceride ≥ 11.3 mmol/L 
3. History of a clinically significant cardiac arrhythmia or clinically significant 
abnormal ECG results at Screening 
4. Significant peripheral or coronary vascular disease 
5. Clinically significant abnormal blood pressure at Screening, defined as supine blood 
pressure ≥160/100 or < 90/60 mmHg. 
6. Primary hypothyroidism (thyroid stimulating hormone [TSH] > upper limit or 
normal [ULN] and free T4 < lower limit of normal [LLN]), primary subclinical 
hypothyroidism (screening TSH > ULN and free T4 within normal limits [WNL]), or 
secondary hypothyroidism (screening TSH < LLN and free T4< LLN) at Screening. 
7. Glucose-6-phosphate dehydrogenase (G6PD) deficiency 
8. History of unstable proliferative retinopathy or maculopathy and/or severe 
neuropathy, in particular autonomic neuropathy, as judged by the Investigator 
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1801.PCT004
Final
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24


CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 24 of 50 
 
9. Malignancy within 5 years, except for curatively treated basal cell, squamous cell 
carcinoma of the skin or carcinoma in-situ of the cervix. 
10. Known history of, or positive test for, human immunodeficiency virus (HIV), 
hepatitis C, or chronic hepatitis B 
11. Active infection that is currently producing symptoms or in which the causative 
organism of the disease is rapidly reproducing 
12. Current or recent history (verbal report) in last 6 months of drug or alcohol abuse, or 
consumption of more than 30 g of alcohol (3 standard drinks) per day (for male and 
female participants) within 4 weeks prior to Screening, or positive urine drug screen 
for drugs of abuse  
13. Clinically significant abnormalities identified during physical examination or from 
the participant’s medical history such as: 
a. Any history of cardiac insufficiency defined as New York Heart Association 
(NYHA) Class II to IV  
b. Angina pectoris within the last 6 months 
c. Acute myocardial infarction at any time 
d. Major surgery within the last 3 months 
e. Stroke 
14. Treatment with any agent that decreases body weight, actively enrolled in a weight 
loss program or following a special diet  
15. Gastrointestinal conditions that involve malabsorption or inflammation (e.g., 
ulcerative colitis, Crohn’s disease), and recent or past bariatric surgery of any kind  
16. Current or recent use of prohibited medications including (Section 4.4) 
17. Current outpatient insulin use, or history of outpatient insulin use for more than 2 
weeks in the last year. 
18. Whole blood donation or significant blood loss within 30 days prior to screening or 
Plasma donation within 14 days prior to the first study drug administration. 
19. User of any nicotine containing products within the past 6 months. 
20. Unwillingness to comply with study procedures, including follow-up, as specified by 
this protocol, or unwillingness to cooperate fully with the Investigator. 
21. Participation in an investigational drug trial within 30 days prior to dosing or 10 
half-lives within the last dose of said investigational drug, whichever is longer. 
22. The presence of any other conditions, which, in the opinion of the Investigator would 
make the participant unsuitable for inclusion, or could interfere with the participant 
participating in or completing the trial. 
 
 
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HTD1801
1801.PCT004
Final
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22 July 2019
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25


CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 25 of 50 
 
4. STUDY DESIGN AND PROCEDURES 
4.1 
Study Design 
This is a randomized, double-blind, placebo controlled, multicenter, multiple ascending dose 
(MAD) study with the primary objective of evaluating the safety and tolerability of HTD1801 
in overweight to obese participants with hypercholesterolemia.  
There are three planned dose escalation cohorts. Each cohort will consist of 16 participants, 
randomized 3:1 to receive either HTD1801 or placebo. The three planned cohorts may enroll up 
to 48 participants. Participants who withdraw from the trial may be replaced following 
consultation with the Sponsor. The cohorts will be enrolled sequentially. The ascending dose 
cohort may be initiated once it has been established that HTD1801 is well-tolerated at the 
previous dose, independent of preliminary efficacy findings.  
Participants in each cohort will participate in a Screening Visit, two 2-day in-house visits 
separated by a 4-week Outpatient Period (includes one Out-Patient Visit), and one Follow-up 
telephone contact. Eligible participants who are currently taking anti-dyslipidemia medications 
must consent, with approval of their physician, to discontinue these medications and undergo a 
Washout Period, prior to completion of screening and participating in the trial. The washout 
period is at least 4 weeks prior to dosing. 
During the first in-house Visit 1, participants will undergo baseline glucose and lipid metabolic 
assessments on the day prior to dosing, receive their first dose of study drug on Day 1, and 
undergo post-dosing safety monitoring.  On Day 2 the participants will receive their second 
dose of study medication in the morning, and receive dietary counseling and instruction for 
taking study drug during the Outpatient Period.  
The Outpatient Period will last for approximately 3 weeks. There will be one outpatient visit 
during this period, on Day 14 (±3 days), to obtain samples for PK, glucose and lipid metabolism 
biomarkers, liver function biomarkers, vital signs, safety evaluations and to review treatment 
compliance. 
The second in-house Visit 2 will begin on Day 27 (±3 days), followed by discharge on the 
morning of Day 29 (±3 days).  During this period participants will undergo evaluations for PK, 
glucose and lipid metabolism biomarkers, liver function biomarkers, vital signs, safety 
evaluations and to review treatment compliance. post-dosing metabolic assessments. A safety 
Follow-up phone call will occur on Day 42±3. The trial is expected to take approximately ten 
weeks for each participant from Screening through Follow-up. 
Study drug should be administered/taken orally, once per day immediately following the 
morning meal on Day 1, twice per day following the morning and evening meals on Days 2 to 
27 inclusive, and once per day immediately following the morning meal on Day 28.  All study 
drug should be taken with a 240 mL of water (no more).  Each in-house visit is expected to last 
approximately 2 days.   
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HTD1801
1801.PCT004
Final
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22 July 2019
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26


CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 26 of 50 
 
  
Figure 4-1 Overall Study Design Schematic 
 
 
4.2 
Study Procedures 
See Table 1 for the Schedule of Time and Events which summarizes the tests and evaluations to 
be performed on each study day. 
4.2.1 Screening Period 
The Screening Period will generally begin approximately 28 days before the first dose of study 
drug.  Written informed consent must be obtained prior to the initiation of any study-related 
procedures.  Investigators must account for all participants who sign informed consent forms. 
The Investigator or designee will keep a Participant Screening and Enrollment Log at the 
investigational site.  
All inclusion and exclusion criteria must be met during the Screening Period.  These screening 
procedures will include the collection of demographic information, and a thorough medical 
history.  Potential participants will undergo a physical examination including height and 
weight, the collection of vital signs (blood pressure, heart rate, respiratory rate, temperature 
measured after at least 5 minutes in a seated position), 12-lead ECG, a urine drug screen and an 
alcohol breath test.  Females of child-bearing potential will qualify based on a urine pregnancy 
test (to be confirmed prior to Baseline by a serum pregnancy test).  Potential participants will 
also provide a fasting urine sample for urinalysis, and fasting blood samples for hematology, 
clinical chemistry, lipids, HIV, hepatitis B and C, G6PD, TSH, and Free T4. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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27


CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 27 of 50 
 
Eligible participants who are currently taking anti-dyslipidemia agents will need to discontinue 
those agents for at least 28 days prior to Baseline measurements.  Inclusion and Exclusion 
criteria (excluding the confirmatory serum pregnancy test result) must be met prior to the 
washout of anti-dyslipidemia medications. Participants will be educated about the factors that 
may influence insulin sensitivity or lipid metabolism, such as strenuous exercise, alcohol, 
certain medications, dietary supplements, caffeine, smoking and illness/infection. 
Participants who have failed screening may be allowed to re-screen once at the discretion of the 
Investigator. A new screening number will be assigned. 
4.2.2 Visit 1 (Baseline and Dosing) 
Participants will be asked to report to the clinic in a fasting state, and to undergo the following:  
• Urine drug screen and an alcohol breath test 
• Serum pregnancy test (for females of child-bearing potential) 
• Weight (baseline) and vital signs (baseline is pre-dose, then one hour post-dose, 
and pre-discharge on Day 2), 
• Baseline information to update medical history and current medications,  
• Baseline blood sampling for:  
o PK (-18 hr, -12 hr, -6 hr and pre-dose),  
o hematology, 
o clinical chemistry,  
o lipids, 
o liver function biomarkers AST and ALT, if not included in standard 
panel above, 
o glucose metabolism biomarkers (HbA1c, FPG, fasting insulin, and 
fasting C-peptide), if not included in standard panel above, 
o C-reactive protein (high-sensitivity), if not included in panels above, 
o FFA, ApoA1, ApoB, Lp(a) and LDH, if not included in one of the panels 
above. 
• Urinalysis  
• Baseline ECG 
The procedures outlined above can occur at any time during the pre-dose period once the 
participant has arrived at the study site, except as noted for blood PK sampling which should 
occur prior to a standardized morning meal on what will be referred to as the beginning of 
Day 1.  
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HTD1801
1801.PCT004
Final
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22 July 2019
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 28 of 50 
 
Immediately following the morning meal, the participant will then receive their first dose of 
study drug, under supervision.  The dose is to be taken with 240 mL of water (not more).  
Post-dose PK sampling will begin as described in Table 2. A 12-lead ECG is to be performed 
approximately 3 hrs post-dose.   
Any adverse changes from Baseline represent an adverse event.   
Participants will begin twice per day dosing on the morning of Day 2.  The morning dose on 
Day 2 will be administered under the supervision of qualified study personnel.  Participants will 
receive dietary counseling on Day 2 in preparation for the Outpatient Period. Participants will 
be discharged on Day 2 after the morning 24-hr PK sample, after which they will 
self-administer the study drug at home.  Participants will be instructed to return to the study site 
in a fasted state and with their supply of study drug on Day 14±3. 
4.2.3 Outpatient Period (with one Outpatient Visit) 
Participants are to continue taking the study drug twice daily throughout the Outpatient Period, 
after breakfast and after dinner. The amount of liquid is not restricted.   
Upon their return to the study site on Day 14±3 in a fasted state and with their supply of study 
drug, participants will undergo the following:  
• Urine drug screen and an alcohol breath test 
• Physical examination including weight and vital signs, 
• Update current medications (new medications raise the possibility of being 
needed to treat an adverse event),  
• Urine pregnancy test for women of child-bearing potential, 
• Blood sampling for:  
o hematology, 
o clinical chemistry,  
o lipids, 
o liver function biomarkers AST and ALT, if not included in standard 
panel above, 
o glucose metabolism biomarkers (HbA1c, FPG, fasting insulin, and 
fasting C-peptide), if not included in standard panel above, 
o C-reactive protein (high-sensitivity), if not included in panels above, 
o  FFA, ApoA1, ApoB, Lp(a) and LDH, if not included in one of the 
panels above. 
• Urinalysis 
• ECG  
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 29 of 50 
 
