Clinical trial NCT04164888
Conditions: Hypercholesterolemia
Sponsor: Civi Biopharma, Inc.
Start date: 2019-11-11; Completion date: 2020-11-17
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluation of the clinical profile (lipid efficacy, safety and PK) across a number of doses of CIVI 007, a PCSK9 inhibitor. Patients to be evaluated will be on a stable background of statin therapy with or without ezetimibe.

Detailed description:

Arms: arm 1: Subcutaneous (SC) injection of a PCSK9 inhibitor- low dose given twice arm 2: SC injection of PCSK9 inhibitor- dose titration arm 3: SC injection of PCSK9 inhibitor- high dose given twice arm 4: Placebo SC injection matching PCSK9 inhibitor given twice
Interventions: intervention 1: CIVI 007
Intervention descriptions: intervention 1: hypercholesterolemia agent

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
A Placebo-controlled, Randomized, Phase 2a, Study to Assess the Safety, 
Tolerability, Pharmacodynamics and Pharmacokinetics of CIVI 007 in 
Patients on a background of Stable Statin Therapy  
 
Investigational Product: CIVI 007 
Protocol Number: CIVI 007-2-01 
 
 
Sponsor: 
CiVi Biopharma, Inc.  
200 Four Falls Corporate Center, Suite 107 
West Conshohocken, PA 19428, USA 
Office: 484-222-6246 
Fax: 484-222-6264 
 
 
Version Number: 3.0 
Original Protocol Date: 01 July 2019 
Amendment 1 Date: 09 Sept 2019 
Amendment 2 Date: 14 Nov 2019 
 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of CiVi Biopharma, Inc. (CiVi, hereinafter) except to the extent that disclosure would be 
required by law and for the purpose of evaluating and/or conducting a clinical study for CiVi. 
You are allowed to disclose the contents of this document only to your Institutional Review 
Board or Independent Ethics Committee and study personnel directly involved with conducting 
this protocol. Persons to whom the information is disclosed must be informed that the 
information is confidential and proprietary to CiVi and that it may not be further disclosed to 
third parties. 


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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by CiVi Biopharma, Inc. (CiVi, hereinafter) to study personnel under my supervision. I will 
discuss this material with them to ensure they are fully informed about the study product and study 
procedures. I will let them know that this information is confidential and proprietary to CiVi and 
that it may not be further disclosed to third parties. I understand that the study may be terminated 
or enrollment suspended at any time by CiVi, with or without cause, or by me if it becomes 
necessary to protect the best interests of the study patients. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and International Council for 
Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 


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SYNOPSIS
 
TITLE: A Placebo-controlled, Randomized, Phase 2a, Study to Assess the Safety, Tolerability, 
Pharmacodynamics and Pharmacokinetics of CIVI 007 in Patients on a background of Stable Statin 
Therapy  
PROTOCOL NUMBER: CIVI 007-2-01 
INVESTIGATIONAL PRODUCT: CIVI 007 
PHASE: 2 
INDICATION: Treatment of hypercholesterolemia 
OBJECTIVES: 
The primary objective of the study is to assess the safety and tolerability of CIVI 007 following multiple 
subcutaneous (SC) doses in patients on a background of a stable dose of statin therapy.  
The secondary objective is to assess the pharmacodynamic (PD) effect of CIVI 007 on total plasma 
proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDL-C levels in the study population. 
The exploratory objectives include the following: 
• 
To assess the effect of CIVI 007 on other lipid and lipoproteins including triglycerides (TG), 
high-density lipoprotein cholesterol (HDL-C), non-HDL-C, very low-density lipoprotein cholesterol 
(VLDL-C), total cholesterol, apolipoproteins B, A-I and lipoprotein(a) 
• 
To assess the effect of CIVI 007 on high-sensitivity C-reactive protein (hsCRP) 
• 
To collect antidrug antibody (ADA) samples for potential future assessments of immunogenicity  
• 
To further inform the population pharmacokinetic (PK) model of CIVI 007 with sparse PK sampling 
in patients on a background of statin therapy 
POPULATION: 
The population for this study includes male and female patients aged 18-70 currently on standard of care 
treatment for high blood cholesterol consistent with 2018 ACC/AHA guidelines (Appendix C) that 
includes a stable dose of background statin therapy with or without ezetimibe. 
INCLUSION CRITERIA: 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Willing and able to provide written and signed informed consent prior to any study-specific 
procedures. 
2. Males or females, 18-70 years of age at the time of consent. 
3. Body mass index (BMI) between 18.0 and 40.0 kg/m2, inclusive, and a body weight of ≥60 kg at 
screening. 
4. Currently on a stable (>4 weeks prior to the Screening Visit) dose of statin therapy (with or without 
ezetimibe).  


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5. Fasting low-density lipoprotein cholesterol (LDL-C): 
a. ≥100 mg/dL for those without any evidence of established ASCVD at the Screening Visit  
or, 
b. ≥70 mg/dL for those with evidence of established ASCVD at the Screening Visit. 
• 
Established ASCVD is defined as a history of at least 1 of the following occurring no more 
recently than 3 months prior to screening:  
o Acute coronary syndrome 
o Myocardial infarction 
o Stroke or transient ischemic attack presumed to be of atherosclerotic origin 
o Coronary revascularization (Coronary Artery Bypass Grafting or Percutaneous 
Coronary Intervention) 
o Peripheral vascular disease or revascularization 
o In the absence of an above event, ASCVD as diagnosed >3 months prior to the 
Screening Visit based on invasive or noninvasive imaging such as angiography, 
coronary artery calcium (CAC) score >75th percentile, or >50% stenosis in any arterial 
bed. 
 
Note: Retesting will be allowed once at Screening Visit for LDL-C that is in the range of 65-69 
mg/dL.   
6. Fasting TGs <400 mg/dL at the Screening Visit. 
Note: Retesting will be allowed once at Screening Visit for TGs in the range of 401-450 mg/dL. 
7. Women of childbearing potential (i.e., not postmenopausal [documented amenorrhea for 1 year 
in the absence of other biological or physiological causes] or surgically sterile including tubal 
ligation) must have a negative serum pregnancy test at the Screening Visit and a negative urine 
dipstick prior to dosing on Day 1. Postmenopausal status will be confirmed with a Screening Visit 
serum follicle-stimulating hormone (FSH) level >40 mIU/mL. Women aged >60 years whose FSH 
values are not >40 mIU/mL may be included at the discretion of the Investigator and in 
consultation with the Sponsor. Participating women of childbearing potential must agree to use 
2 acceptable methods of contraception throughout the duration of the study and for 30 days after 
the last dose of study drug. Acceptable methods of contraception include condom, indwelling 
intrauterine device, or a vasectomized partner. 
8. Male patients must be willing to use condoms during sexual intercourse from the Screening Visit 
until at least 90 days after administration of the last dose of study drug. 
EXCLUSION CRITERIA: 
Patients who meet any of the following medical history, concurrent medication or laboratory abnormality 
criteria will be excluded from participation in the study: 
1. Women who are pregnant, nursing or breast feeding. 
2. Currently prescribed a lipid lowering agent other than a statin or ezetimibe. 
3. Abnormal liver function test at the Screening Visit (aspartate aminotransferase or alanine 
aminotransferase >1.5 × the upper limit of normal [ULN], total bilirubin >1.5 × ULN, or alkaline 
phosphatase >1.5 × ULN, based on appropriate age and gender normal values). Participants with 
bilirubin >1.5 × ULN and a history of Gilbert’s syndrome may be included. 
4. Active liver disease as defined by the investigator (e.g., cirrhosis, alcoholic liver disease, hepatitis B 
virus, hepatitis C virus, autoimmune hepatitis, liver failure, and/or liver cancer) or history of liver 


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transplant. NASH is considered exclusionary while non-alcoholic fatty liver (NAFL) is not 
exclusionary. 
5. Known diagnosis of human immunodeficiency virus. 
6. Mild, moderate or severe renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) 
<60 mL/min/1.73m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration 
eGFR formula), at the Screening Visit. 
7. Uncontrolled thyroid disease: hypothyroidism or hyperthyroidism, as defined by thyroid-stimulating 
hormone below the lower limit of normal or >1.5 × ULN, respectively, based on results from the 
Screening Visit. If controlled, treatment should be stable for at least 3 months prior to the Screening 
Visit. 
8. Type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus, defined as hemoglobin A1c value 
>9%, based on results from the Screening Visit. 
9. New York Heart Association Class II, III, or IV heart failure. 
10. Myocardial infarction, severe or unstable angina pectoris, coronary revascularization, or other major 
cardiovascular event(s) resulting in hospitalization within 3 months of the Screening Visit. 
11. Uncontrolled cardiac arrhythmia or prolonged QT interval on the Screening Visit  electrocardiogram 
(ECG) (QT corrected using Fridericia’s formula >450 msec for men and >470 msec for women), or 
known family history of prolonged QT interval or unexplained sudden cardiac death. 
12. Currently receiving cancer treatments or, in the Investigator’s opinion, is at risk of relapse for recent 
cancer within the study period. 
13. A history of autoimmune disorder(s).  
14. A history of hematologic or coagulation disorders.  
15. Abnormal PT, aPTT, or INR at the screening visit. 
16. Concomitant antiplatelet or anticoagulation medication. Allowable are low-dose aspirin (81 mg or 
less, daily) for CVD risk reduction, or PRN for occasional pain relief.  Other antiplatelet drugs (e.g., 
P2Y12 inhibitors) and all anticoagulants are exclusionary.   
17. Except as noted above, patients who have a clinically significant disorder that, in the opinion of the 
Investigator, could contraindicate the administration of study drug, affect compliance, interfere with 
study evaluations, or confound the interpretation of study results. 
18. History of drug or alcohol abuse within the past year. 
19. Previous treatment with CIVI 007.  
20. Participation in another clinical study of an investigational agent or device concurrently or within 1 
month prior to the Screening Visit or use of an investigational agent within 1 month or 5 half-lives (if 
known), whichever is longer, prior to the Screening Visit. 
21. Donation of blood from 3 months prior, plasma 2 weeks prior, and platelets 6 weeks prior to the 
Screening Visit. 
22. Any other findings that, in the opinion of the Investigator, would compromise the participant’s safety 
or participation in the study. 
STUDY DESIGN AND DURATION: 
This is a Phase 2a, randomized, double-blind (investigator/subject), sponsor-open, parallel-group, 
multicenter study to evaluate the early clinical profile (safety, tolerability, pharmacodynamics and 


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pharmacokinetics) of CIVI 007 in patients on a background of statin therapy with or without ezetimibe. 
Patients are required to be on standard of care treatment for high blood cholesterol consistent with 2018 
ACC/AHA guidelines that includes a stable dose of statin therapy (with or without ezetimibe) for at least 
4 weeks prior to the Screening Visit. The study will enroll approximately 48 patients who will be 
randomized to 1 of 3 active treatment groups or the placebo reference group (12 patients per active 
treatment group and 12 in the placebo treatment group). 
All potentially eligible patients will partake in the Screening Visit up to 21 days prior to Day 1. The 
Screening Visit will be the first study visit. 
The Treatment Period will be approximately 28 days from Day 1 to Day 29; each treatment group will 
receive 2 administrations of study drug. Eligible patients will be randomized on Day 1 in a 1:1:1:1 ratio to 
one of the following treatment groups: 
• 
Group 1: 
mg CIVI 007 administered SC on Days 1 and 29 
• 
Group 2: 
mg CIVI 007 administered SC on Day 1 followed by
mg CIVI 007 administered 
SC on Day 29 
• 
Group 3:
 mg CIVI 007 administered SC on Days 1 and 29 
• 
Group 4: Placebo for CIVI 007 administered SC on Days 1 and 29 
The Follow-up Period will be approximately 8 weeks and begin following the last dose of study drug, 
unless extended follow-up is required based on the Day 85 LDL-C assessment or other Investigator 
determined safety considerations.  
Extended follow-up visits will be conducted on a monthly basis for up to 3 months if Day 85 LDL-C levels 
are <80% of their baseline level; extended follow-up will end within the 3-month period if LDL-C levels 
are ≥80% of baseline. Extended follow-up visits (frequency and assessments will be at the discretion of 
the Investigator) to monitor Investigator determined safety considerations may extend beyond 3 months, 
if deemed appropriate by the Investigator, and will continue until there are no safety observations requiring 
further follow-up. The total duration of the study for each patient will be approximately 3 to 6.5 months, 
depending on the length of the screening, and follow up periods. 
The study design is graphically summarized below. 
 
Patients will be routinely monitored for safety, tolerability and pharmacodynamic effects. The schedule of 
procedures and clinical laboratory analytes are detailed in Appendices: Measurements will be taken as 
detailed in Appendix A (schedule) and Appendix B (clinical laboratory analytes).  
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DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
CIVI 007 and placebo are sterile solutions to be administered by SC injection. Placebo for CIVI 007 will 
be commercially available sterile saline for injection. An unblinded pharmacist will prepare the study drug 
for blinded administration by the investigator site as detailed in the protocol’s Pharmacy Manual. 
Dosing is to be in the morning following an overnight fasting. 
• 
CIVI 007 is to be administered SC into the abdomen (or thigh or upper arm, if necessary) from a 
solution at 150 mg/mL .  
• 
Doses of CIVI 007 are
 mg Q4W x2, 
mg on Day 1 followed by 
mg on Day 29 and
 mg 
Q4W x2. 
• 
Placebo is to be administered SC into the abdomen (or in thigh or upper arm, if necessary) on Day 
1 and Day 29. The volume of injection will be randomly assigned to match the active CIVI 007 
dose. 
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SAFETY/EFFICACY/PK VARIABLES AND ENDPOINTS:  
Primary Endpoints 
The primary safety/tolerability endpoints for this study are as follows: 
• 
incidence and severity of any drug-related AE 
• 
incidence of clinically significant laboratory abnormalities, based on drug-induced changes from 
baseline in hematology, clinical safety chemistry, and urinalysis test results 
Secondary Endpoints 
The secondary efficacy endpoints include the following changes from baseline measured approximately 
28 days after the first and 28 and 56 days after the last injection of study drug: 
• 
percent change in total plasma PCSK9 and LDL-C  
Exploratory Endpoints 
The exploratory PD endpoints are the absolute and % changes from baseline (except where indicated) in 
the levels of the following in serum or plasma over the time course of the treatment period and follow-up: 
• 
PCSK9 (absolute only) 
• 
LDL-C (absolute only) 
• 
VLDL-C 
• 
triglycerides 
• 
HDL-C 
• 
Non-HDL-C 
• 
total cholesterol 
• 
lipoprotein (a) 
• 
apolipoproteins B and A-I 
• 
hsCRP 
 
The following PK parameters will be calculated for CIVI 007, where possible: 
• 
Cmax 
• 
time of the maximum observed plasma concentration (tmax) 
• 
AUC0-t 
• 
concentration observed at pre-dose (Ctrough) 
 
Additional exploratory PK parameters, which may include but are not limited to the following, may be 
calculated:  
• 
area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) 
• 
area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24) 
• 
area under the plasma concentration-time curve from time 0 to 48 hours (AUC0-48) 
• 
percentage of AUC0‑∞ that is due to extrapolation (%AUCextrap) 
• 
apparent termination elimination rate constant (λz) 
• 
apparent plasma terminal elimination half‑life (t1/2) 
• 
apparent total plasma clearance (CL/F) 
• 
apparent volume of distribution during the terminal phase (Vz/F) 
SAFETY VARIABLES: 
The safety variables include adverse events, clinical safety laboratory parameters (including clinical safety 
chemistry, hematology, coagulation parameters including fibrinogen, complement activation, cytokines 


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and urinalysis), 12-lead ECGs, physical examinations, and vital signs. Samples will also be collected for 
the potential future assessment of anti-drug antibodies.   
PHARMACOKINETICS: 
Sparse PK sampling will be conducted for all consenting patients in each active treatment group. Sampling 
will be performed on dosing days, and at each study visit during the Treatment and Follow-up Periods. For 
each of the dosing days, a PK sample will be drawn pre-dose (-1 hour), 3 hours (±1 hour) post-dose, and 
at 8 hours (±1 hour) post-dose. 
The population PK model created based on data from the ongoing  Phase 1 study will be refined to evaluate 
the relationship of CIVI 007 PK to demographics and background statin therapy. The model will be 
periodically refined as new and broader datasets emerge to include the covariates of special populations, 
concomitant medications, and disease state. 
STATISTICAL ANALYSES: 
All adverse events (AEs) will be listed and summarized using descriptive methodology. The incidence of 
AEs for each treatment will be presented by severity and by association with the study drug (CIVI 007 or 
placebo) as determined by the Investigator (or designee). Each AE will be coded using the Medical 
Dictionary for Regulatory Activities. Injection site reactions will be listed (those recorded as AEs will also 
be included in the AE outputs).  
Observed values and clinically important changes from baseline for clinical laboratory test data, 12 lead 
ECGs, and vital signs will be listed and summarized. CTCAE grading (using the most recent version 
available) summaries will be provided as appropriate. All other safety data will be listed.  
Plasma concentrations of CIVI 007 will be listed; PK parameters (where possible) of CIVI 007 after each 
dose will be listed and summarized using descriptive statistics. Individual and mean CIVI 007 plasma 
concentration time profiles for each treatment cohort will also be presented graphically. 
The PD data will be listed and summarized using descriptive statistics by cohort.  
The Intent-to-Treat (ITT) Population will include all patients who are randomized to the study and will be 
used to assess efficacy. The change from baseline measures in lipids and lipoproteins will be analyzed 
using an analysis of covariance (ANCOVA) model to compare the mean percent change from baseline in 
PCSK9 and LDL-C 28 days after the first injection and 28 and 56 days after the second injection of study 
drug between treatment groups with placebo. This ANCOVA model will include treatment as a factor and 
baseline LDL-C level as a covariate.  
The Per-Protocol Population will include all patients who are randomized to the study and do not have any 
major protocol deviations. Analysis of the primary efficacy endpoint will be repeated with the Per-Protocol 
Population.  
Further details will be specified in the Statistical Analysis Plan (SAP).  
SAMPLE SIZE DETERMINATION: 
Approximately 48 patients (12 patients per active treatment group, 12 per placebo treatment) will be 
randomized into 1 of 4 treatment groups. 
The sample size chosen for this study was not based on power calculations. However, the number of 
participating patients in each part of the present study is common in early clinical studies and is 
considered sufficient to achieve the objectives of the study without exposing undue numbers of patients 
to study drug. 


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Following discussion between the Investigator and the Sponsor, additional patients may be enrolled to 
replace patients who do not complete the study. 
SITES:  Approximately 7 sites in the United States. 
SPONSOR: 
CiVi Biopharma, Inc. 
200 Four Falls Corporate Center, Suite 107 
West Conshohocken, PA 19428  USA 
Office: 484-222-6246 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis….. .................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 12 
List of Figures ............................................................................................................................... 16 
List of Appendices ........................................................................................................................ 17 
List of Abbreviations and Definition of Terms............................................................................. 18 
1 Introduction and Background Information ............................................................................. 21 
1.1 
Overview ....................................................................................................................... 21 
1.2 
Summary of Preclinical Pharmacology ......................................................................... 22 
1.2.1 Primary Pharmacodynamics .............................................................................. 22 
1.2.2 Effect on Plasma Ceramide Levels in Monkeys ............................................... 22 
1.3 
Summary of Safety Pharmacology and Toxicology ..................................................... 23 
1.3.1 Safety Pharmacology ......................................................................................... 23 
1.3.2 Toxicology ........................................................................................................ 23 
1.4 
Summary of Animal Pharmacokinetics ......................................................................... 26 
1.5 
Toxicokinetics and Distribution .................................................................................... 26 
1.6 
Metabolism .................................................................................................................... 27 
1.7 
Clinical Summary .......................................................................................................... 27 
1.8 
Rationale ........................................................................................................................ 28 
1.9 
Risk/Benefit ................................................................................................................... 28 
2 Study Objectives ..................................................................................................................... 29 
2.1 
Primary Objective ......................................................................................................... 29 
2.2 
Secondary Objective ..................................................................................................... 29 
2.3 
Exploratory Objectives .................................................................................................. 29 
3 Study Description.................................................................................................................... 30 
3.1 
Summary of Study Design ............................................................................................ 30 
3.2 
Study Design Rationale ................................................................................................. 31 
3.3 
Study Start and End of Study Definitions ..................................................................... 32 
3.4 
Study Termination ......................................................................................................... 32 
3.5 
Study Indication ............................................................................................................ 32 