• Study drug compliance check 
Adverse changes from Baseline represent an adverse event.   
Participants will again be counseled about proper dietary habits and be discharged from the 
study site, with instructions to return to the study site with their supply of study drug on Day 
27±3.  Fasting is not required for arrival on Visit 2. 
4.2.4 Visit 2 (Final Assessments) 
Participants are to return to the clinic on Study Day 27±3.  The morning dose of study drug will 
have been taken at home.  Participants will be asked to undergo the following:  
• Urine drug screen and an alcohol breath test 
• Physical examination including weight and vital signs, 
• Update current medications (new medications raise the possibility of being 
needed to treat an adverse event),  
• Urine pregnancy test for women of child-bearing potential,  
• ECG  
• Study drug compliance check 
The following day (Day 28±3), participants are to undergo the following in a fasted state: 
• Vital signs 
• Blood sampling for:  
o hematology, 
o clinical chemistry,  
o lipids, 
o liver function biomarkers AST and ALT, if not included in standard 
panel above, 
o glucose metabolism biomarkers (HbA1c, FPG, fasting insulin, and 
fasting C-peptide), if not included in standard panel above, 
o C-reactive protein (high-sensitivity), if not included in panels above, 
o  FFA, ApoA1, ApoB, Lp(a) and LDH, if not included in one of the 
panels above. 
• Urinalysis  
Following the completion of these sample collections, a standardized morning meal is to be 
given to the participants.  The participant will then receive their final dose of study drug, under 
HighTide Biopharma Pty Ltd 
HTD1801
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Final
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30


CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 30 of 50 
 
supervision, and post-dose PK sampling will begin as described in Table 2. A 12-lead ECG is to 
be performed approximately 3 hrs post-dose.   
Participants will be discharged on the morning of Day 29±3 following the 24 hr post-dose PK 
blood sample, collection of vital signs, and AE evaluation, assuming they are considered by the 
investigator to be stable and suitable for discharge.  Participants will be advised to expect and 
be ready for a follow-up phone call from the study site approximately 2 weeks later.  
4.2.5 Follow-up  
A safety follow-up call will be performed by study site personnel on Day 42±3.  At that time, 
the participants will be asked about their general health and be queried for any findings that 
might be considered an adverse event.  Following that call, and assuming there are no adverse 
conditions that require follow-up, participants will be terminated form the study. 
4.3 
Dose Escalation, Study Discontinuation and Stopping Criteria 
4.3.1 Dose Escalation Algorithm 
This trial includes three planned dose escalation cohorts. The doses of HTD1801 to be 
administered are summarized below in Table 4. 
Table 4. Planned Dose Escalation Cohorts 
Cohort 
Number 
Number of 
Participants Planned 
Dose Regimen   
1  
12 
HTD1801:     500 mg/day (250 mg bid) 
4 
Placebo:         2 tablets/day (1 tablet bid) 
2 
12 
HTD1801:     1000 mg/day (500 mg bid) 
4 
Placebo:         4 tablets/day (2 tablets bid) 
3 
12 
HTD1801:     2000 mg/day (1000 mg bid) 
4 
Placebo:         8 tablets/day (4 tablets bid) 
 
4.3.2 Dose Escalation Stopping Criteria 
Participants will stop the study drug if any of the following stopping rules are met: 
• 
Clear toxicity of the study medication or any anaphylaxis. 
• 
Increase in LDL-C more than 3-times compared to baseline. 
• 
Decrease in HDL-C to less than 33% of baseline result. 
• 
ALT or AST increase 3-times above the reference range. 
• Profuse diarrhea, gastroparesis or vomiting. 
• Signs and symptoms of hepatitis. 
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
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•  Two (2) or more of the participants in a cohort experience severe AEs, judged to be at 
least possibly study drug related by the Investigator 
• Fifty percent (50%) or more of the participants experience moderate to severe AEs, 
judged to be at least possibly study drug related by the Investigator 
• Two (2) or more participants develop similar clinically significant laboratory, ECG, or 
vital sign abnormalities, or severe AEs in the same organ class, indicating dose-limiting 
intolerance. Dose escalation could proceed if, after review of the data by the 
Investigator and discussion with Sponsor, it was concluded that the events were not 
drug related. 
4.3.3 Criteria for Early Termination of the Study 
The trial will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the trial. 
• New information or other evaluation regarding the safety or efficacy of the trial 
medication that indicates a change in the known risk/benefit profile for the compound, 
such that the risk/benefit is no longer acceptable for participants participating in the 
trial. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises participant safety. 
• Failure to meet expected enrollment goals. 
• Administrative reasons. 
The Sponsor, Human Research Ethics Committee (HREC), or regulatory authority may elect to 
terminate or suspend the trial or the participation of an investigational site at any time. 
4.3.4 Criteria for Early Termination of Individual Participants 
Participants may withdraw their consent to participate in the trial at any time. 
If a participant withdraws consent, the date and reason for consent withdrawal should be 
documented. Participants will be encouraged to remain in the clinic for safety assessments until 
the Investigator deems that it is safe for the participant to be discharged. Participant data will be 
included in the analysis up to the date of the consent withdrawal. 
• An AE that requires discontinuation at the discretion of the Investigator. 
• Lost to follow-up. The participant did not return to the clinic and attempts to contact the 
participant were unsuccessful. Attempts to contact the participant must be documented. 
• Voluntary withdrawal of consent (mandatory removal from trial). 
• Discretion of Investigator (document reason on the case report form [CRF]). 
• Participant becomes pregnant or begins breastfeeding (mandatory). 
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Final
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 32 of 50 
 
Wherever possible, the tests and evaluations, including those listed for the Follow-up Visit 
should be performed for all participants who discontinue prior to the completion of the trial. 
In the event the Investigator terminates a participant's participation in the study, the Investigator 
must notify the Sponsor of such decision and rationale immediately in writing. In all cases, the 
appropriate HREC and other applicable regulatory authorities shall be informed. 
4.4 
Prohibited Medications 
Use of the agents listed in  Table 5.  (prescription or nonprescription) is prohibited from the 
time points specified until completion of all trial activities. 
 
 Table 5. Prohibited Medications 
Medication or Class 
Indication 
Reason 
From time point 
specified 
Oral anti-diabetic 
medication other than 
metformin (sulfonylurea, 
dipeptidyl peptidase-4 
inhibitor or acarbose). 
Glycemic 
control 
Affect glucose metabolism 
Within 12 weeks prior to 
dosing. 
Thiazolidinedione  
Affect glucose metabolism 
Within 12 weeks prior to 
dosing. 
Glucagon-like-peptide-1 
analogues 
Affect glucose metabolism 
Within 12 weeks prior to 
dosing. 
Omega-3 fatty acids, and 
nicotinic acid or 
derivatives of nicotinic 
acid 
Atherogenic 
plaque and 
prevention of 
atherogenesis  
Affect lipid metabolism and 
bioavailability 
Must be stable at least 12 
weeks prior to dosing. 
 
Systemic corticosteroids. 
Inflammation  
Affect carbohydrate and lipid 
metabolism 
Within 6 weeks prior to 
dosing. 
Fibrates 
Dyslipidemia  
Affect lipid bioavailability 
and distribution 
Within 4 weeks prior to 
dosing. 
Antihypertensives 
Hypertension 
Safety- uncontrolled 
hypertension can increase 
number of AE or SAE. 
Must be stable at least 4 
weeks prior to dosing. 
 
4.5 
Contraception 
Female participants must be non-pregnant and non-lactating, and either surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or 
post-menopausal, abstinent, or if engaged in sexual relations of childbearing potential, must be 
willing to: 
 
1. Use one of the following contraceptive methods for 4 weeks prior to the treatment 
period, for the 4 weeks of the Treatment Period, and for at least 2 weeks after the last 
dose of study drug (total of 10 weeks): 
a. Abstinence from heterosexual intercourse OR  
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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Page 33 of 50 
 
b. Use a highly-effective form of contraception (e.g. hormonal contraception, or an 
intrauterine device) 
AND 
 
2. Use a barrier method (by the female or her sexual partner).  
The adequacy of other methods of contraception will be assessed on a case-by-case basis by the 
Principal Investigator (PI). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
The site will make an effort to retrieve medical records to document sterility. Postmenopausal 
status will be confirmed through testing of FSH levels ≥ 40 IU/mL at screening for amenorrheic 
female participants <55 years of age 
A urine pregnancy test will be performed for female participants at Screening, at the Check-in 
visits for the in-house periods, Day 14, and Day 27.  Serum pregnancy test will be conducted 
when urine pregnancy test is positive at screening. 
Male participants must be surgically sterile, abstinent, or if engaged in sexual relations of 
child-bearing potential, the participant and his partner must be using the contraceptive methods 
described above for the 4 weeks of the Treatment Period, and for at least 2 weeks after the last 
dose of study drug.  
Male participants will be advised not to donate sperm during this period.  
 
4.6 
Dietary Counseling 
Participants will be counseled to follow the healthy eating practices at the time points indicated 
in the SOE. 
At each period, the importance of maintaining the body weight within a 5% range throughout 
the study will be explained. The counseling for each participant will be individualized based on 
their actual measured body weight. Additionally, participants will be counseled to maintain 
their normal diet and exercise regimen. They will be instructed not to start any new diets, 
supplements, or exercise programs during the study, and to avoid overeating and high sodium 
and salt intake on the day before check-in. 
Instructions are based on the US Department of Agriculture’ 2015-2020 key recommendations 
that recommend a healthy eating pattern that accounts for all foods and beverages within an 
appropriate calorie level. 
A healthy eating pattern includes: 
• 
A variety of vegetables from all of the subgroups-dark green, red and orange, legumes 
(beans and peas), starchy, and other 
HighTide Biopharma Pty Ltd 
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
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• 
Fruits, especially whole fruits 
• 
Grains, at least half of which are whole grains 
• 
Fat-free or low-fat dairy, including milk, yogurt, cheese, and/or fortified soy beverages 
• 
A variety of protein foods, including seafood, lean meats and poultry, eggs, legumes 
(beans and peas), and nuts, seeds, and soy products 
• 
Oils 
A healthy eating pattern limits: 
• 
Saturated fats and trans fats, added sugars, and sodium 
Key Recommendations that are quantitative are provided for several components of the diet 
that should be limited. These components are of particular public health concern in the United 
States, and the specified limits can help individuals achieve healthy eating patterns within 
calorie limits: 
• 
Consume less than 10 percent of calories per day from added sugars 
• 
Consume less than 10 percent of calories per day from saturated fats 
• 
Consume less than 2,300 milligrams (mg) per day of sodium 
If alcohol is consumed, it should be consumed in moderation—up to one standard drink per day 
for women and up to two standard drinks per day for men. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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35


CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 35 of 50 
 
5. STUDY MATERIALS 
5.1 
Investigational Products 
5.1.1 HTD1801 
Study drug will be provided by the Sponsor in the form of film-coated tablets suitable for oral 
administration, with each tablet containing either 250 mg of HTD1801 or placebo. The study 
drug should be taken with 240 mL of water. There are no particular post-dose fasting 
requirements or water restrictions.  
5.1.2 Placebo 
The placebo is identical in appearance to the active HTD1801. Within each cohort the number 
of tablets of placebo will be the same as the number of tablets of active study drug. 
5.2 
Packaging, and Labeling of Investigational Products 
The Sponsor will provide the Investigator with the labeled study drug in accordance with 
specific country regulatory requirements.  When a participant is enrolled, a pre-randomized kit 
will be dispensed to the participant. 
5.3 
Storage and Drug Accountability of Investigational Products 
All study drug should be stored in a monitored 2-8oC refrigerator in the original containers.  
Containers should be kept tightly closed and should not be exposed to moisture, excessive heat 
or direct sunlight. 
The study staff are required to document the receipt, dispensing, and return/destruction of study 
drugs and supplies provided by or on behalf of the Sponsor. At the end of the trial, the study site 
must return all unused study drug and unopened containers to the Sponsor or designee, or 
destroy them upon request. The study drug supplies will be counted and reconciled at the site 
before being returned to the Sponsor or designee, or being destroyed. 
Investigational product taken home for the outpatient period should be stored in a refrigerator.  
The participants do not have to maintain refrigeration during daily transportation or for the 
duration of a day or weekend trip, provided the drug product is kept away from sources of 
excessive heat (e.g., not left out in the sun or in a non-air-conditioned vehicle, etc.). 
No study drugs may be dispensed to any person not enrolled in the trial.  
Treatment compliance will be monitored using standard methods including but not limited to: 
drug PK measurements, drug accountability assessments (i.e., pill counting), and any other 
methods deemed appropriate for this trial. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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22 July 2019
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 36 of 50 
 
6. ADVERSE EVENTS 
6.1 
Definitions 
6.1.1 Adverse Event 
An AE is any undesirable and unintended medical event occurring to a participant in a clinical 
trial, whether or not related to the study products. This includes events from the first study 
related activity after the participant has signed the informed consent and until post treatment 
follow-up period as defined in the protocol. The following should not be recorded as AEs, if 
recorded as medical history/concomitant illness on the CRF at screening: 
• Pre-planned procedure, unless the condition for which the procedure was planned has 
worsened from the first study related activity after the participant has signed the informed 
consent. 
• Pre-existing conditions found as a result of screening procedures. 
• Pre-existing events that have not worsened in intensity or frequency from baseline. 
6.1.2 Treatment Emergent Adverse Event 
A treatment-emergent AE (TEAE) is defined as any clinically significant event not present 
before exposure to study drug or any event already present that worsens in either intensity or 
frequency after exposure to study drug. 
6.1.3 Clinical Laboratory Event 
A clinical laboratory AE is any clinically significant laboratory abnormality that suggests a 
disease and/or organ toxicity and is of a severity, which requires active management, (i.e. 
change of dose, discontinuation of investigational study product, more frequent follow-up or 
diagnostic investigation). 
A laboratory re-test and/or continued monitoring of an abnormal value is not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention. 
6.1.4 Serious Adverse Event (SAE) 
An SAE is defined as any untoward medical occurrence that at any dose 
• Results in death 
• Is life threatening. The term “life threatening” refers to an event in which the participant 
was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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22 July 2019
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     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 37 of 50 
 
• Results in persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• Is an important medical event that satisfies any of the following: 
• 
May require intervention to prevent items 1 through 5 above. 
• 
May expose the participant to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
6.1.5 Severity of AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient, easily tolerated by the participant and does not affect 
the participant’s daily activities. 
Moderate: 
The event causes the participant discomfort and interrupts the participant’s 
usual daily activities. 
Severe: 
The event is incapacitating and causes considerable interference with the 
participant’s usual activities. 
6.1.6 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
 
Not related:  
The event is clearly related to other factors such as the participant’s 
clinical state, therapeutic interventions or concomitant drugs 
administered to the participant.  This is especially so when an event 
occurs prior to the commencement of treatment with the IP. 
Unlikely:   
The event was most likely produced by other factors such as the 
participant’s clinical state, therapeutic interventions, or a concomitant 
drug administered to the participant and does not follow a known 
response to the IP, although a causal relationship cannot be ruled out. 
Possible: 
The event follows a reasonable temporal sequence from the time of IP 
administration or follows a known response to the IP but could have 
been produced by other factors such as the participant's clinical state, 
other therapeutic interventions, or concomitant drugs administered to the 
participant. 
Probable: 
The event follows a reasonable temporal sequence from the time of IP 
administration and follows a known response to the IP and cannot be 
reasonably explained by other factors such as the participant's clinical 
state, other therapeutic interventions, or concomitant drugs administered 
to the participant. 
 
 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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22 July 2019
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 38 of 50 
 
6.2 
Recording and Reporting Procedures 
6.2.1 Collection and Recording of AEs 
Collection of all AEs (serious and non-serious) will commence from the time the participant 
signs the informed consent to participate in the study. At each study visit or Study Day, the 
Investigator or designee will assess whether any AEs have occurred. In order to avoid bias in 
eliciting adverse events, a non-specific question, such as “How have you been feeling since 
your last visit?” may be asked. Participants may report AEs occurring at any other time during 
the study. 
All participants experiencing AEs, whether considered associated with the use of the study 
medication or not, should generally be monitored until the symptoms subside, any clinically 
relevant changes in laboratory values have returned to baseline, or until there is a satisfactory 
explanation for the changes observed. All AEs will be documented in the AE eCRF, whether or 
not the Investigator concludes that the event is related to the drug treatment. The event term, 
start and stop dates and severity, action taken with study drug, outcome, will be documented, 
along with the Investigator’s opinion of the causal relationship between the event and the study 
drug.  
6.2.2 Collection and Reporting of SAEs 
The Sponsor has a legal responsibility to notify the appropriate regulatory authorities about the 
safety of the IMP. Accordingly, the Investigator must report all SAEs, regardless of presumed 
causal relationship, to the sponsor’s assigned safety representative (INC Research Safety & 
Pharmacovigilance), by fax or email on a SAE Form within 24 hours of learning of the event. 
INC Research Safety & Pharmacovigilance will forward the information to the Sponsor with 
preliminary review and assessment comments.  
INC Research Safety & Pharmacovigilance fax/email details: 
Attention: INC Research Safety & Pharmacovigilance 
Local Toll-Free Fax (Australia):  
1800 256 952 
Alternate (Global) Fax:  
+1 877 464 7787 
Email: INCDrugSafety@incresearch.com  
For medical emergencies contact: 
Dr. David Fuller (Medical Monitor), phone: +61 (0) 450 965 709  
Information on SAEs will be recorded on a SAE Form. Blank copies are included in the study 
Investigator’s File.  It is not acceptable for the Investigator to send photocopies of the subjects’ 
medical records to INC Research Safety & Pharmacovigilance in lieu of completion of the 
appropriate AE CRF page and / SAE Form. However, there may be instances when copies of 
medical records for certain cases are requested by INC Research Safety & Pharmacovigilance. 
In this instance, all subject identifiers will be blinded on the copies of the medical records prior 
to submission. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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22 July 2019
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 39 of 50 
 
The completed SAE Form and SAE Fax Cover Sheet should be sent via fax or email 
immediately upon completion to the Sponsor’s assigned safety representative (INC Research 
Safety & Pharmacovigilance).  Additional relevant information or clinical follow-up should be 
sent via fax or email to the Sponsor through INC Research Safety & Pharmacovigilance as soon 
as it becomes available. The Investigator should follow up the event until resolution or 
stabilization of the condition. Follow-up reports (as many as required) should be completed and 
faxed following the same procedure above. 
A final report is required in any case once the condition is resolved or stabilized and no more 
information about the event is expected. The final report should be completed and faxed or 
emailed following the same procedure above. 
All pregnancies in a female subject or in a female partner of a male study subject should be 
reported on a Pregnancy Report Form following the same reporting process and timelines 
required for SAEs. 
The Investigator must keep a copy of all documentation related to the event in the site’s study 
files. 
If the Investigator learns of any SAE, including death, at any time after a subject completes the 
study, and he/she considers the event reasonably related to the IMP, the Investigator will 
promptly notify the Sponsor (through INC Research Safety & Pharmacovigilance) and the 
Medical Monitor. This shall include pregnancy in a female subject or in a female partner of a 
male study subject. 
When an SAE occurs, it should be reported according to the following procedure: 
An SAE form must be completed immediately or within 24 hours of first onset or notification of 
the event. The information should be completed as fully as possible but contain, at a minimum a 
short description of the event and the reason why the event is categorized as serious, participant 
identification number, Investigator’s name, name of the study medication and a causality 
assessment. 
The collection of SAEs will begin after the participant signs the informed consent form and will 
stop at the end of the participant’s follow-up period. 
6.3 
Anticipated Adverse Events 
Anticipated adverse events are primarily gastrointestinal in nature, and mild-to-moderate in 
severity. 
6.4 
Follow-up of Adverse Events and Serious Adverse Events 
All adverse events should be followed until resolution, or until the Investigator and Sponsor 
conclude that further follow-up is not necessary. 
If information on SAEs is not available at the time of the first report and becomes available at a 
later date, the Investigator should provide that information to the Sponsor within 24 hours of 
receipt of the information. Copies of any relevant data from the hospital notes, which may or 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 40 of 50 
 
may not include ECGs, laboratory tests, discharge summary and/or postmortem results, should 
be sent accordingly.  The Sponsor or designated qualified vendor will be responsible for all 
reporting to regulatory authorities. 
6.5 
Safety Monitoring Committee 
The Safety Monitoring Committee (SMC) is expected to consist of  
• the Principal Investigator (PI) at each site,  
• an independent local INC Medical Monitor,  
• others as may be requested by the Principal Investigator.  
The members of SMC will review the safety data before the decision is made to advance to the 
next dose cohort. 
 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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22 July 2019
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 41 of 50 
 
7. DATA HANDLING AND MANAGEMENT 
7.1 
Data Management 
The full details of procedures for data handling will be documented in the Data Management 
Plan (DMP). 
AEs and medical history will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Concomitant medications will be coded using the World 
Health Organization (WHO) Drug Dictionary Enhanced (DDE). The MedDRA version used 
will be recorded in the Study Master File documentation. 
Unique numbers will identify the participant and the biological material obtained from the 
participant. Appropriate measures such as encryption or deletion will be enforced to protect the 
identity of human participants in all presentations and publications as required by 
local/regional/national requirements. 
Data from screening failures will not be entered into the database. 
Laboratory data from the central laboratory will be electronically transferred to INC Research 
for database reconciliation purposes. The electronic laboratory data will be considered source 
data. In cases where sensitive non-PK laboratory data is transferred via non-secure electronic 
networks, data will be encrypted during transfer. 
All other results, including PK, PD data, and laboratory tests will be transferred electronically 
to the responsible Data Management Unit.  
7.2 
CRFs (Electronic) 
7.2.1 Clinical Data Management Workflow 
eCRFs will be developed by appropriate personnel, in collaboration with the clinical trial team 
and statistician. Those responsible for data management will document the process workflow in 
the Data Management Plan (DMP). After data entry, monitor(s) will source data verify (SDV) 
the eCRFs against the source documents. Queries may be issued to clarify the data entered. The 
PI will electronically sign the eCRFs after all data have been entered and all queries have been 
resolved. If corrections and/or resolution of queries are required after Investigator approvals, 
those eCRFs affected by changes will be re-signed by the PI. The database may be locked after 
the PI approvals are completed. 
The Investigator will receive all laboratory data electronically or based on FAX reports directly 
from the laboratory. An Investigator must review, evaluate, sign, and date the laboratory reports 
upon receipt. 
After database lock, CDM study design documentation and locked eCRFs (PDF) will be 
created and will be provided to the Sponsor, if requested. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 42 of 50 
 