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4 Selection and Withdrawal of Patients ..................................................................................... 33 
4.1 
Inclusion Criteria ........................................................................................................... 33 
4.2 
Exclusion Criteria .......................................................................................................... 34 
4.3 
Retesting ........................................................................................................................ 35 
4.4 
Rescreening ................................................................................................................... 35 
4.5 
Withdrawal Criteria ....................................................................................................... 35 
5 Study Treatments .................................................................................................................... 37 
5.1 
Treatment Groups .......................................................................................................... 37 
5.2 
Rationale for Dosing ..................................................................................................... 37 
5.3 
Randomization and Blinding ......................................................................................... 37 
5.4 
Breaking the Blind ........................................................................................................ 38 
5.5 
Drug Supplies ................................................................................................................ 38 
5.5.1 Formulation and Packaging ............................................................................... 38 
5.5.2 Study Drug Preparation and Dispensing ........................................................... 38 
5.5.3 Study Drug Administration ............................................................................... 38 
5.5.4 Treatment Compliance ...................................................................................... 39 
5.5.5 Storage and Accountability ............................................................................... 39 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 39 
5.6.1 Excluded Medications and/or Procedures ......................................................... 39 
5.6.2 Restricted Medications and/or Procedures ........................................................ 39 
5.6.3 Allowed Medications and/or Procedures .......................................................... 39 
5.6.4 Documentation of Prior and Concomitant Medication Use .............................. 40 
5.7 
Dietary and Lifestyle Restrictions ................................................................................. 40 
5.7.1 Diet……. ........................................................................................................... 40 
5.7.2 Smoking ............................................................................................................ 40 
5.7.3 Exercise ............................................................................................................. 40 
5.7.4 Blood Donation ................................................................................................. 40 
5.7.5 Contraception .................................................................................................... 40 
6 Study Procedures .................................................................................................................... 42 
6.1 
Screening Visit (Up to Day -21) ................................................................................... 42 
6.2 
Treatment Period (Days 1 to 29) ................................................................................... 42 
6.2.1 Day 1….. ........................................................................................................... 42 
6.2.2  Day 8 43 


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6.2.2 Day 15….. ......................................................................................................... 43 
6.2.3 Day 22….. ......................................................................................................... 44 
6.2.4 Day 29….. ......................................................................................................... 44 
6.3 
Follow-Up Period (Days 36 to 85 or End of Treatment) .............................................. 45 
6.3.1 Day 36  .............................................................................................................. 45 
6.3.2 Day 43  .............................................................................................................. 45 
6.3.3 Day 57….. ......................................................................................................... 46 
6.3.4 Day 85 or Early Termination ............................................................................ 46 
6.4 
Extended Follow-up Visits ............................................................................................ 47 
6.5 
Early Termination Visit and Withdrawal Procedures ................................................... 47 
7 Efficacy Assessments.............................................................................................................. 49 
7.1 
Primary Endpoints ......................................................................................................... 49 
7.2 
Secondary Endpoints ..................................................................................................... 49 
7.3 
Exploratory Endpoints ................................................................................................... 49 
7.4 
Pharmacokinetics .......................................................................................................... 50 
8 Safety Assessments ................................................................................................................. 51 
8.1 
Individual Patient Safety Monitoring and Criteria For Discontinuation of Study Drug 51 
8.2 
Adverse Events .............................................................................................................. 52 
8.2.1 Adverse (Drug) Reaction .................................................................................. 53 
8.2.2 Unexpected Adverse Drug Reaction ................................................................. 53 
8.2.3 Assessment of Adverse Events by the Investigator .......................................... 53 
8.2.4 Adverse Events of Special Interest .................................................................... 54 
8.3 
Serious Adverse Events ................................................................................................. 55 
8.4 
Serious Adverse Event Reporting - Procedures for Investigators ................................. 55 
8.5 
Pregnancy Reporting ..................................................................................................... 56 
8.6 
Expedited Reporting ...................................................................................................... 56 
8.7 
Special Situation Reports .............................................................................................. 57 
8.8 
Injection Site Assessment .............................................................................................. 57 
8.9 
Clinical Laboratory Evaluations .................................................................................... 58 
8.10 Vital Signs ..................................................................................................................... 58 
8.11 12-Lead Electrocardiograms ......................................................................................... 58 
8.12 Physical Examinations .................................................................................................. 58 
8.13 Pharmacokinetic Assessments ....................................................................................... 58 


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8.14 Pharmacodynamic Assessments .................................................................................... 59 
9 Statistics .................................................................................................................................. 60 
9.1 
Analysis Populations ..................................................................................................... 60 
9.2 
Statistical Methods ........................................................................................................ 60 
9.2.1 Analysis of Primary Safety/Tolerability Data ................................................... 60 
9.2.2 Secondary and Exploratory Efficacy Analysis .................................................. 60 
9.2.2.1 Secondary efficacy analysis ................................................................ 60 
9.2.2.2 Pharmacokinetic analysis .................................................................... 61 
9.2.3 Interim Analysis ................................................................................................ 61 
9.2.4 Sample Size Determination ............................................................................... 61 
10 Data Management and Record Keeping ................................................................................. 63 
10.1 Data Management ......................................................................................................... 63 
10.1.1 Data Handling ................................................................................................... 63 
10.1.2 Computer Systems ............................................................................................. 63 
10.1.3 Data Entry ......................................................................................................... 63 
10.1.4 Medical Information Coding ............................................................................. 63 
10.1.5 Data Validation ................................................................................................. 63 
10.2 Record Keeping ............................................................................................................. 63 
10.3 End of Study .................................................................................................................. 64 
11 Investigator Requirements and Quality Control ..................................................................... 65 
11.1 Ethical Conduct of the Study ........................................................................................ 65 
11.2 Institutional Review Board ............................................................................................ 65 
11.3 Informed Consent .......................................................................................................... 65 
11.4 Study Monitoring Requirements ................................................................................... 65 
11.5 Disclosure of Data ......................................................................................................... 66 
11.6 Retention of Records ..................................................................................................... 66 
11.7 Publication Policy ......................................................................................................... 66 
11.8 Financial Disclosure ...................................................................................................... 67 
12 Study Administrative Information .......................................................................................... 68 
12.1 Protocol Amendments ................................................................................................... 68 
13 References ............................................................................................................................... 69 
Appendicies…............................................................................................................................... 71 


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LIST OF FIGURES 
Figure 1. Summary of the Study Design .................................................................................... 31 
 


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LIST OF APPENDICES 
Appendix A:  Schedule of Procedures .......................................................................................... 71 
Appendix B:  Clinical Laboratory Analytes ................................................................................. 73 
Appendix C:  2018 Guideline on the Management of Blood Cholesterol .................................... 76 
 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
λz 
apparent termination elimination rate constant  
ADA 
antidrug antibody 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
apo 
apolipoprotein  
aPTT 
ASCVD 
activated Partial Thromboplastin Time 
atherosclerotic cardiovascular disease 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 extrapolated to
infinity 
AUC0-24 
area under the plasma concentration-time curve from time 0 to 24 hours 
AUC0-48 
area under the plasma concentration-time curve from time 0 to 48 hours 
AUC0-t 
area under the plasma concentration-time curve from time 0 to the time of last
quantifiable concentration 
AUCextrap 
extrapolation of area under plasma concentration 
BP 
blood pressure 
CAC 
coronary artery calcium 
CFR 
Code of Federal Regulations 
CiVi 
CiVi Biopharma, Inc. 
CL/F 
apparent total plasma clearance 
Cmax 
maximum observed plasma concentration 
Ctrough 
concentration observed at pre-dose 
CRA 
Clinical Research Associate 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
cardiovascular 
CYP 
cytochrome 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
EIU 
exposure in utero 
FIH 
first in human 
FSH 
follicle-stimulating hormone 
GalNAc 
Galactose/N-Acetylgalactosamine   


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Abbreviation 
Definition 
Gb3 
globotriaosylceramides 
GCP 
Good Clinical Practice 
Glc/GalCer 
glucosyl/ galactosylceramides 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HbA1c 
hemoglobin A1c 
HDL-C 
high-density lipoprotein cholesterol 
HEK 
human embryonic kidney 
hERG 
human ether-à-go-go-related gene 
hsCRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
IC50 
concentration of drug required to produce 50% inhibition 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Investigational Review Board 
ISR 
injection site reaction 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IV 
intravenous(ly) 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein cholesterol 
LDL-R 
low-density lipoprotein receptor 
LFT 
liver function test 
LNA 
locked nucleic acid 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
mRNA 
messenger ribonucleic acid 
NAFL 
non-alcoholic fatty liver 
NASH 
non-alcoholic steatohepatitis 
NOAEL 
no observed adverse effect level 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
QT 
measure between Q wave and T wave in heart’s electrical cycle 
QTcF 
heart-rate corrected QT interval using Fridericia’s formula 
Q4W 
every 4 weeks 
SAD 
single ascending dose 