7.2.2 Data Entry of Electronic Case Report Forms 
Data required for analyses and participant safety assessments will be entered from source 
documentation into eCRFs. Instructions for data entry will be provided in the eCRF Completion 
Guidelines, developed by the local sponsor’s Data Management Department. All site staff 
involved with entering data into the eCRFs will be trained prior to gaining access to the study 
database. 
7.2.3 Corrections to Electronic Case Report Forms 
Queries may be generated by the eCRF system during data entry, and queries may be generated 
by data management personnel, staff, monitors, PIs, the Sponsor, and other data reviewers 
during the course of the study. Only specific site personnel will be authorized to make 
corrections to the eCRFs with the permission of the Investigator. Corrections will be made 
directly in the eCRF – by modifying existing data, adding new data, or deleting data, as 
appropriate. All data corrections will be logged in the electronic audit trail. 
7.2.4 Investigator Approval of Electronic Case Report Form Data 
The Investigator or Investigator’s authorized staff must ensure that all information derived from 
source documentation is consistent with the source information and accurately reflected in the 
eCRFs. By electronically signing the eCRFs, the Investigator confirms that the information is 
complete and correct. 
7.3 
Retention of Documents 
Participant notes must be kept for the maximum period permitted by the hospital, institution, or 
private practice. Other source documents and the Investigator’s Trial File must be retained for 
at least 15 years or longer in accordance with local regulation. 
The Investigator must agree to archive the documentation pertaining to the trial in an archive 
after completion or discontinuation of the trial if not otherwise notified. The Investigator should 
not destroy any documents without prior permission from the Sponsor. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 43 of 50 
 
8. STATISTICAL METHODS 
8.1 
Statistical and Analytical Plans 
The data will be summarized in tables by 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 tests will be two-sided with an alpha (α) level of 0.05. 
8.2 
Sample Size Calculation 
For the current study, the sample size for the safety evaluation was determined based on 
experience from typical initial clinical safety studies. Sufficient number of participants will be 
enrolled to assess safety at a given dose level such that decisions can be made to escalate to the 
next dose level.  This study is not intended to show statistical differences of treatment effects 
between groups. 
8.3 
Analysis Population 
The following populations will be used to summarize and analyze the study data. 
• Safety Population: Includes all participants who received at least one dose of study drug or 
placebo.    
• Efficacy Population:  Includes all participants who received at least one dose of study drug 
or placebo, and had at least one post-dose assessment for the various secondary endpoints.    
• PK Population:  Includes all participants who received active drug (HTD1801) and have 
sufficient data to calculate the PK parameters for UDCA and/or BBR. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 44 of 50 
 
9. QUALITY CONTROL AND QUALITY ASSURANCE 
9.1 
Monitoring 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol and GCP are followed, CRFs are completed correctly, and drug 
accountability is monitored. The Monitor will visit the study site at least once before First 
Participant First Visit (FPFV) (Initiation Visit), at least once during the clinical part of the 
study, and at least once after Last Participant Last Visit (LPLV). Furthermore, the Monitor must 
be available for discussions by telephone.  
The Monitor must be given direct access to source documents, such as original documents, 
data, and records. Direct access includes permission to examine, analyze, verify and reproduce 
any record(s) and report(s) that are important to evaluation of the clinical trial. The study will be 
monitored to verify integrity and validity of the data. Monitoring will follow a Monitoring Plan. 
9.2 
Protocol Deviations 
The Investigator must not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study participants. Should other circumstances arise that will require 
deviation from protocol-specified procedures, the Investigator is directed to contact the 
Sponsor in advance to review and discuss the implications of the deviation and determine the 
appropriate course of action. The Investigator is not otherwise authorized to deviate from the 
protocol without Sponsor permission, and with notification sent to the HREC. Any deviation 
must be documented, stating the reason and date, the action taken, and the impact for the 
participant and/or the study. The documentation must be kept in the Investigator’s Study File 
and the Sponsor’s Study Master File. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 45 of 50 
 
10. ETHICAL ASPECTS OF THE STUDY 
This study will be conducted in accordance with the principles that have their origin in 
the Declaration of Helsinki (World Medical Association), the International Conference on 
Harmonization (ICH) Guideline for Good Clinical Practice (GCP) Guidance E6, and all other 
applicable regulatory requirements. 
10.1 
Institutional Review Board and/or Independent Ethics Committee 
Prior to commencement of the study, the protocol, any amendments, participant 
information/informed consent form, any other written information to be provided to the 
participant, participant recruitment procedures, information about payments and compensation 
available to participants if not mentioned in the participant information, the Investigator’s 
current curriculum vitae (CV) and/or other documentation evidencing qualifications, and other 
documents as required by the local HREC should be submitted. Written approval/favorable 
opinion must be obtained from HREC prior to commencement of the clinical trial. 
During the trial, the Investigator must promptly report the following to the HREC: Updates to 
the Investigator’s Brochure (IB), unexpected SAEs where a causal relationship cannot be ruled 
out, substantial amendments to the protocol, non-substantial amendments, deviations to the 
protocol implemented to eliminate immediate hazards to the participants, new information that 
may affect adversely the safety of the participants or the conduct of the study (including new 
risk/benefit analysis in case it will have an impact on the planned follow-up of the participants), 
annually written summaries of the study status and other documents as required by the local 
HREC. 
Substantial amendments must not be implemented before approval, unless necessary to 
eliminate hazards to the participants. 
The Investigator must maintain an accurate and complete record of all submissions made to the 
HREC. The records should be filed in the Investigator’s Trial File and copies must be provided 
to the Sponsor.  
10.2 
Informed Consent 
Once signed, the original informed consent form, participant authorization form (if applicable), 
and participant information sheet (if applicable) will be stored in the Investigator’s site file. The 
Investigator must document the date the participant signs the informed consent in the 
participant’s medical record. Copies of the signed informed consent form, the signed 
participant authorization form (if applicable), and participant information sheet (if applicable) 
shall be given to the participant. 
All revised informed consent forms must be reviewed and signed by relevant participants or the 
relevant participant’s legally acceptable representative in the same manner as the original 
informed consent. The date the revised consent was obtained should be recorded in the 
participant’s medical record, and the participant should receive a copy of the revised informed 
consent form. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 46 of 50 
 
10.3 
Participant Confidentiality 
The Sponsor and designees affirm and uphold the principle of the participant’s right to 
protection against invasion of privacy. Throughout this study, a participant’s source data will 
only be linked to the Sponsor’s clinical study database or documentation via a unique 
identification number. As permitted by all applicable laws and regulations, limited participant 
attributes, such as sex, age, or date of birth, and participant initials may be used to verify the 
participant and accuracy of the participant’s unique identification number. 
The Investigator must agree to permit the Sponsor’s monitor or designee’s monitor, 
representatives from any regulatory authority, the Sponsor’s designated auditors, and the 
HREC to review the participant’s source data or documents, including, but not limited to, 
laboratory test result reports, ECG reports, admission and discharge summaries for hospital 
admissions occurring during a participant’s study participation, and autopsy reports. Access to 
a participant’s original medical records requires the specific authorization of the participant as 
part of the informed consent process. Copies of any participant source documents that are 
provided to the Sponsor must have certain personally identifiable information removed. 
 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 47 of 50 
 
11. PUBLICATION, DISCLOSURE, AND CLINICAL TRIAL REGISTRATION 
POLICY 
The Investigator will provide the Sponsor with complete test results and all data derived by the 
Investigator from the study. During the study, only the Sponsor may make study information 
available to other study Investigators or to regulatory agencies, except as required by law or 
regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the 
Sponsor. 
All publications and presentations must be prepared in accordance with this section and the 
Master Services Agreement or equivalent agreement. In the event of any discrepancy between 
the protocol and the Master Services Agreement or equivalent agreement the Master Services 
Agreement or equivalent agreement will prevail. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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This document is confidential.
48


CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 48 of 50 
 
12. REFERENCES 
Dong et al. 2013 
Dong H, Zhao Y, Zhao L, Lu F. (2013). The Effects of Berberine on Blood Lipids: A Systemic 
Review and Meta-analysis of Randomized Controlled Trials. Planta Med. 79(6):437-46. 
Doi:10.1055/s-0032-1328321. 
Lan et al. 2015 
Lan J, Zhao Y, Dong F, Yan Z, Zheng W, Fan J, Sun G. (2015). Meta-Analysis of the Effect and 
Safety of Berberine in the Treatment of Type 2 Diabetes Mellitus, Hyperlipidemia, and 
Hypertension. J. Ethnopharmacol. 161:69-81. doi:10.1016/j.jep.2014.09.049. 
Mitchell et al. 2016 
Mitchell S, Roso S, Samuel M, Pladevall-Vila M. Unmet Need in the Hyperlipidemia 
Population with High Risk of Cardiovascular Disease: A Targeted Literature Review of 
Observational Studies. BMC Cardiovasc Disord. 16:74. doi:10.1186/s12872-016-0241-3. 
NCEP 2002 
National Cholesterol Education Program, National Heart, Lung, and Blood Institute, National 
Institute of Health (2002). Third Report of the National Cholesterol Education Program Expert 
Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult 
Treatment 
Panel 
III). 
(Report 
No. 
02-5215). 
Retrieved 
from: 
http://circ.ahajournals.org/content/106/25/3143  
Nelson 2013 
Nelson RH. (2013). Hyperlipidemia as a Risk Factor for Cardiovascular Disease. Prim Care. 
40(1):1995-211. doi:10.1016/j.pop.2012.11.003. 
Rosei and Salvetti 2016 
Rosei EA and Slavetti M. (2016). Management of Hypercholesterolemia, Appropriateness of 
Therapeutic Approaches and New Drugs in Patients with High Cardiovascular Risk. High 
Blood Press Cardiovasc Prev. 23(3):217-230. doi: 10.1007/s4029*2-016-0155-2. 
Singh and Mahajan 2013 
Singh IP and Mahajan S. (2013). Berberine and its Derivatives: A Patent Review (2009-2012). 
Expert Opin Ther Pat. 23(2):215-31. doi: 10.1517/13543776.2013.746314. 
Tavori et al. 2016 
Tavori H, Giunzioni I, and Fazio S. (2016). PCSK9 Inhibition to Reduce Cardiovascular 
Disease Risk: Recent Findings from the Biology of PCSK9. Curr Opin Endocrinol Diabetes 
Obes. 22(2):126-132. doi: 10.1097/MED.0000000000000137. 
Zhu et al. 2015 
Zhu GQ, Shi KQ, Huang S, Huang GQ, Lin YQ, Zhou ZR, Braddock M, Chen YP, Zheng MH. 
(2015). Network Meta-Analysis of Randomized Controlled Trials: Efficacy and Safety of 
UDCA-Based Therapies in Primary Biliary Cirrhosis. Medicine (Baltimore). 94(11):e609. 
doi:10.1097/MD.0000000000000609. 
HighTide Biopharma Pty Ltd 
HTD1801
1801.PCT004
Final
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49


CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
Page 49 of 50 
 
13. APPENDICES 
13.1 
Principal Investigator Compliance Statements 
 
 
 
 
 
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This document is confidential.
50


CONFIDENTIAL 
 
     Phase 1b/2a Trial of HTD1801 in Hypercholesterolemia 
HighTide Biopharma Pty Ltd 
Protocol 1801.PCT004 
19 January 2018 
                   HTD1801 Tablets 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained  
                                   herein is strictly prohibited without written consent from HighTide Biopharma Pty Ltd.       
            