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Abbreviation 
Definition 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
t½  
apparent plasma terminal elimination half-life 
TG 
triglyceride 
tmax 
time to maximum observed plasma concentration 
TSH 
thyroid-stimulating hormone 
UGT 
uridine glucuronyl transferase 
ULN 
upper limit of normal 
VLDL 
very low-density lipoprotein 
VLDL-C 
very low-density lipoprotein cholesterol 
Vz/F 
apparent volume of distribution during the terminal phase 
WBC 
white blood cell 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
Refer to the Investigator’s Brochure (IB)1 for additional detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile 
of the investigational medicinal product (IMP). 
1.1 
Overview 
CIVI 007 
 is an antisense oligonucleotide under development 
as an adjunct to diet with or without concurrent hypolipidemic agents for treatment of adults who 
require additional lowering of low-density lipoprotein cholesterol (LDL-C). 
Consistent evidence from experimental, clinical and genetic studies unequivocally establishes that 
low-density lipoprotein (LDL) causes atherosclerotic cardiovascular disease (ASCVD).2 First-line 
drug treatment for hypercholesterolemia is with statins, which inhibit 3 hydroxy-3-methyl-
glutaryl-coenzyme A reductase, a key step in cholesterol synthesis. They decrease plasma levels 
of cholesterol by increasing its hepatic clearance through the upregulation of LDL receptors 
(LDL-R) on hepatocytes. As a result, statins are effective in preventing ASCVD occurrence, the 
effectiveness of which is dependent on the patient’s baseline ASCVD risk, absolute degree and 
length of cholesterol lowering achieved.3 However, there are important limitations to statin 
therapy, including muscular intolerance to therapy,4 dose limiting side effects including 
transaminitis5 as well as limitations on their LDL-C lowering capacity and the ability to achieve 
recommended LDL-C target levels.6 An important factor limiting statin’s LDL-C lowering 
capacity is the result of the upregulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) 
that occurs concurrently with the intended upregulation of LDL-R. This statin mediated PCSK9 
upregulation counteracts LDL-R upregulation by enhancing LDL-R degradation which limits the 
hepatic uptake of cholesterol, and therefore paradoxically limits the level of plasma cholesterol 
reduction that can be achieved.7 Thus, there remains an unmet medical need beyond statin therapy 
for novel pharmaceutical agents to reduce cardiovascular (CV) morbidity and mortality caused by 
elevated LDL-C, particularly for patients with inadequate response of LDL-C to statin therapy, 
those intolerant to it and those with very high LDL-C levels caused by genetic mutations, such as 
familial hypercholesterolemia. 
The inhibition of PCSK9 is one novel approach being taken to overcome the residual shortcomings 
of statin therapy. As PCSK9 acts to inactivate LDL-R, its inhibition reverses this process and has 
been shown to cause a decrease in plasma LDL levels of up to 60% in humans. Currently, 
2 monoclonal antibodies (mAbs) to PCSK9 have been approved for clinical use, and 2 outcomes 
trials have shown reductions in CV events, thus validating the clinical benefit of inhibiting the 
PCSK9 target.8,9 The PCSK9 mAbs (evolocumab, alirocumab) target only the circulating levels of 
PCSK9 and have the potential for production of antidrug antibodies. Common side effects include 
injection site reactions, common cold, and influenza. Serious allergic reactions have also been 
reported. 
An alternative approach to reducing the impact of PCSK9 on LDL-C is blocking its production at 
the level of messenger ribonucleic acid (mRNA) using an antisense inhibitor complementary and 
specific to human PCSK9 mRNA. Compared to mAb therapy, this mode of action will have the 
advantage of blocking both intra- and extracellular PCSK9 levels, reducing the potential for 
antidrug antibody formation and impacting novel ASCVD risk biomarkers such as ceramides.10 In 
addition, due to its high potency and long half-life in liver administration of CIVI 007 to human 
subjects, CIVI 007 treatment is expected to lead to stable reductions in LDL-C when dosed 


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monthly at a single low volume dose (
mg), thus improving patient convenience 
and compliance and potentially reducing local pain at the injection site compared to mAbs that can 
require 3 injections of each 1.5ml or an on-body infusor when dosed monthly. 
CIVI 007 is currently under development by CiVi Biopharma, Inc. (CiVi, hereinafter). CIVI 007 
is an antisense inhibitor complementary to human PCSK9 mRNA and is based on the Locked 
Nucleic Acid (LNA) drug platform, which was pioneered by Santaris Pharma. The LNA 
oligonucleotide is designed to specifically bind to, and degrade, the mRNA encoding PCSK9, 
using the endogenously expressed enzyme, ribonuclease H, to cleave the mRNA. To facilitate 
optimal delivery of the drug to the intended target organ (liver), the LNA oligonucleotide is 
conjugated to a galactose/N-acetylgalactosamine (GalNAc) moiety that facilitates functional 
uptake by hepatocytes through binding to the surface expressed asialoglycoprotein receptor.  
In summary, treatment with CIVI 007, through its degradation of PCSK9 mRNA, is designed to 
increase the number of LDL-R on the surface of hepatocytes leading to a reduction in circulating 
LDL-C. Ultimately, this therapeutic approach may be a useful addition to currently available drug 
therapy for hypercholesterolemia either as a monotherapy or as combination therapy with existing 
LDL-C lowering drugs, such as statins. 
1.2 
Summary of Preclinical Pharmacology 
1.2.1 
Primary Pharmacodynamics 
In monkeys administered CIVI 007 at 0.5 and 1.5 mg/kg once weekly for 4 weeks via the 
subcutaneous (SC) route, the PCSK9 protein in serum was reduced by
 compared to 
the baseline level, respectively. The maximum effect was achieved on Day 29, and PCSK9 levels 
did not fully return to pre-study values during the 8-week recovery phase. The effects were 
substantially greater than those seen with 
(the oligonucleotide moiety of CIVI 007, 
without GalNAc conjugate), underpinning the ability of the GalNAc moiety to drive effective liver 
delivery. 
In the same study, CIVI 007 caused dose responsive LDL-C reductions of 53% and 70% compared 
to baseline, respectively, with maximum effect on Day 29; the half-life for reversal of the LDL-C 
reductions was 
 days, respectively. As expected, LDL reductions were tracked by 
apolipoprotein (apo) B reductions. On Day 29, apoB levels were down dose dependently by 
 
, respectively, and apoB levels did not return fully to baseline during the 7 weeks of 
recovery in either of the 2 dose groups. Weak or no effects on high-density lipoprotein cholesterol 
(HDL-C), total cholesterol, and triglycerides were observed. 
The administration route seemed to have an effect on the intended pharmacology (serum PCSK9, 
plasma apoB, and LDL-C), with the intravenous (IV) route being significantly less effective than 
the SC route. Receptor saturation differences might account for an apparent greater effect with the 
more protracted distribution phase associated with SC administration than with the shorter 
distribution phase associated with IV administration. 
1.2.2 
Effect on Plasma Ceramide Levels in Monkeys 
To investigate the potential effect of CIVI 007 on ceramides in monkeys, samples were drawn 
from 6 animals receiving 1.5 mg/kg/week for 4 weeks, on pretreatment Day -8, Day -1, and 
Day 29, one week after the final dose. Compared to both 
pretreatment days, 
treatment with CIVI 007 significantly decreased the levels of ceramides 
 
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. In these lipid classes, the total levels and practically all molecular species within the class 
were decreased by approximately
 when compared to the pre-dose levels. This is quite 
similar to the effect of the PCSK9 loss of function mutation (R46L) in humans, suggesting that 
treatment with CIVI 007 may recapitulate the known CV benefit of this mutation. For some reason, 
the
 levels varied considerably between pre-dose samples, obscuring 
any potential effect of the treatment on this class of ceramides. 
1.3 
Summary of Safety Pharmacology and Toxicology 
1.3.1 
Safety Pharmacology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3.2 
Toxicology 
In the pivotal GLP toxicology studies (2-week and 13-week studies in both rats and monkeys), 
doses of CIVI 007 were administered SC at either weekly (2-week studies) or biweekly (13-week 
studies) intervals at 0, 5, 20, or 50 mg/kg/dose (rats) and 0, 3, 10, or 30 mg/kg/dose (monkeys). 
 


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Based on the combined observations in the 2 and 13-week studies, the no observed adverse effect 
level (NOAEL) was considered to be 20 mg/kg/dose in the rat, which corresponds to a Cmax of 
 and an AUC0-336 of 
 (mean of both sexes on Day 85), and 30 mg/kg/dose 
in the monkey, which corresponded to CIVI 007 exposures (mean of both sexes on Day 85) of
 
 for AUC0.5-24 and 
 for Cmax.  
The genotoxic and mutagenic potential of CIVI 007 was evaluated in GLP in vitro bacterial 
mutagenicity and chromosomal aberrations studies and were found to be negative at maximum 
“limit” doses specified in regulatory guidelines. 
 
 
 
 
 
 
 
 
 
  
In conclusion, it is considered that the available safety information supports the administration of 
CIVI 007 to volunteers in this study.  
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1.7 
Clinical Summary 
The first in human (FIH) study is a placebo controlled, single blind, randomized, Phase 1, single 
ascending dose (SAD) and multiple ascending dose (MAD) study to assess the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of CIVI 007 SC administered in otherwise 
healthy male and female subjects with an elevated LDL-C level. This study is currently ongoing 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
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1.8 
Rationale 
The purpose of this study is to further investigate the early clinical profile of lower doses of 
CIVI 007 in patients with hypercholesterolemia and on a stable dose of background statin therapy.  
The principal objective of this study is to obtain safety and tolerability data when CIVI 007 is 
administered SC given twice over a 28-day dosing interval. This information, together with the 
PK and PD data, will help establish the doses and dosage regimen suitable for administration to 
larger groups of patients in Phase 2b and 3 clinical development.  
1.9 
Risk/Benefit 
Patients in the current study are not expected to receive any significant, long-term health benefit 
(beyond that of an assessment of their medical status) from participating in the study.  
The risks of participation are primarily those associated with adverse reactions to the study 
treatment as previously described. Based on initial observations in the ongoing Phase 1 trial, CIVI 
007 has a favorable clinical profile at lower doses and number of injections to justify advancement 
of CIVI 007 to Phase 2a clinical development. The proposed Phase 2a study will provide robust 
information to determine advancement of the program to Phase 2b/3 testing. 
There may also be some discomfort from collection of blood samples and other study procedures. 
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events associated with CIVI 007 may be found in the IB1. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to assess the safety and tolerability of CIVI 007 following 
multiple SC doses in patients on a background of a stable dose of statin therapy.  
2.2 
Secondary Objective 
The secondary objective is to assess the PD effect of CIVI 007 on total PCSK9 and LDL-C levels 
in the study population. 
2.3 
Exploratory Objectives 
The exploratory objectives include the following: 
• To assess the effect of CIVI 007 on other lipid and lipoproteins including triglycerides (TG), 
HDL-C, non-HDL-C, very low density lipoprotein-cholesterol (VLDL-C), total cholesterol, 
apolipoproteins B, A-I and lipoprotein(a) 
• To assess the effect of CIVI 007 on high-sensitivity C-reactive protein (hsCRP) 
• To collect antidrug antibody (ADA) samples for potential future assessments of 
immunogenicity  
• To further inform the population PK model of CIVI 007 with sparse PK sampling in patients 
on a background of statin therapy 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a Phase 2a, randomized, double-blind (investigator/subject), sponsor open, parallel-group, 
multicenter study to evaluate the early clinical profile (safety, tolerability, PD, and PK) of 
CIVI 007 in patients on a background of statin therapy with or without ezetimibe. Patients are 
required to be on standard of care treatment for high blood cholesterol consistent with 2018 
ACC/AHA guidelines14, that includes a stable dose of statin therapy for at least 4 weeks prior to 
the Screening Visit. The study will enroll approximately 48 patients who will be randomized to 1 
of 3 active treatment groups or the placebo reference group (12 patients per active treatment group 
and 12 in the placebo treatment group). 
All potentially eligible patients will partake in the Screening Visit up to 21 days prior to Day 1. 
The Screening Visit will be the first study visit. 
The Treatment Period begins with the first administration of study drug on Day 1 where eligible 
patients will be randomized in a 1:1:1:1 ratio to one of the following treatment groups: 
• Group 1: 
mg CIVI 007 administered SC on Day 1 and Day 29 
• Group 2: 
mg CIVI 007 administered SC on Day 1 followed by
mg CIVI 007 administered 
SC on Day 29 
• Group 3: 
 mg CIVI 007 administered SC on Day 1 and Day 29 
• Group 4: Placebo for CIVI 007 administered SC on Day 1 and Day 29 
Patients will receive an initial dose of CIVI 007 or placebo at the study site on Day 1. For 
convenience, eligible patients will have the option to be admitted to the study site the day prior to 
Day 1. Patients will be discharged from the study site after completing the 8-hour post-dose follow-
up assessments and will attend scheduled outpatient visits at Days 8, 15 and 22 to assess safety, 
tolerability, PK, and PD prior to their second dose. These visits and associated lab results will be 
used to assess eligibility to receive the second study drug administration. All doses will be 
administered in the fasted state in the morning, in accordance with a randomization schedule. 
The second administration of study drug ends the Treatment Period and is to occur 4 weeks later 
on Day 29. Patients will again be discharged from the study site after completing the 8-hour post 
dose follow-up assessments. This will end the Treatment Period.  
The Follow-up Period then begins and patients will attend scheduled follow-up visits at Days 36, 
43, 57 and 85 to assess safety, tolerability, PK, and PD. The duration of the Follow-up Period will 
therefore be approximately 2 months from the last dose of study drug, unless extended follow-up 
is required based on Day 85 LDL-C assessments or other Investigator determined safety 
considerations.  
Extended follow-up visits will be conducted on a monthly basis for up to 3 months if Day 85 
LDL-C levels are <80% of their baseline level; extended follow-up will end within the 3-month 
period if LDL-C levels are ≥80% of baseline. Extended follow-up visits (frequency and 
assessments will be at the discretion of the Investigator) to monitor Investigator determined safety 
considerations may extend beyond 3 months, if deemed appropriate by the Investigator, and will 
continue until there are no safety observations requiring further follow-up. The total duration of 
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the study for each patient will be approximately 3 to 6.5 months, depending on the variable length 
of the screening, and follow up periods.  
A Safety Review Committee (SRC) will perform interim unblinded reviews of safety, tolerability, 
and available PK and PD data collected for the purposes of protecting subject safety as well as 
providing guidance to the Sponsor on the evolving clinical profile of CIVI 007. The SRC will 
comprise, at a minimum, the Sponsor’s clinical development contact, the study Medical Monitor, 
a gastroenterologist not involved in study conduct and a pharmacokineticist. A separate document 
will detail the SRC’s operating procedures. 
The study design is graphically summarized in Figure 1: 
Figure 1. Summary of the Study Design 
 
Mo = month; Q4W = Every 4 weeks; Wk = week; R = randomization; 
 
A visit window of ±3 days will be permitted for each study visit except for the first day of study 
drug administration.  
Appendices A and B define the detailed Schedule of Procedures and Clinical Laboratory Analyte 
measures, respectively, to be performed during the study.   
3.2 
Study Design Rationale 
Based on initial data from the ongoing FIH study and within the context of a limited experience, 
CIVI 007 appears to provide the expected pharmacologic profile associated with PCSK9 
inhibition. CIVI 007 shows PCSK9 knockdown that begins around 12.5 mg with maximal 
inhibition of approximately 90% at
mg. The efficacy profile includes robust, dose-dependent 
reductions in atherogenic lipoproteins and lipids that appear to peak within a week following 
administration and are stable out to 4 weeks after administration. Changes in lipoproteins and lipids 
after multiple doses are consistent with those after single doses.  
 
 
 
 
 
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CIVI 007 therefore appears to have a favorable clinical profile 
 and 
 justify 
advancement to Phase 2 testing in this study. The Phase 2a study will provide robust information 
to determine advancement of the program to Phase 2b/3 testing. A forced up-titration dosing group 
(
mg) will provide an initial understanding of this dosing strategy on CIVI 007’s clinical 
profile. 
A parallel group design, as opposed to an ascending dose design, has been chosen as initial Phase 1 
observations have demonstrated safety in the study dose range. Subcutaneous dosing has been 
chosen as this is the intended clinical route of administration. 
Dosing and follow-up will occur in a double-blind state for the Investigator and clinical staff in 
order to avoid bias in the collection of data.   
Conducting the study in patients with LDL-C levels in the study range and on a background of a 
stable dose of statin therapy (with or without ezetimibe) will enable safety, tolerability, PK, and 
PD data to be collected in the intended clinical population in whom additional drug treatment may 
be warranted to optimize their LDL-C levels. 
Placebo has been chosen as the control treatment to assess whether any observed effects are 
treatment-related or simply reflect the study conditions. 
3.3 
Study Start and End of Study Definitions 
The start of the study is defined as the date the first patient who is subsequently enrolled to the 
study signs an Informed Consent Form (ICF). The end-of-the study is defined as the date of the 
last patient’s last assessment (scheduled or unscheduled). 
3.4 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of patients and execution of the study 
• Cancellation of drug development 
3.5 
Study Indication 
Treatment of hypercholesterolemia. 
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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
4.1 
Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Willing and able to provide written and signed informed consent prior to any study-specific 
procedures. 
2. Males or females, 18-70 years of age at the time of consent. 
3. Body mass index (BMI) between 18.0 and 40.0 kg/m2, inclusive, and a body weight of 
≥60 kg at screening. 
4. Currently on a stable (>4 weeks prior to the Screening Visit) dose of statin therapy (with 
or without ezetimibe). 
5. Fasting LDL-C: 
a. ≥100 mg/dL for those without any evidence of established ASCVD at the Screening 
Visit  
or, 
b. ≥70 mg/dL for those with evidence of established ASCVD at the Screening Visit. 
• Established ASCVD is defined as a history of at least 1 of the following occurring 
no more recently than 3 months prior to screening:  
o Acute coronary syndrome 
o Myocardial infarction 
o Stroke or transient ischemic attack presumed to be of atherosclerotic origin 
o Coronary revascularization (Coronary Artery Bypass Grafting or Percutaneous 
Coronary Intervention) 
o Peripheral vascular disease or revascularization 
o In the absence of an above event, ASCVD as diagnosed >3 months prior to the 
Screening Visit based on invasive or noninvasive imaging such as angiography, 
coronary artery calcium (CAC) score >75th percentile, or >50% stenosis in any 
arterial bed. 
Note: Retesting will be allowed once at Screening Visit for LDL-C that is in the range of 
65-69 mg/dL.  
6. Fasting TGs <400 mg/dL at the Screening Visit. 
Note: Retesting will be allowed once at Screening Visit for TGs in the range of 401-450 
mg/dL. 
7. Women of childbearing potential (i.e., not postmenopausal [documented amenorrhea for 
1 year in the absence of other biological or physiological causes] or surgically sterile 
including tubal ligation) must have a negative serum pregnancy test at the Screening Visit 
and a negative urine dipstick prior to dosing on Day 1. Postmenopausal status will be 
confirmed with a Screening Visit serum follicle-stimulating hormone (FSH) level 
>40 mIU/mL. Women aged >60 years whose FSH values are not >40 mIU/mL may be 
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Participating women of childbearing potential must agree to use 2 acceptable methods of 
contraception throughout the duration of the study and for 30 days after the last dose of 
study drug. Acceptable methods of contraception include condom, nonhormonal 
intrauterine device, or a vasectomized partner. 
8. Male participants must be willing to use condoms during sexual intercourse from the 
Screening Visit until at least 90 days after administration of the last dose of study drug. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Women who are pregnant, nursing or breast feeding. 
2. Currently prescribed a lipid lowering agent other than a statin or ezetimibe. 
3. Abnormal liver function test at the Screening Visit (aspartate aminotransferase or alanine 
aminotransferase >1.5 × the ULN, total bilirubin >1.5 × ULN, or alkaline phosphatase 
>1.5 × ULN, based on appropriate age and gender normal values). Participants with 
bilirubin >1.5 × ULN and a history of Gilbert’s syndrome may be included. 
4. Active liver disease as defined by the investigator (e.g., cirrhosis, alcoholic liver disease, 
hepatitis B virus, hepatitis C virus, autoimmune hepatitis, liver failure, and/or liver cancer) 
or history of liver transplant. NASH is considered exclusionary while non-alcoholic fatty 
liver (NAFL) is not exclusionary. 
5. Known diagnosis of human immunodeficiency virus. 
6. Mild, moderate or severe renal insufficiency, defined as an estimated glomerular filtration 
rate (eGFR) <60 mL/min/1.73m2 (calculated using the Chronic Kidney Disease 
Epidemiology Collaboration eGFR formula), at the Screening Visit. 
7. Uncontrolled thyroid disease: hypothyroidism or hyperthyroidism, as defined by 
thyroid-stimulating hormone below the lower limit of normal or >1.5 × ULN, respectively, 
based on results from the Screening Visit. If controlled, treatment should be stable for at 
least 3 months prior to the Screening Visit. 
8. Type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus, defined as hemoglobin 
A1c (HbA1c) value >9%, based on results from the Screening Visit. 
9. New York Heart Association Class II, III, or IV heart failure. 
10. Myocardial infarction, severe or unstable angina pectoris, coronary revascularization, or 
other major cardiovascular event(s) resulting in hospitalization within 3 months of the 
Screening Visit. 
11. Uncontrolled cardiac arrhythmia or prolonged QT interval on the Screening Visit or the 
pre-dose Day 1 ECG (QT corrected using Fridericia’s formula [QTcF] >450 msec for men 
and >470 msec for women), or known family history of prolonged QT interval or 
unexplained sudden cardiac death. 
12. Currently receiving cancer treatments or, in the Investigator’s opinion, is at risk of relapse 
for recent cancer within the study period. 
13. A history of autoimmune disorder(s). 