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Principal Investigator Compliance Statement 
 
 
The Principal Investigator agrees to conduct the trial as outlined in this protocol with reference 
to international/national/local regulations and in accordance with current Good Clinical 
Practice (GCP) guidelines, and the current version of the Declaration of Helsinki. Any 
modification to the protocol must be agreed upon in advance by both the Investigator and 
HighTide Biopharma Pty. Ltd., and documented in writing. By written agreement to this 
protocol, the Investigator approves of the protocol and agrees to allow direct access to all 
documentation, including source data, to authorized individuals representing HighTide 
Biopharma Pty. Ltd., (including monitoring staff and auditors), to Human Research Ethics 
Committees (HREC), and/or to regulatory authorities. 
 
Name:  
 
 
Title: Principal Investigator 
Facility/Institution: 
 
 
Telephone: 
 
 
Fax: 
 
 
 
E-mail: 
 
 
 
Signature: ____________________________________________  Date: _____________               
  
 
 
 
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SAP_001.pdf: 
Statistical Analysis Plan 
 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
Syneos Health 
Page 1 of 34 
 
Sponsor Name: 
HighTide Biopharma Pty Ltd 
Protocol Number and Title: 
 
1801.PCT004 
A Randomized, Double Blind, Placebo Controlled, 
Multicenter, Multiple Ascending Dose Study to 
Evaluate the Safety and Tolerability of HTD1801 in 
Adults with Hypercholesterolemia 
Protocol Version and Date: 
1.0, 12 Dec 2017 
2.0, 9 May 2019 
 
Syneos Health Project Code: 
1010353A 
Authors: 
Catlin Wei 
Biostatistician, Syneos Health 
Petya Slavova 
Senior Biostatistician, Syneos Health 
Philip Lavin PhD, FASA, FRAPS 
Senior Biostatistician, Boston Biostatistics Research 
Foundation  
 
SAP Version: 
Final Version 2.0 
SAP Version Date:  
9 May 2019 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to HighTide Biopharma Pty Ltd. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein will 
be published or disclosed without prior written authorization from an official of HighTide Biopharma Pty 
Ltd.  However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the condition that they 
are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, Syneos 
Health should be notified promptly. 
\ ) 
Syneos. 
Hea lth 


Statistical Analysis Plan 
HighTide Biopharma Pty Ltd Protocol # 1801.PCT004 
Final Version 2.0 
Syneos Health # 1010353A 
 
This document is proprietary and confidential to Syneos Health 
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Revision History 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
Final Version 1.0 
16-Jan-2019 
Syneos Health 
Initial Release Version 
Final Version 2.0 
09-May-2019 
Boston Biostatistics 
Research Foundation 
Updated following Results 
Review Meeting 
 
 


Statistical Analysis Plan 
Final Version 2.0 
HighTide Biopharma Pty Ltd Protocol# 1801.PCT004 
Syneos Health # 1010353A 
1 confirm that I have reviewed this document and agree with the content. 
APPROVALS 
Bnston Biostatistics Research Foundation 
Philip Lavi PhD, FASA, FRAPS 
Senior Bios atistician 
Sponsor Contact 
Bao-Van Linberg, MS 
Director, Clinical Development 
ffiohTide Bio harma Pty Ltd 
23-MAY-2019 
Date (dtl-i\lmm-yyyy) 
03.007A.03 
This document is proprietary and confidential to Syneos Health 
Syneos Health 
Page 3 of 34 


Statistical Analysis Plan 
HighTide Biopharma Pty Ltd Protocol # 1801.PCT004 
Final Version 2.0 
Syneos Health # 1010353A 
 
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Page 4 of 34 
TABLE OF CONTENTS 
Contents 
 
GLOSSARY OF ABBREVIATIONS ................................................................. 7 
 
PURPOSE ......................................................................................................... 9 
 
Responsibilities ...................................................................................................................... 9 
 
Timings of Analyses ............................................................................................................... 9 
 
STUDY OBJECTIVES .................................................................................... 10 
 
Primary Objective ................................................................................................................ 10 
 
Secondary Objectives ........................................................................................................... 10 
 
Brief Description .................................................................................................................. 11 
 
Subject Selection .................................................................................................................. 12 
 
Inclusion Criteria .......................................................................................................... 12 
 
Exclusion Criteria ......................................................................................................... 12 
 
Determination of Sample Size ............................................................................................... 14 
 
Treatment Assignment ......................................................................................................... 14 
 
Administration of Study Medication ..................................................................................... 14 
 
ANALYSIS POPULATIONS ........................................................................... 16 
 
Randomized Population ....................................................................................................... 16 
 
Safety Population ................................................................................................................. 16 
 
Efficacy Population .............................................................................................................. 16 
 
Pharmacokinetic Population ................................................................................................. 16 
 
Protocol Deviations .............................................................................................................. 16 
 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................. 17 
 
General Methods .................................................................................................................. 17 
 
Key Definitions ..................................................................................................................... 17 
1. 
2. 
2.1. 
2.2. 
3. 
3.1. 
3.2. 
3.3. 
3.4. 
3.4.1. 
3.4.2. 
3.5. 
3.6. 
3.7. 
4. 
4.1. 
4.2. 
4.3. 
4.4. 
4.5. 
5. 
5.1. 
5.2. 


Statistical Analysis Plan 
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Missing Data ........................................................................................................................ 18 
 
Visit Windows ...................................................................................................................... 18 
 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ................................................................................................ 19 
 
Subject Disposition and Withdrawals ................................................................................... 19 
 
Demographic and Other Baseline Characteristics ................................................................. 19 
 
Medical History .................................................................................................................... 19 
 
Other Baseline Characteristics ............................................................................................. 19 
 
Medication ........................................................................................................................... 19 
 
Prior Medication ........................................................................................................... 20 
 
Concomitant Medication ................................................................................................ 20 
 
SAFETY .......................................................................................................... 21 
 
Extent of Exposure ............................................................................................................... 21 
 
Treatment Compliance ......................................................................................................... 21 
 
Adverse Events ..................................................................................................................... 21 
 
Laboratory Evaluations ........................................................................................................ 22 
 
ANALYSIS OF PHARMACODYNAMICS ...................................................... 23 
 
Lipid Metabolism ................................................................................................................. 23 
 
Glucose Metabolism ............................................................................................................. 23 
 
Markers of Liver Function ................................................................................................... 24 
 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ............................. 25 
 REFERENCE LIST ......................................................................................... 27 
 PROGRAMMING CONSIDERATIONS ......................................................... 28 
 
General Considerations ........................................................................................................ 28 
 
Table, Listing, and Figure Format ........................................................................................ 28 
 
General ........................................................................................................................ 28 
 
Headers ........................................................................................................................ 28 
 
Display Titles ............................................................................................................... 29 
5.3. 
5.4. 
6. 
6.1. 
6.2. 
6.3. 
6.4. 
6.5. 
7. 
6.5.1 . 
6.5.2. 
7.1. 
7.2. 
7.3. 
7.4. 
8. 
8.1. 
8.2. 
8.3. 
9. 
10. 
11. 
11.1. 
11.2. 
11.2.1. 
11.2.2. 
11.2.3. 


Statistical Analysis Plan 
HighTide Biopharma Pty Ltd Protocol # 1801.PCT004 
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Column Headers ........................................................................................................... 30 
 
Body of the Data Display ............................................................................................... 30 
 
Footnotes ...................................................................................................................... 32 
 QUALITY CONTROL .................................................................................... 33 
 APPENDICES ................................................................................................. 34 
 
 
 
 
11.2.4. 
11.2.5. 
11.2.6. 
12. 
13. 


Statistical Analysis Plan 
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Final Version 2.0 
Syneos Health # 1010353A 
 
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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ApoA1 
Apolipoprotein A-1 
ApoB 
Apolipoprotein B 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BBR 
Berberine 
bid or b.i.d 
Twice per day 
BMI 
Body Mass index 
CI 
Confidence Interval 
Cmax 
Maximum concentration 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
ECG 
Electrocardiogram 
FPG 
Fasting plasma glucose 
G6PD 
Glucose-6-Phosphate Dehydrogenase 
HbA1c 
Glycosylated hemoglobin 
HDL-C 
High Density Lipoprotein Cholesterol 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
LDL-C 
Low Density Lipoprotein Cholesterol 
LLN 
Lower Limit of Normal 
Lp(a) 
Lipoprotein(a) 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
N/A 
Not Applicable 
NEFA 
Non-Esterified Fatty Acid (synonymous with FFA) 
1. 


Statistical Analysis Plan 
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Abbreviation 
Description 
NYHA 
New York Heart Association 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred Term 
QTc 
Corrected QT Interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
t1/2 
half-life 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Table, Listing and Figure 
Tmax 
Time to maximum serum concentration 
Tmin 
Time to minimum serum concentration  
TSH 
Thyroid-stimulating hormone 
UDCA 
Ursodeoxycholic acid 
ULN 
Upper limit of normal 
WHODrug 
World Health Organization Drug Dictionary 
WNL 
Within Normal Limits 
 


Statistical Analysis Plan 
HighTide Biopharma Pty Ltd Protocol # 1801.PCT004 
Final Version 2.0 
Syneos Health # 1010353A 
 
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PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables 
and figures which will be produced, and the statistical methodologies that will be used, are 
complete and appropriate to allow valid conclusions regarding the study objectives. 
 
RESPONSIBILITIES 
Syneos Health will perform statistical analyses and are responsible for the production and quality 
control of all tables, figures and listings pre-defined in SAP Version 1.0.  Boston Biostatistics 
Research Foundation will perform statistical analyses and are responsible for the production and 
quality control of additional post-hoc tables, figures and listings defined in SAP Version 2.0. 
Pharmacokinetic (PK) analysis will be carried out by HighTide Biopharma Pty Ltd and will be 
documented in a separate file. External vendor (TetraQ) will conduct the PK analysis using the 
concentration data on behalf of the Sponsor. The vendor will prepare a separate SAP for that 
purpose. 
 
TIMINGS OF ANALYSES 
The primary analysis of safety and tolerability and pharmacodynamics is planned after all subjects 
complete the final study visit or terminate early from the study. 
2. 
2. 1. 
2.2. 


Statistical Analysis Plan 
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STUDY OBJECTIVES 
 
PRIMARY OBJECTIVE 
The primary objective for this study is to assess the safety and tolerability of multiple ascending 
dose levels of HTD1801 in participants with hypercholesterolemia. 
 