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14. A history of hematologic or coagulation disorders.  
15. Abnormal PT, aPTT, or INR at the screening visit. 
16. Concomitant antiplatelet or anticoagulation medication. Allowable are low-dose aspirin 
(81 mg or less, daily) for CVD risk reduction, or PRN for occasional pain relief.  Other 
antiplatelet drugs (e.g., P2Y12 inhibitors) and all anticoagulants are exclusionary.   
17. Except as noted above, patients who have a clinically significant disorder that, in the 
opinion of the Investigator, could contraindicate the administration of study drug, affect 
compliance, interfere with study evaluations, or confound the interpretation of study results 
18. History of drug or alcohol abuse within the past year. 
19. Previous treatment with CIVI 007.  
20. Participation in another clinical study of an investigational agent or device concurrently or 
within 1 month prior to the Screening Visit or use of an investigational agent within 1 
month or 5 half-lives (if known), whichever is longer, prior to the Screening Visit. 
21. Donation of blood from 3 months prior, plasma 2 weeks prior, and platelets 6 weeks prior 
to the Screening Visit. 
22. Any other findings that, in the opinion of the Investigator, would compromise the 
participant’s safety or participation in the study. 
4.3 
Retesting 
Laboratory values can be retested once during screening for LDL-C that is in the range of 65-69 
mg/dL, or for triglycerides in the range of 401- 450 mg/dL. 
4.4 
Rescreening 
Participants may be rescreened on one occasion only, following consultation with the Medical 
Monitor, after a minimum of 5 days have elapsed from a patient’s last screening visit. 
4.5 
Withdrawal Criteria 
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
• The patient withdraws consent or requests discontinuation from the study for any reason. 
• Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol. 
• Any serious adverse event (SAE), clinically significant adverse event, severe laboratory 
abnormality, intercurrent illness, or other medical condition which indicates to the 
Investigator that continued participation is not in the best interest of the patient. Specific 
guidance for monitoring of patients and the withdraw of study drug is found in Section 8.1. 
• Pregnancy. 
• Requirement of prohibited concomitant medication.  
• Patient failure to comply with protocol requirements or study-related procedures. 


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• Termination of the study by the Sponsor or the regulatory authority. 
Patients are encouraged not to change their statin dose or use of ezetimibe during the study. If such 
occurs, they should not be withdrawn from the study.  
If a patient withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
end of follow-up visit (Day 85). The reason for patient withdrawal must be documented in the 
electronic case report form (eCRF). 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for scheduled 
visits and is unable to be contacted by the clinical study site. In the case of patients lost to follow-
up, attempts to contact the patient must be made and documented in the patient’s medical records. 


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
All eligible patients will participate in the Screening Visit up to 21 days prior to Day 1. The 
Screening Visit will be their first study visit. 
The Treatment Period will consist of two administrations of study drug. Eligible patients will be 
randomized on Day 1 in a 1:1:1:1 ratio to one of the following treatment groups: 
• Group 1:
mg CIVI 007 administered SC on Days 1 and 29 
• Group 2: 
mg CIVI 007 administered SC on Day 1 followed by
 mg CIVI 007 
administered SC on Day 29 
• Group 3: 
 mg CIVI 007 administered SC on Days 1 and 29 
• Group 4: Placebo for CIVI 007 administered SC on Days 1 and 29 
5.2 
Rationale for Dosing 
Standard antisense molecules have been demonstrated to scale allometrically between the mouse, 
monkey, and human based on body weight.15 Accordingly, with a NOAEL in monkeys of 
30 mg/kg, the doses of
and
mg/patient (based on an average body weight of 60 kg) is 
>
-fold below the NOAEL. 
More importantly, based on initial data from the ongoing FIH study and within the context of a 
limited experience, CIVI 007 appears to provide the expected pharmacologic profile associated 
with PCSK9 inhibition. CIVI 007 shows PCSK9 knockdown that begins around 12.5 mg with 
maximal inhibition of approximately 90% at 
 mg. The efficacy profile includes robust, dose-
dependent reductions in atherogenic lipoproteins and lipids that begin within 1 week of 
administration and are stable out to 4 weeks after administration. Changes in lipoproteins and lipids 
after multiple doses are consistent with those after single doses.  
There were no obvious drug-related safety findings in the dose range of 12.5 to
mg. Grade 1 
ALT elevations appeared in both placebo and active doses with similar frequency. At higher doses, 
and based on higher levels of ALT increase, a signal of hepatotoxicity was apparent at 300 mg 
with a potential signal in one subject at 150 mg that was confounded with alcohol intake at the 
time of liver testing.  
CIVI 007 therefore appears to have a favorable clinical profile at lower doses and these justify 
advancement to Phase 2a testing in this study. 
5.3 
Randomization and Blinding 
Approximately 48 patients will be assigned randomly to placebo, 
mg CIVI 007, 
mg CIVI 
007 followed by
mg CIVI 007 or 
mg CIVI 007 in a 1:1:1:1 allocation ratio.  
Throughout the study, study treatment will be administered in a double-blinded fashion for the 
Investigator, clinical staff, and patients. Only where required will key site staff (such as 
pharmacist) be unblinded throughout the study. 
The following controls will be employed to maintain the double-blind execution of the study: 
• The placebo solution will be identical in appearance to the CIVI 007 solution. 
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• The Investigator and other members of staff involved with the study will remain blinded. 
• Lipid levels after randomization will be blinded to the study site. 
• Appropriate firewalls will exist to prevent communication between the unblinded SRC and 
personnel involved in study execution.  
5.4 
Breaking the Blind 
In order to manage patient safety (in the event of possible treatment-related SAEs or severe adverse 
events), the decision to unblind resides solely with the Investigator. Whenever possible, and 
providing it does not interfere with or delay any decision in the best interest of the patient, the 
Investigator will discuss the intended code-break with the study Medical Monitor. If it becomes 
necessary to break the code it will be done using the IRT and the date, time, and reason will be 
recorded in the patient’s source data. 
5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
CIVI 007 for SC administration will be supplied by the Sponsor in vials packaged in a study drug 
kit (2 vials per kit). The placebo study drug (commercial grade sterile saline solution for SC 
administration) will also be supplied by the Sponsor. 
Study drug will be packaged according to current Good Manufacturing Practice (GMP) and Good 
Clinical Practice (GCP) guidelines.  
Study drug will be labeled according to the requirements of local law and legislation, as well as 
current GMP and GCP guidelines. Proof labels, detailing actual label text, will be available in the 
study files.  
An unblinded pharmacist will prepare the appropriate study drug or placebo for blinded 
administration by the Investigator site. 
5.5.2 
Study Drug Preparation and Dispensing 
The study drugs will be transferred from the pharmacy to the area where patients will be dosed by 
qualified clinical staff who will remain blinded to the treatment group. 
5.5.3 
Study Drug Administration 
CIVI 007 and placebo are sterile solutions to be administered by SC injection.  
Dosing is to be in the morning following an overnight fast: 
• CIVI 007 (
or 
mg) is to be administered SC into the abdomen (or thigh or upper arm, if 
necessary) from a solution at 150 mg/mL (
mg per 
mL vial).  
• Placebo is to be administered SC into the abdomen (or in thigh or upper arm, if necessary). 
The volume of injection will be randomly assigned to match one of the two active CIVI 007 
doses. 
Note: For the second dose of CIVI 007 or placebo administration, the investigators should try 
to avoid using the same injection site area as the first dose. For other permitted concomitant 
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medications administered subcutaneously, do not administer in same injection site area as the 
study drug, for at least 2 weeks after the last dose of study drug. 
5.5.4 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
• All doses will be administered by and under the supervision of suitably qualified study site 
staff. 
5.5.5 
Storage and Accountability 
Both CIVI 007 and placebo will be stored at the study site, according to the instructions on the 
label, in a location that is locked with restricted access. 
The unblinded pharmacist will maintain an accurate record of the receipt of CIVI 007  and placebo 
vials received. In addition, an accurate drug disposition record will be kept, specifying the amount 
dispensed to each patient and the date of dispensing. This drug accountability record will be 
available for inspection at any time. At the completion of the study, the original drug accountability 
record will be available for review by the Sponsor upon request. 
Used and empty dose kits will be discarded upon satisfactory completion of the compliance and 
accountability procedures by study CRO personnel monitoring the study. Any unused or partially 
used kits will be retained until completion of the study. 
At the completion of the study, all unused CIVI 007 kits and vials will be returned to the Sponsor 
or disposed of by the study site, per the Sponsor’s written instructions. 
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
Once eligibility is determined, and until study completion, patients are to be counseled from use 
of any new, or change in dose, of any prescription or nonprescription medications/products. 
Specific attention is to be paid to maintaining the concurrent dose of statin/ezetimibe therapy 
during the course of the study.  
5.6.2 
Restricted Medications and/or Procedures 
Patients are restricted from using any new prescription or over-the-counter cholesterol lowering 
medication. In addition, until completion of follow-up, change in the concurrent dose or 
discontinuation of statin/ezetimibe medication during the course of the study is prohibited unless 
deemed medically necessary by the Investigator (or designee) or the patient’s medical care 
provider.  
5.6.3 
Allowed Medications and/or Procedures 
Except as noted in restricted medications, and if medically warranted and deemed necessary by 
the Investigator (or designee) or the patient’s medical care provider, concurrent medication is to 
be added or doses changed as needed given the patient’s prior consent to its use. 


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5.6.4 
Documentation of Prior and Concomitant Medication Use 
Any medication taken by a patient during the course of the study and the reason for its use will be 
documented in the source data. For patients not taking a lower than recommended statin therapy, 
the reason should be documented in the CRF. 
5.7 
Dietary and Lifestyle Restrictions 
5.7.1 
Diet
 
Most study visits require measurement of fasting lipids. Those study visits requiring lipid 
measurement should be following an overnight fast by the patient (10 hours ±2 hours). 
In addition, on Day 1 and Day 29, patients will be fasted overnight (10 ±2 hours) prior to study 
drug administration and until 3 hours post-dose, after which a meal will be provided by study staff 
(lunch times will be staggered as needed between patients to ensure this 3-hour interval in each 
case). Patients may consume water ad libitum during the days of study drug administration. 
At all other times during the study, patients are to follow their normal dietary pattern and may 
consume water ad libitum.  
Consumption of alcohol will not be permitted the day immediately prior to and days of study drug 
administration.  Alcohol intake will be limited to a maximum of 2 units/day on all other days, from 
screening through the final Follow-up Visit. 
5.7.2 
Smoking 
Smoking will not be permitted on days of study drug administration until after lunch, and for 
1 hour before each BP and pulse rate measurement outside these periods. Patients will otherwise 
be permitted to smoke their normal daily number of cigarettes. 
5.7.3 
Exercise 
Patients are required to refrain from strenuous exercise from the screening visit until the final 
Follow-up Visit and will otherwise maintain their normal level of physical activity during this time 
(i.e., will not begin a new exercise program nor participate in any unusually strenuous physical 
exertion). 
5.7.4 
Blood Donation 
Patients are required to refrain from donation until 3 months after the final Follow-up Visit. 
5.7.5 
Contraception 
Female patients who are of non-childbearing potential will not be required to use contraception. 
Women of non-childbearing potential are defined as permanently sterile (i.e., due to hysterectomy, 
bilateral salpingectomy, or bilateral oophorectomy) or postmenopausal (defined as at least 1-year 
post cessation of menses without an alternative medical cause). Postmenopausal status will be 
confirmed with a screening serum FSH level >40 mIU/mL. FSH testing will be conducted in all 
postmenopausal females who are not surgically sterile regardless of age. Women aged >60 years 
whose FSH values are not >40 mIU/mL may be included at the discretion of the Investigator and 
in consultation with the Sponsor. 


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Female patients of childbearing potential must be willing to use a highly effective method of birth 
control (i.e., contraceptive measure with a failure rate of <1% per year) in conjunction with male 
barrier contraception (i.e., male condom with spermicide) from the time of signing the ICF until 
30 days after the last dose of study drug. Highly effective methods of contraception include the 
following: 
• Intrauterine device (IUD; e.g., Mirena®). Steel or copper IUDs are acceptable.  
• Established use of oral, implanted, transdermal, or injectable hormonal method of 
contraception associated with inhibition of ovulation.  
• Male sterilization (performed at least 90 days prior to the Screening Visit), with verbal 
confirmation of surgical success (for female patients on the study, the vasectomized male 
partner should be the sole partner for that patient). 
• Bilateral tubal ligation or occlusion (performed at least 90 days prior to the Screening Visit). 
Male patients with partners of childbearing potential must use a male barrier method of 
contraception (i.e., male condom with spermicide) in addition to a second method of acceptable 
contraception used by their female partners, from Day 1 until 90 days after the last dose of study 
drug. In addition to the list of highly effective contraception methods above, other acceptable 
methods of contraception for the female partner include the following: 
• Established use of progesterone-only oral contraception, where inhibition of ovulation is not 
the primary mode of action. 
• Diaphragm, cap, or sponge in conjunction with spermicide. 
For male patients, sexual intercourse with female partners who are pregnant or breastfeeding 
should be avoided unless condoms are used from the time of the first dose until 90 days after the 
last dose of study drug. Male patients are required to refrain from donation of sperm from Day 1 
until 90 days after the last dose of study drug. 
Patients who practice true abstinence, because of the patient’s lifestyle choice (i.e., the patient 
should not become abstinent just for the purpose of study participation) are exempt from 
contraceptive requirements. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post 
ovulation methods) and withdrawal are not acceptable methods of contraception. If a patient who 
is abstinent at the time of signing the ICF becomes sexually active they must agree to use 
contraception as described previously.  
For patients who are exclusively in same sex relationships, contraceptive requirements do not 
apply. If a patient who is in a same sex relationship at the time of signing the ICF becomes engaged 
in a heterosexual relationship, they must agree to use contraception as previously described. 
The contraceptive method(s) being employed by patients should be reviewed with the patient 
during the course of the trial. 


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6 
STUDY PROCEDURES 
6.1 
Screening Visit (Up to Day -21) 
The following procedures will be performed at the Screening Visit: 
• Obtain informed consent. 
• Review inclusion/exclusion criteria. 
• Record medical/surgical history and demographics. 
• Perform full physical examination 
• Record vital signs, height and weight (height will only be collected at the screening visit). 
• Collect urinalysis assessment. 
• Perform serum pregnancy test. 
• Perform FSH testing. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and hematology 
assessments. 
• Collect blood samples for TSH, HbA1c, and serology measurements. 
• Collect blood samples for drugs of abuse. 
• Collect blood for fasting lipid panel assessment. 
• Perform 12-lead ECG measurements. 
• Record adverse events. 
• Record concomitant medications. 
6.2 
Treatment Period (Days 1 to 29) 
6.2.1 
Day 1
 
The following procedures will be performed at Day 1: 
• Perform symptom-directed physical examination. 
• Record vital signs and weight. 
• Collect urine sample for urinalysis assessment. 
• Perform urine pregnancy test. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and hematology 
assessments. 
• Collect blood samples for fasting lipid panel assessment and statin PK. 
• Collect blood samples for fasting apolipoproteins and LDL-C (beta-quant). 
• Collect blood samples for hsCRP, PCSK9, and fibrinogen analysis. 


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• Collect blood samples for anti-drug antibody analysis 
• Perform 12-lead ECG measurements. 
• Randomize patients. 
• Administer study drug. 
• Collect blood samples for sparse PK, cytokine panel and complement activation analysis. 
• Record adverse events including injection site reactions. 
• Record concomitant medications.  
6.2.2  
Day 8 
The following procedures will be performed at Day 8: 
• Perform symptom-directed physical examination. 
• Record vital signs and weight. 
• Collect urine sample for urinalysis assessment. 
• Perform urine pregnancy test. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and hematology 
assessments. 
• Collect blood samples for fasting lipid panel assessment. 
• Collect blood samples for fasting apolipoproteins and LDL-C (beta-quant). 
• Collect blood samples for hsCRP, PCSK9, and fibrinogen analysis. 
• Collect blood samples for sparse PK, cytokine panel and complement activation analysis. 
• Record adverse events. 
• Record concomitant medications. 
6.2.2 
Day 15
 
The following procedures will be performed at Day 15: 
• Perform symptom-directed physical examination. 
• Record vital signs and weight. 
• Collect urine sample for urinalysis assessment. 
• Perform urine pregnancy test. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and hematology 
assessments. 
• Collect blood samples for fasting lipid panel assessment. 
• Collect blood samples for fasting apolipoproteins and LDL-C (beta-quant). 
• Collect blood samples for hsCRP, PCSK9, and fibrinogen analysis. 


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• Collect blood samples for anti-drug antibody analysis 
• Collect blood samples for sparse PK, cytokine panel and complement activation analysis. 
• Perform 12-lead ECG measurements. 
• Record adverse events. 
• Record concomitant medications. 
6.2.3 
Day 22
 
The following procedures will be performed at Day 22: 
• Perform symptom-directed physical examination. 
• Record vital signs and weight. 
• Collect urine sample for urinalysis assessment. 
• Perform urine pregnancy test. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and hematology 
assessments. 
• Collect blood samples for fasting lipid panel assessment. 
• Collect blood samples for hsCRP, PCSK9, and fibrinogen analysis. 
• Collect blood samples for sparse PK, cytokine panel and complement activation analysis. 
• Record adverse events. 
• Record concomitant medications. 
6.2.4 
Day 29
 
The following procedures will be performed at Day 29: 
• Perform symptom-directed physical examination. 
• Record vital signs and weight. 
• Collect urine sample for urinalysis assessment. 
• Perform urine pregnancy test. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and hematology 
assessments. 
• Collect blood samples for fasting lipid panel assessment and statin PK. 
• Collect blood samples for fasting apolipoproteins and LDL-C (beta-quant). 
• Collect blood samples for hsCRP, PCSK9, and fibrinogen analysis. 
• Determine eligibility to receive 2nd study drug injection. 
• Administer study drug. 
• Collect blood samples for sparse PK, cytokine panel and complement activation analysis. 


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• Collect blood samples for anti-drug antibody analysis.   
• Perform 12-lead ECG measurements. 
• Record adverse events including injection site reactions. 
• Record concomitant medications. 
6.3 
Follow-Up Period (Days 30 to 85 or End of Treatment) 
6.3.1 
Day 36 
The following procedures will be performed at Day 36: 
• Perform symptom-directed physical examination. 
• Record vital signs and weight. 
• Collect urine sample for urinalysis assessment. 
• Perform urine pregnancy test. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and hematology 
assessments. 
• Collect blood samples for fasting lipid panel assessment. 
• Collect blood samples for hsCRP, PCSK9, and fibrinogen analysis. 
• Collect blood samples for sparse PK, cytokine panel and complement activation analysis. 
• Record adverse events. 
• Record concomitant medications. 
6.3.2 
Day 43 
The following procedures will be performed at Day 43: 
• Perform symptom-directed physical examination. 
• Record vital signs and weight. 
• Collect urine sample for urinalysis assessment. 
• Perform urine pregnancy test. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and hematology 
assessments. 
• Collect blood samples for fasting lipid panel assessment. 
• Collect blood samples for hsCRP, PCSK9, and fibrinogen analysis. 
• Collect blood samples for anti-drug antibody analysis 
• Collect blood samples for sparse PK, cytokine panel and complement activation analysis. 
• Record adverse events. 


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• Record concomitant medications. 
6.3.3 
Day 57
 
The following procedures will be performed at Day 57: 
• Perform symptom-directed physical examination. 
• Record vital signs and weight. 
• Collect urine sample for urinalysis assessment. 
• Perform urine pregnancy test. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and hematology 
assessments. 
• Collect blood samples for fasting lipid panel assessment and statin PK. 
• Collect blood samples for fasting apolipoproteins and LDL-C (beta-quant). 
• Collect blood samples for hsCRP, PCSK9, and fibrinogen analysis. 
• Collect blood samples for anti-drug antibody analysis 
• Collect blood samples for sparse PK, cytokine panel and complement activation analysis. 
• Perform 12-lead ECG measurements. 
• Record adverse events. 
• Record concomitant medications. 
6.3.4 
Day 85 or Early Termination 
The following procedures will be performed at Day 85 or early termination: 
• Perform full physical examination. 
• Record vital signs and weight. 
• Collect urine urinalysis assessment. 
• Perform urine pregnancy test. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and hematology 
assessments. 
• Collect blood samples for fasting lipid panel assessment. 
• Collect blood samples for fasting apolipoproteins and LDL-C (beta-quant). 
• Collect blood samples for hsCRP, PCSK9, and fibrinogen analysis. 
• Collect blood samples for anti-drug antibody analysis 
• Collect blood samples for sparse PK, cytokine panel and complement activation analysis. 
• Perform 12-lead ECG measurements. 
• Record adverse events. 