SECONDARY OBJECTIVES 
There are four secondary pharmacokinetic (PK)/pharmacodynamic (PD) objectives for this trial. 
1) To assess the PK profile of HTD1801 after repeat doses as assessed by derived PK 
parameters including but not limited to: 
• 
Plasma half-life of HTD1801 components (t1/2) 
• 
Maximum plasma concentration of HTD1801 components (Cmax) 
• 
Minimum plasma concentration of HTD1801 components (Cmin) 
• 
Time to Cmax (Tmax) 
• 
Time to Cmin (Tmin) 
2) To determine the effects of HTD1801 on lipid metabolism: 
• 
Fasting lipid metabolism and atherogenic biomarkers as assessed by actual values and 
change from baseline of: 
o Low-density lipoprotein-C (LDL-C) 
o Non-high-density lipoprotein-C (non-HDL-C) 
o Total cholesterol (TC), HDL-C, and TC/HDL-C ratio 
o Apolipoprotein B (ApoB) and A-1 (ApoA1) 
o Triglycerides and non-esterified fatty acid (NEFA) 
o Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) 
o C- reactive protein (CRP) measured using a high-sensitivity assay 
o Lipoprotein(a) [Lp(a)] 
3) To determine the effects of HTD1801 glucose metabolism: 
3. 
3.1. 
3.2. 


Statistical Analysis Plan 
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Final Version 2.0 
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• 
Glycosylated hemoglobin (HbA1c) levels 
• 
Markers of fasting glucose metabolism as assessed by actual values and change from 
baseline of: 
o Fasting plasma glucose (FPG) 
o Fasting serum insulin 
o C-peptide 
4) To determine the effects of HTD1801 on markers of liver function 
• 
Actual values and change from baseline in Alanine aminotransferase (ALT) and 
Aspartate aminotransferase (AST) 
 
BRIEF DESCRIPTION 
This is a randomized, double-blind, placebo controlled, multicenter, multiple ascending dose 
(MAD) study with the primary objective of evaluating the safety and tolerability of HTD1801 in 
overweight to obese participants with hypercholesterolemia. 
There are three planned dose escalation cohorts. Each cohort will consist of 16 participants, 
randomized 3:1 to receive either HTD1801 or placebo. The three planned cohorts may enroll up to 
48 participants. Participants who withdraw from the trial may be replaced following consultation 
with the Sponsor. The cohorts will be enrolled sequentially. The ascending dose cohort may be 
initiated once it has been established that HTD1801 is well-tolerated at the previous dose, 
independent of preliminary efficacy findings. 
Participants in each cohort will participate in a Screening Visit, two 2-day in-house visits separated 
by a 4-week Outpatient Period (includes one Out-Patient Visit), and one Follow-up telephone 
contact. Eligible participants who are currently taking anti-dyslipidemia medications must consent, 
with approval of their physician, to discontinue these medications and undergo a Washout Period, 
prior to completion of screening and participating in the trial. 
The washout period is at least 4 weeks prior to dosing. 
During the first in-house Visit 1, participants will undergo baseline glucose and lipid metabolic 
assessments on the day prior to dosing, receive their first dose of study drug on Day 1, and undergo 
post-dosing safety monitoring. On Day 2 the participants will receive their second dose of study 
medication in the morning, and receive dietary counseling and instruction for taking study drug 
during the Outpatient Period. 
The Outpatient Period will last for approximately 3 weeks. There will be one outpatient visit during 
this period, on Day 14 (±3 days), to obtain samples for PK, glucose and lipid metabolism 
biomarkers, liver function biomarkers, vital signs, safety evaluations and to review treatment 
compliance. 
3.3. 


Statistical Analysis Plan 
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The second in-house Visit 2 will begin on Day 27 (±3 days), followed by discharge on the morning 
of Day 29 (±3 days). During this period participants will undergo evaluations for PK, glucose and 
lipid metabolism biomarkers, liver function biomarkers, vital signs, safety evaluations and to 
review treatment compliance, post-dosing metabolic assessments. A safety Follow-up phone call 
will occur on Day 42±3. The trial is expected to take approximately ten weeks for each participant 
from Screening through Follow-up. 
Each in-house visit is expected to last approximately 2 days. 
 
SUBJECT SELECTION 
This trial will be performed in overweight to obese participants with hypercholesterinemia. 
 Inclusion Criteria 
Participants meeting all the following criteria will be eligible to participate in this trial: 
1) Have given written informed consent 
2) Males or females aged 18 to 70 years old at the time of first dosing 
3) Satisfy the following: 
• 
Females: Non-pregnant and non-lactating; documented surgically sterile, confirmed post-
menopausal, or abstinent; or if engaged in sexual relations of childbearing potential, 
participant agrees to use two acceptable methods of contraception for 4 weeks prior to the 
treatment period, for the 4 weeks of the Treatment Period, and for at least 2 weeks after 
the last dose of study drug. One of the methods must be an appropriate hormonal 
contraceptive (stable for at least 4 weeks prior to treatment), and the other method can be 
an acceptable method of barrier contraception, e.g., a condom for the male partner. 
• 
Males: Surgically sterile or abstinent; or if engaged in sexual relations of childbearing 
potential, the participant and his partner must agree to use an acceptable contraceptive 
method during the 4 weeks of the Treatment Period and for 2 weeks after the last dose of 
study drug. 
4) Have a body mass index (BMI) of >25.0 and ≤ 45.0 kg/m2 at Screening 
5) Have a documented history of dyslipidemia defined as LDL-C ≥ 2.59 mmol/L 
 Exclusion Criteria 
1) Participants meeting any of the following criteria will be excluded from this trial: 
2) The use of any anti-dyslipidemia agent within 28 days prior to dosing 
3) History of a total cholesterol ≥ 10.35 mmol/L or triglyceride ≥ 11.3 mmol/L 
3.4. 
3.4.1. 
3.4.2. 


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4) History of a clinically significant cardiac arrhythmia or clinically significant abnormal 
ECG results at Screening 
5) Significant peripheral or coronary vascular disease 
6) Clinically significant abnormal blood pressure at Screening, defined as supine blood 
pressure ≥160/100 or < 90/60 mmHg. 
7) Primary hypothyroidism (thyroid stimulating hormone [TSH] > upper limit or normal 
[ULN] and free T4 < lower limit of normal [LLN]), primary subclinical hypothyroidism 
(screening TSH > ULN and free T4 within normal limits [WNL]), or secondary 
hypothyroidism (screening TSH < LLN and free T4< LLN) at Screening. 
8) Glucose-6-phosphate dehydrogenase (G6PD) deficiency 
9) History of unstable proliferative retinopathy or maculopathy and/or severe neuropathy, in 
particular autonomic neuropathy, as judged by the Investigator. 
10) Known history of, or positive test for, human immunodeficiency virus (HIV), hepatitis C, 
or chronic hepatitis B 
11) Active infection that is currently producing symptoms or in which the causative organism 
of the disease is rapidly reproducing 
12) Current or recent history (verbal report) in last 6 months of drug or alcohol abuse, or 
consumption of more than 30 g of alcohol (3 standard drinks) per day (for male and female 
participants) within 4 weeks prior to Screening, or positive urine drug screen for drugs of 
abuse 
13) Clinically significant abnormalities identified during physical examination or from the 
participant’s medical history such as: 
a. Any history of cardiac insufficiency defined as New York Heart Association (NYHA) 
Class II to IV 
b. Angina pectoris within the last 6 months 
c. Acute myocardial infarction at any time 
d. Major surgery within the last 3 months 
e. Stroke 
14) Treatment with any agent that decreases body weight, actively enrolled in a weight loss 
program or following a special diet 
15) Gastrointestinal conditions that involve malabsorption or inflammation (e.g., ulcerative 


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colitis, Crohn’s disease), and recent or past bariatric surgery of any kind 
16) Current or recent use of prohibited medications including (Section 4.4) 
17) Current outpatient insulin use, or history of outpatient insulin use for more than 2 weeks in 
the last year. 
18) Whole blood donation or significant blood loss within 30 days prior to screening or Plasma 
donation within 14 days prior to the first study drug administration. 
19) User of any nicotine containing products within the past 6 months. 
20) Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator. 
21) Participation in an investigational drug trial within 30 days prior to dosing or 10 half-lives 
within the last dose of said investigational drug, whichever is longer. 
22) The presence of any other conditions, which, in the opinion of the Investigator would make 
the participant unsuitable for inclusion, or could interfere with the participant participating 
in or completing the trial. 
 
DETERMINATION OF SAMPLE SIZE 
The sample size of 16 participants per cohort, with 12 receiving HTD1801 and 4 receiving placebo, 
was empirically determined and consistent with typical sample sizes used for similar studies to 
assess robust data for safety and PK.  
 
TREATMENT ASSIGNMENT  
There are three planned dose escalation cohorts. Each cohort will consist of 16 participants 
randomized 3:1 to receive either HTD1801 or placebo. The cohorts will be enrolled sequentially, 
but may overlap (the next cohort can begin during the Follow-up Period of the prior cohort). The 
decision to move to the next dose level will be based on safety findings and will not be dependent 
on establishing preliminary efficacy findings.  Placebos will be pooled across cohorts to allow 
comparisons of each active dose vs placebo.   
 
ADMINISTRATION OF STUDY MEDICATION 
Study drug should be administered orally, once per day immediately following the morning meal 
on Day 1, twice per day following the morning and evening meals on Days 2 to 27 inclusive, and 
once per day immediately following the morning meal on Day 28. All study drug should be taken 
with a 240 mL of water (no more).  
This trial includes three planned dose escalation cohorts. The doses of HTD1801 to be 
administered are summarized below in Table 1.  The data will be analyzed for each active dose as 
3.5. 
3.6. 
3. 7. 


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well as for pooled placebos with comparisons compared against pooled placebo and within each 
active dose group and pooled placebo. 
Table 1. Planned Dose Escalation Cohorts 
Cohort 
Number 
Number of 
Participants Planned 
Dose Regimen 
1 
12 
HTD1801: 500 mg/day (250 mg bid) 
4 
Placebo: 2 tablets/day (1 tablet bid) 
2 
12 
HTD1801: 1000 mg/day (500 mg bid) 
4 
Placebo: 4 tablets/day (2 tablets bid) 
3 
12 
HTD1801: 2000 mg/day (1000 mg bid) 
4 
Placebo: 8 tablets/day (4 tablets bid) 
 


Statistical Analysis Plan 
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ANALYSIS POPULATIONS 
All analysis populations will be defined and confirmed prior to database lock. 
 
RANDOMIZED POPULATION 
The Randomized Population will include all subjects randomized. Unless specified otherwise, this 
Population will be used for summaries and listings of subject disposition. 
 
SAFETY POPULATION 
The Safety Population will include all participants who received at least one dose of study drug or 
placebo. Subjects will be analyzed according to treatment received.  The Safety Population will be 
used for subject listings unless otherwise stated and all analyses of safety. 
 
 
EFFICACY POPULATION 
The Efficacy Population will include all participants who received at least one dose of study drug 
or placebo, and had at least one post-dose assessment for the various secondary PD endpoints 
outlined in Section 8. Subjects will be analyzed according to treatment received. The Efficacy 
Population will be used for all analyses of PD endpoints. 
 
PHARMACOKINETIC POPULATION 
The Pharmacokinetic (PK) Population will include all participants who received active drug 
(HTD1801) and have sufficient data to calculate the PK parameters for UDCA and/or BBR. 
 
PROTOCOL DEVIATIONS 
No subject will be removed from analysis populations because of a protocol deviation. 
4. 
4.1. 
4.2. 
4.3. 
4.4. 
4.5. 


Statistical Analysis Plan 
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GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
 
GENERAL METHODS 
Statistical methodology and analyses are in accordance with the principles outlined by the 
International Conference on Harmonization (ICH) E9 guidelines1. All statistical analyses will be 
done using SAS statistical software version 9.4 or higher. 
The dictionary (MedDRA and WHODrug) version used will be specified in corresponding data 
display footnote. 
Unless otherwise stated, all listings will include all subjects in Safety population, and all listings 
will be sorted by subject ID and assessment date/time. 
Tabular summaries of data will be descriptive in nature (i.e., number of subjects [n], mean 
(arithmetic or geometric when appropriate), SD, median, minimum, and maximum for continuous 
variables and n and percent for categorical variables). Data from all cohorts will be summarized by 
treatment group in the order: Placebo, HTD1801 500 mg, HTD1801 1000 mg and HTD1801 2000 
mg. 
To help stabilize the variability for each laboratory parameter, the screening and baseline values 
will be averaged per subject in all calculations of mean change and mean percent change from 
averaged screening and baseline to Days 14 and 28. 
For all percentage calculations, the denominator will be the number of subjects in the relevant 
population, unless otherwise stated. 
Only data from protocol scheduled visits will be included in the summary tables. Data from 
unscheduled visits will not be included in the summary tables but will be included in the listings. 
All AE/SAE data will be included in the summary tables and respective listings. 
Unless otherwise stated, baseline values defined in Section 5.2 will be used in summary tables. 
However, data collected at both the Screening visit and the Baseline visit will used in the listings. 
No formal hypothesis testing will be performed in this Phase I study. 
 
KEY DEFINITIONS 
• 
Averaged Screening and Baseline Value: unless otherwise defined, the averaged screening 
and baseline value per subject will be used in all calculations of the change and percent 
change calculations; in the event that either screening or baseline value are missing, then 
the last available, valid, non-missing assessment prior to first dosing will serve as the 
averaged screening and baseline value.  
5. 
5. 1. 
5.2. 


Statistical Analysis Plan 
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Unknown, Not Done, Not Applicable and other classifications of missing data will not be 
considered when calculating baseline observations. However, valid categorical 
observations will be considered for baseline calculations. 
• 
Study day: number of days since the study drug administration, which is counted as Day 1. 
Study day is calculated using the formula below:  
Study day = date of assessment - date of first dosing + 1, when date of assessment is on or 
after date of first dosing;  
Study day = date of assessment - date of first dosing, when date of assessment is before 
date of first dosing. 
 
MISSING DATA 
For each endpoint, in the event of missing Day 14 data, then the Baseline value will be carried 
forward; if the Baseline value is missing, then the Screening value will be carried forward.  In the 
event of missing Day 28 data, then the Day 14 value will be carried forward; if the Day 14 value is 
missing, then the Baseline value will be carried forward. 
Adverse events with partial/missing start date will be attributed to treatment emergent adverse 
event TEAE (Section 7.3 for definition of TEAE) based on imputed start date. Likewise, 
Medications with partial stop date will be attributed to prior or concomitant medications based on 
imputed stop date. However, start/stop date without imputation will be presented in listings. 
1) Imputation for partial/missing start date of an adverse event: 
• 
Completely missing, the earlier of stop date and first dosing; 
• 
Only year reported, the earlier of stop date and last day of reported year; 
• 
Only year and month reported, the earlier of stop date and last day of reported year and 
month. 
2) Imputation for partial stop date of a medication: 
• 
Only year reported, the last day of reported year; 
• 
Only year and month reported, last day of reported year and month. 
 
 
VISIT WINDOWS 
No visit windows will be applied to any data. 
5.3. 
5.4. 


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DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS 
AND MEDICATION 
 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition will be summarized and listed for Randomized population.  
The number and percentage of subjects in each population, completed and discontinued the study, 
together with the reasons for discontinuation (withdrew consent, adverse event, protocol violation, 
lost to follow-up, investigator decision, pregnancy, study discontinued by sponsor, and other) will 
be presented. 
 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and baseline characteristics will be summarized and listed for Safety population. 
Demographic data including age (years), sex (male, female), child bearing potential (yes, no), race 
(American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or other 
Pacific Islander, White, other), ethnicity (Hispanic or Latino, Not Hispanic or Latino) collected at 
study Screening will be summarized descriptively. Likewise, baseline characteristics including 
height (cm) and weight (kg) will also be summarized. 
 
MEDICAL HISTORY  
Medical history and physical exam findings will be coded with Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary and summarized by system organ class (SOC) and preferred term 
(PT) based on the Safety population.  
Subject listing of medical history will be provided. 
 
OTHER BASELINE CHARACTERISTICS 
The following baseline characteristics will be listed only. 
• 
Diagnostics including Glucose-6-Phosphate Dehydrogenase (G6PD), Thyroid-Stimulating 
Hormone (TSH) and free T4 collected at Screening; 
• 
Virology test including Human Immunodeficiency Virus (HIV), hepatitis B and C 
collected at Screening. 
 
MEDICATION 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug). Prior and concomitant medications will be listed for Safety population 
with the classification (prior and/or concomitant) identified. 
6. 
6. 1. 
6.2. 
6.3. 
6.4. 
6.5. 


Statistical Analysis Plan 
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 Prior Medication 
All medications stopped before first dosing will be considered as prior medications. In case of a 
medication with partial stop date, imputation rule outlined in Section 5.3 will be applied.  
Prior medications will only be included in data listings. 
 Concomitant Medication 
All medications stopped on or after first dosing will be considered as concomitant medications. 
Medications with missing stop date will be considered as concomitant medication. In case of a 
medication with partial stop date, imputation rule outlined in Section 5.3 will be used. 
Concomitant medications will be summarized by cohort, treatment, Anatomical Therapeutic 
Chemical (ATC) class and preferred term for all subjects in the Safety Set. Subjects who take the 
same medication (in terms of the preferred term) more than once will only be counted once for that 
medication. 
 
6.5.1. 
6.5.2. 


Statistical Analysis Plan 
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SAFETY 
Safety population will be used for all safety analysis. Safety will be assessed on the basis of 
adverse events, clinical laboratory, and vital signs. 
 
EXTENT OF EXPOSURE 
Extent of exposure will be summarized descriptively as a continuous variable. The CRF will 
capture the date of first dosing on Day 1 and the end date of last dosing. The extent of exposure 
(days) will be calculated as date of last dosing – date of first dosing + 1. 
 
 TREATMENT COMPLIANCE  
Treatment compliance is defined as number of tablets taken/planned number of tablets. Number of 
tablets dispensed and returned will be recorded in CRF. Number of tablets taken will be calculated 
as number of tablets dispensed – number of tablets returned. Number of tablets planned will be 
calculated as number of exposure days * planned daily tables (2 tablets). 
Treatment compliance as well as number of tablets dispensed, returned, and taken will be 
summarized descriptively as continuous variables. 
 
ADVERSE EVENTS  
Adverse Events (AEs) will be coded with Medical Dictionary for Regulatory Activities (MedDRA) 
and grouped by system organ class (SOC) and preferred term (PT).  
AEs will be displayed for each active dose group and pooled placebo.  
All AE summaries will be restricted to Treatment Emergent Adverse Events (TEAEs) only, but all 
AEs will be included in data listings. TEAEs are defined as any AE that commence on or after 
exposure to study drug or any pre-existing AE that worsens in either intensity or frequency after 
exposure to study drug. AE that worsened in either intensity or frequency will be recorded as a new 
AE in eCRF. In case of AE with partial/missing start date, data imputation rule outlined in Section 
5.3 will be applied. 
Drug-related TEAEs are defined as TEAEs with possible or probable relationship to study drug. 
The number and percentage of subjects as well as number of events will be presented for TEAE 
summaries. For summaries by SOC and PT, a subject will be counted once at the SOC level and 
once at each PT within the SOC level. For summaries by SOC, PT, and severity, a subject will be 
counted once at each severity level for which the event occurred at the SOC level and at each 
severity level for which the event occurred for each unique PT within that SOC level. Summaries 
by relationship to study drug will be handled similar to the summaries by severity.   
The following summaries will be provided. 
7. 
7. 1. 
7.2. 
7.3. 


Statistical Analysis Plan 
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• 
An overall summary of TEAEs presenting the number and percentage of subjects reporting 
TEAEs, serious TEAEs, severe TEAEs, drug-related TEAEs, TEAEs leading to 
withdrawal.  
• 
TEAEs by SOC and PT 
• 
TEAEs by SOC, PT and severity 
• 
TEAEs by SOC, PT and relationship to study drug 
• 
Serious TEAEs by SOC and PT 
All AEs will be listed with TEAE identified. In addition, drug-related AEs, SAEs, and AEs leading 
to treatment interrupted or discontinued will be listed separately. 
 
LABORATORY EVALUATIONS 
Laboratory data including hematology, clinical chemistry, and urinalysis will be summarized 
descriptively at each protocol scheduled visit (Screening, Baseline, Day 14, Day 28), by cohort and 
treatment, as absolute values and changes from baseline. Baseline values will be determined as 
outlined in Section 5.2.  
Low, normal, and high classifications will be applied to determine whether the laboratory test value 
was below (low), within (normal), or above (high) its reference range. Shifts from baseline in 
Low/normal/high classification for each parameter will be summarized by treatment group.  
Each active dose will be compared to pooled placebo cohorts using an unpaired t-test while 
changes from baseline within each treatment group will be compared using a paired t-test. 
Subject listing of laboratory evaluations will be provided. 
 
7.4. 


Statistical Analysis Plan 
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ANALYSIS OF PHARMACODYNAMICS 
Efficacy population will be used for all pharmacodynamics analysis. Pharmacodynamics will be 
assessed on the basis of lipid metabolism, glucose metabolism, and markers of liver function. 
 
LIPID METABOLISM 
Fasting lipid metabolism and atherogenic biomarkers will be assessed at Screening, Baseline, Day 
14 and Day 28. Summary statistics for actual values, absolute changes from averaged screening 
and baseline, and percent changes from averaged screening and baseline will be tabulated by cohort 
and treatment. The averaged Screening and Baseline value will be determined as outlined in 
Section 5.2. 
• 
Low-density lipoprotein-C (LDL-C) 
• 
Non-high-density lipoprotein-C (non-HDL-C) 
• 
Total cholesterol (TC), HDL-C, and TC/HDL-C ratio 
• 
Apolipoprotein B (ApoB) and A-1 (ApoA1) 
• 
Triglycerides and non-esterified fatty acid (NEFA) 
• 
Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) 
• 
C- reactive protein (CRP) measured using a high-sensitivity assay 
• 
Lipoprotein(a) [Lp(a)] 
Column graph of mean and median change from baseline (absolute value and percentage) will be 
presented by dose group. 
Each active dose will be compared to pooled placebo cohorts using an unpaired t-test while 
changes from baseline within each treatment group will be compared using a paired t-test. 
 
GLUCOSE METABOLISM 
Fasting glucose markers will be assessed at Screening, Baseline, Day 14 and Day 28. Summary 
statistics for actual values, absolute changes from averaged screening and baseline, and percent 
changes from averaged screening and baseline will be tabulated by cohort and treatment. The 
averaged Screening and Baseline value will be determined as outlined in Section 5.2. 
• 
Glycosylated hemoglobin (HbA1c) level 
• 
Fasting plasma glucose (FPG) 
8. 
8.1. 
8.2. 


Statistical Analysis Plan 
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• 
Fasting serum insulin 
• 
C-peptide 
Column graph of mean and median change from baseline (absolute value and percentage) will be 
presented by dose group. 
Each active dose will be compared to pooled placebo cohorts using an unpaired t-test while 
changes from baseline within each treatment group will be compared using a paired t-test. 
 
MARKERS OF LIVER FUNCTION 
Markers of liver function including alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) assessed at Screening, Baseline, Day 14 and Day 28. Summary statistics for actual values, 
absolute changes from averaged screening and baseline, and percent changes from averaged 
screening and baseline will be tabulated by cohort and treatment. The averaged Screening and 
Baseline value will be determined as outlined in Section 5.2. 
Column graph of mean and median change from baseline (absolute value and percentage) will be 
presented by dose group. 
Each active dose will be compared to pooled placebo cohorts using an unpaired t-test while 
changes from baseline within each treatment group will be compared using a paired t-test. 
8.3. 


Statistical Analysis Plan 
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CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
1. Section 4.3, the Efficacy Population will include all participants who received at least one 
dose of study drug or placebo, and had at least one post-dose assessment for the various 
secondary PD endpoints. Secondary PK endpoints will not be considered when 
determining Efficacy Population. 
2. Section 5.2 redefines the Baseline to be the averaged Screening and Baseline in order to 
help stabilize the variance for each safety endpoint in computing mean change and mean 
percent change from averaged Screening and Baseline vs just Baseline.  The mean change 
from averaged Screening and Baseline is also provided for each safety endpoint. 
3. A carry forward algorithm is used to impute any missing Day 14 or 28 data.  This is 
intended to be a conservative imputation strategy. 
4. The following tables will be split in two as follows: 
14.2.1.1 – lipid metabolism (secondary endpoint/ efficacy population) 
o   the value and the change from averaged screening and baseline 
o   the % change from averaged screening and baseline 
14.2.2.1 – glucose metabolism (secondary endpoint/ efficacy population) 
o   the value and the change from averaged screening and baseline 
o   the % change from averaged screening and baseline 
14.2.3.1 – liver function (secondary endpoint/ efficacy population) 
o   the value and the change from averaged screening and baseline 
o   the % change from averaged screening and baseline 
14.3.4.1.1 – haematology (safety population) 
o   the value and the change from averaged screening and baseline 
o   the % change from averaged screening and baseline 
14.3.4.1.2 – serum chemistry (safety population) 
o   the value and the change from averaged screening and baseline 
o   the % change from averaged screening and baseline 
14.3.4.1.3 – urinalysis (safety population) 
9. 


Statistical Analysis Plan 
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o   the value and the change from averaged screening and baseline 
o   the % change from averaged screening and baseline 
5. Each active dose will be compared to pooled placebo cohorts using an unpaired t-test while 
changes from baseline within each treatment group will be compared using a paired t-test. 
 


Statistical Analysis Plan 
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REFERENCE LIST 
1. ICH Guidance “E9 Statistical Principles for Clinical Trials. 
 
 


Statistical Analysis Plan 
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PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using SAS® for 
Windows, Release 9.4 or higher (SAS® Institute Inc., Cary, NC, USA). Computer-generated table, 
listing and figure output will adhere to the following specifications. 
 
GENERAL CONSIDERATIONS 
• 
One SAS program can create several outputs.  
• 
Each output will be stored in a separate file. 
• 
Output files will be delivered in RTF format. 
• 
Numbering of TFLs will follow ICH E3 guidance. 
 
TABLE, LISTING, AND FIGURE FORMAT 
 General 
• 
All TLFs will be produced using the Courier New font, size 8  
• 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
• 
Headers and footers for figures will be in Courier New font, size 8. 
• 
Legends will be used for all figures with more than 1 variable, group, or item displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied 
formats, as appropriate. 
 Tables 
• 
The following tables will be produced: 
o 14.2.1.1 – lipid metabolism (secondary endpoint/ efficacy population) 
o 14.2.2.1 – glucose metabolism (secondary endpoint/ efficacy population) 
o 14.2.3.1 – liver function (secondary endpoint/ efficacy population) 
o 14.3.4.1.1 – haematology (safety population) 
o 14.3.4.1.2 – serum chemistry (safety population) 
11. 
11 . 1. 
11.2. 
11.2.1. 
11.2.2. 


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o 14.3.4.1.3 – urinalysis (safety population) 
• 
For each of the above six sets of tables, the following will be produced: 
o the value and the change from averaged screening and baseline 
o the % change from averaged screening and baseline 
• 
The following statistical tests will be performed for each of the above six sets of tables: 
o Unpaired t-tests will be used to compare each active dose vs. pooled placebos at each 
post-baseline time. 
o Paired t-tests will be used to compare on-study times vs pooled baseline (average of 
screening and baseline).    
 Headers 
• 
All output should have the following header at the top left of each page: 
<Sponsor Name> Protocol XXX 
          
Draft/Final Run  
• 
All output should have Page n of N at the top or bottom right corner of each page. TLFs should 
be internally paginated in relation to the total length (i.e., the page number should appear 
sequentially as page n of N, where N is the total number of pages in the table). 
• 
The date output was generated should appear along with the program name as a footer on each 
page. 
 Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 
numbering is strongly recommended but sponsor preferences should be obtained prior to final 
determination (see also template 03.007C “Table of Contents  for Tables Listings and Figures 
in Statistical Analysis Plan”). A decimal system (x.y and x.y.z) should be used to identify TLFs 
with related contents. The title is centered. The analysis set should be identified on the line 
immediately following the title. The title and table designation are single spaced. A solid line 
spanning the margins will separate the display titles from the column headers. 
• 
There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Safety Population 
11.2.3. 
11.2.4. 


Statistical Analysis Plan 
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 Column Headers 
• 
Column headings should be displayed immediately below the solid line described above in 
initial upper-case characters.  
• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis population sizes will be presented for each treatment group in the column heading as 
(N=xx). This is distinct from the ‘n’ used for the descriptive statistics representing the number 
of subjects in the analysis set. 
• 
The order of treatments in the tables and listings will be Placebo first. 
 Body of the Data Display 
11.2.6.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
11.2.6.2. Table Conventions 
• 
Units will be included where available 
• 
If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category should be presented in the table, even if n=0 for all treatment groups in a 
given category that is between the minimum and maximum level for that parameter. For 
example, the frequency distribution for symptom severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be presented and so 
any counts of 0 will be presented as 0 and not as 0 (0%). 
• 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 subject represented in 1 or 
more groups should be included. 
• 
An Unknown or Missing category should be added to any parameter for which information is 
not available for 1 or more subjects.  
11.2.5. 
11.2.6. 


Statistical Analysis Plan 
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• 
Unless otherwise specified, the estimated mean and median for a set of values should be 
printed out to 1 more significant digit than the original values, and standard deviations should 
be printed out to 2 more significant digits than the original values. The minimum and 
maximum should report the same significant digits as the original values. For example, for 
systolic blood pressure: 
n 
Xx 
Mean (SD) 
xx.x (xx.xx) 
Median 
xx.x 
Min, Max 
xx, xx 
• 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal 
places. Any p-value less than 0.001 will be presented as <0.001. If the p-value should be less 
than 0.0001 then present as <0.0001. If the p-value is returned as >0.999 then present as >0.999 
• 
Percentage values should be printed to one decimal place, in parentheses with no spaces, one 
space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that 
round down to 0.0.  A common convention is to display as '<0.1', or as appropriate with 
additional decimal places. Unless otherwise noted, for all percentages, the number of subjects 
in the analysis set for the treatment group who have an observation will be the denominator. 
Percentages after zero counts should not be displayed and percentages equating to 100% 
should be presented as 100%, without any decimal places.  
• 
Tabular display of data for medical history, prior / concomitant medications, and all tabular 
displays of adverse event data should be presented by the body system, treatment class, or SOC 
with the highest occurrence in the active treatment group in decreasing order, assuming all 
terms are coded. Within the body system, drug class and SOC, medical history (by preferred 
term), drugs (by ATC1 code), and adverse events (by preferred term) should be displayed in 
decreasing order. If incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics or p-values which cannot be estimated should be 
reported as “-”. 
• 
The percentage of subjects is normally calculated as a proportion of the number of subjects 
assessed in the relevant treatment group (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting 
the denominator, usually the appropriate number of subjects exposed. Describe details of this 
in footnotes or programming notes. 
• 
For categorical summaries (number and percentage of subjects) where a subject can be 
included in more than one category, describe in a footnote or programming note if the subject 
should be included in the summary statistics for all relevant categories or just 1 category and 
the criteria for selecting the criteria. 
• 
Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont)” at the top of each subsequent page.  The 
overall summary statistics for the subheading should only be output on the first relevant page. 


Statistical Analysis Plan 
HighTide Biopharma Pty Ltd Protocol # 1801.PCT004 
Final Version 2.0 
Syneos Health # 1010353A 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
  Syneos Health 
Page 32 of 34 
11.2.6.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
• 
Missing data should be represented on subject listings as either a hyphen (“-”) with a 
corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A 
= not applicable”, whichever is appropriate. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). Dates that 
are missing because they are not applicable for the subject are output as “N/A”, unless 
otherwise specified. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or HH:MM:SS 
format (e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the 
study. 
• 
Units will be included where available 
 Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the footnotes.  
• 
All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
• 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line where possible. 
• 
Subject specific footnotes should be avoided, where possible. 
• 
Footnotes will be used sparingly and must add value to the table, figure, or data listing. If more 
than six lines of footnotes are planned, then a cover page may be used to display footnotes, and 
only those essential to comprehension of the data will be repeated on each page.  
• 
The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (i.e., 
‘Program : myprogram.sas’). 
11.2.7. 


Statistical Analysis Plan 
HighTide Biopharma Pty Ltd Protocol # 1801.PCT004 
Final Version 2.0 
Syneos Health # 1010353A 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
  Syneos Health 
Page 33 of 34 
 
QUALITY CONTROL 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. Syneos Health SOP 03.010 and 03.013 provide an overview 
of the development of such SAS programs. 
Syneos Health SOP 03.009 describes the quality control procedures that are performed for all SAS 
programs and output. Quality control is defined here as the operational techniques and activities 
undertaken to verify that the SAS programs produce the output by checking for their logic, 
efficiency and commenting and by review of the produced output.  
12. 


Statistical Analysis Plan 
HighTide Biopharma Pty Ltd Protocol # 1801.PCT004 
Final Version 2.0 
Syneos Health # 1010353A 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
  Syneos Health 
Page 34 of 34 
 
APPENDICES 
HighTide_1801.PCT004_TLF Shell_Final Version 1.0 
13.