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• Record concomitant medications. 
6.4 
Extended Follow-up Visits 
Extended follow-up visits will be conducted based on either LDL-C level at Day 85 or for safety 
considerations at the Investigator’s discretion.  
• If Day 85 LDL-C levels are <80% of their baseline level; extended follow-up will 
occur monthly for 3 months and end earlier if LDL-C levels are ≥80% of baseline. 
The fasting lipid panel will be assessed and occur monthly for up to 3 months or until 
LDL-C returns to within 80% of its baseline level (whichever is sooner). Those visits 
will also record AEs and concomitant medication. 
• Extended Follow-up visits for safety considerations (frequency and assessments will 
be at the discretion of the Investigator) to monitor Investigator determined safety 
considerations may also occur and extend beyond 3 months, if deemed appropriate by 
the Investigator, and will continue until there are no safety observations requiring 
further follow-up. Those visits will also record AEs and concomitant medication. 
For extended follow-up Visits due to LDL-C <80% of the baseline level. The procedures need to 
be performed will include the following: 
• Record vital signs and weight. 
• Collect blood samples for fasting lipid panel assessment. 
• Record adverse events. 
• Record concomitant medications. 
For extended follow-up Visits for safety considerations, the procedures need to be performed will 
be consideration specific and may include but not be limited to the following: 
• Record vital signs and weight. 
• Collect urine sample for urinalysis assessment. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and 
hematology assessments. 
• Perform 12-lead ECG measurements. 
• Record adverse events. 
• Record concomitant medications. 
6.5 
Early Termination Visit and Withdrawal Procedures 
The end of treatment for patients completing the study is the Day 85 visit. For patients who are 
withdrawn from the study prior to completion, all Day 85 procedures will be performed at an early 
termination visit. These procedures include the following: 
• Perform full physical examination. 
• Record vital signs and weight. 
• Collect urine sample for urinalysis assessment. 


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• Perform urine pregnancy test. 
• Collect blood samples for clinical safety chemistry panel, coagulation, and hematology 
assessments. 
• Collect blood samples for fasting lipid panel assessment. 
• Collect blood samples for fasting apolipoproteins and LDL-C (beta-quant). 
• Collect blood samples for hsCRP, PCSK9, and fibrinogen analysis. 
• Collect blood samples for anti-drug antibody analysis 
• Collect blood samples for sparse PK, cytokine panel and complement activation analysis. 
• Perform 12-lead ECG measurements. 
• Record adverse events. 
• Record concomitant medications. 


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7 
EFFICACY ASSESSMENTS 
7.1 
Primary Endpoints 
The primary safety/tolerability endpoints for this study are as follows: 
• incidence and severity of any drug-related AE 
• incidence of clinically significant laboratory abnormalities, based on drug-induced changes 
from baseline in hematology, clinical safety chemistry, and urinalysis test results. 
7.2 
Secondary Endpoints 
The secondary efficacy endpoints include the following changes from baseline measured 
approximately 28 days after the first and 28 and 56 days after the last injection of study drug: 
• The percent change in PCSK9 and LDL-C  
7.3 
Exploratory Endpoints 
The exploratory endpoints include the following: 
PD endpoints are the absolute and % changes from baseline (except where indicated) in the 
levels of the following in serum or plasma over the time course of the treatment period and 
follow-up: 
• PCSK9 (absolute only) 
• LDL-C (absolute only) 
• VLDL-C 
• triglycerides 
• HDL-C 
• Non-HDL-C 
• total cholesterol 
• lipoprotein (a) 
• apolipoproteins B and A-I 
• hsCRP 
The following PK parameters will be calculated for CIVI 007, where possible: 
• Cmax 
• time of the maximum observed plasma concentration (tmax) 
• Area under the plasma concentration-time curve from time 0 to the time of last 
quantifiable concentration (AUC0-t) 
• concentration observed at pre-dose (Ctrough) 


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Additional exploratory PK parameters, which may include but are not limited to the following, 
may be calculated:  
• area under the plasma concentration-time curve from time 0 extrapolated to infinity 
(AUC0-∞) 
• area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24) 
• area under the plasma concentration-time curve from time 0 to 48 hours (AUC0-48) 
• percentage of AUC0-∞ that is due to extrapolation (%AUCextrap) 
• apparent termination elimination rate constant (λz) 
• apparent plasma terminal elimination half-life (t1/2) 
• apparent total plasma clearance (CL/F) 
• apparent volume of distribution during the terminal phase (Vz/F) 
7.4 
Pharmacokinetics 
Sparse PK sampling will be conducted for all consenting participants. Sampling will be performed 
on dosing days, and at each study visit during the Treatment and Follow-up Periods. For each of 
the dosing days, a PK sample will be drawn pre-dose (- 1 hour), 3 hours (±1 hour) post-dose, and 
at 8 hours (±1 hour) post-dose. 
The population PK model created based on data from the ongoing Phase 1 study will be refined to 
evaluate the relationship of CIVI 007 PK to demographics and background statin therapy. The 
model will be periodically refined as new and broader datasets emerge to include the covariates of 
special populations, concomitant medications, and disease state. 


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8 
SAFETY ASSESSMENTS 
The safety variables include adverse events, safety laboratory parameters (including clinical safety 
chemistry, hematology, coagulation parameters including fibrinogen, complement activation, 
cytokines, and urinalysis), 12-lead ECGs, physical examinations, and vital signs. Samples will also 
be collected for the potential future assessment of anti-drug antibodies.  
8.1 
Individual Patient Safety Monitoring and Criteria For Discontinuation of Study 
Drug 
When any the following criteria are met, patients will be monitored for safety and 
discontinuation of study drug considered using the following guidance. 
• Liver (as per FDA guidance on drug-induced liver injury16) 
- 
Patients with signs or symptoms consistent with liver injury (such as nausea, 
vomiting, anorexia, fatigue, right upper abdominal pain or discomfort) should 
undergo immediate testing of ALT, AST, GGT, bilirubin, ALP, PT, and INR. 
- 
In the absence of clinical symptoms, patients with ALT or AST > 3xULN (if 
normal at baseline) or >2-fold change (if abnormal at baseline) should be retested 
within 48 to 72 hours for the usual serum measures (ALT, AST, ALP, and 
bilirubin) to confirm the abnormalities and to determine if they are increasing or 
decreasing.  There also should be inquiry made about symptoms at the time of 
follow-up.  
- 
If the above abnormalities are confirmed,  
▪ repeat liver enzyme and serum bilirubin tests two or three times weekly.  
The frequency of retesting can decrease to once a week or less if 
abnormalities stabilize or the study drug has been discontinued and the 
patient is asymptomatic. 
▪ Obtain a more detailed history of symptoms and prior or concurrent 
diseases. 
▪ Obtain a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets. 
▪ Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or 
alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary 
tract disease. 
▪ Obtain a history of exposure to environmental chemical agents. 
▪ Obtain additional tests to evaluate liver function, as appropriate (e.g., INR, 
direct bilirubin). 
▪ Considering gastroenterology or hepatology consultations.  
- 
Study drug discontinuation should occur if: 
▪ ALT or AST >8xULN 
▪ ALT or AST >5xULN for more than 2 weeks 
▪ ALT or AST >3xULN and (bilirubin >2xULN or INR >1.5) 
▪ ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%) 
• Platelet Count 


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- 
Patients whose platelet count decreases to <140,000 mm3 should begin weekly 
platelet monitoring, and patient whose platelet count decreases to <75,000 mm3 
should have platelets monitored every 2 to 3 days. Patients whose platelet count 
decreases to <50,000 mm3 should discontinue drug and undergo daily platelet 
monitoring; consultation with a hematologist is also recommended. 
• Renal 
- 
Patients with concern for renal toxicity, spot urine UPCR and/or spot UACR 
should be obtained. Patients with UPCR >50% from baseline or 1.5x ULN should 
be monitored at least every 2 weeks. 
- 
Study drug should be discontinued if patients experience an unexplained, 
confirmed increase in serum creatinine of 0.3 mg/dL above baseline; unexplained, 
confirmed 25% decline in eGFR from baseline; or new-onset hematuria, 
albuminuria (UACR ≥250 mg/g), or proteinuria (≥UPCR 500 mg/g) confirmed on 
repeat testing. 
8.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an IMP, whether or not related to the IMP. All adverse events, including observed or 
volunteered problems, complaints, or symptoms, are to be recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of screening until completion of the Day 85 Visit, early termination 
visit or extended Follow-up, whichever is later. Patients should be instructed to report any adverse 
event that they experience to the Investigator, whether or not they think the event is due to study 
treatment. Beginning at screening, Investigators should make an assessment for adverse events at 
each visit and record the event on the appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure itself.  
Any medical condition already present at Screening, should be recorded as medical history and 
not be reported as an adverse event unless the medical condition or signs or symptoms present at 
baseline changes in severity, frequency, or seriousness at any time during the study. In this case, 
it should be reported as an adverse event. 
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that are 
detected during the study or are present at Screening, and significantly worsen during the study 
should be reported as adverse events, as described below. The Investigator will exercise his or her 
medical and scientific judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, or 
are no longer clinically significant. Abnormal test results that are determined to be an error should 


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not be reported as an adverse event. Laboratory abnormalities or other abnormal clinical findings 
(e.g., ECG abnormalities) should be reported as an adverse event if any of the following are 
applicable: 
• If an intervention is required as a result of the abnormality 
• If action taken with the study drug is required as a result of the abnormality 
• Based on the clinical judgment of the Investigator 
8.2.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
i.e., the relationship cannot be ruled out. 
8.2.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For CIVI 007 the reference safety 
information is included in the IB currently in force. The reference safety information will be 
reviewed yearly and the periodicity of the review will be harmonized with the reporting period of 
the Development Safety Update Report. 
8.2.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study drug 
using the categories of yes or no. 
Assessment of severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
No (unrelated, not related, unlikely to be related) – The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal relationship 
and another cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the adverse event is consistent with a causal 
relationship and no other cause (concomitant drugs, therapies, complications, etc.) can be 
identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 


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The following factors should also be considered: 
• The temporal sequence from study drug administration- 
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases- 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the patient may have. 
• Concomitant drug- 
The other drugs the patient is taking or the treatment the patient receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
• Known response pattern for this class of study drug- 
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
• Exposure to physical and/or mental stresses- 
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event. 
• The pharmacology and PK of the study drug- 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered. 
8.2.4 
Adverse Events of Special Interest 
The Investigator will monitor each patient for clinical and laboratory evidence for adverse events 
of special interest (AESIs) throughout the patient’s participation in this study as defined below.  
The Investigator will assess and record any additional information on the AESI in detail on an 
adverse event form which must be submitted within 24 hours of awareness of the event. 
For this study, AESIs include the following: 
• CTCAE (current version) Grade 2 or higher ALT measurements confirmed on repeat 
measurement 
• Severe or serious injection site reactions (ISRs), ISRs that are associated with a recall 
phenomenon (reaction at the site of a prior injection with subsequent injections), recurrent 
ISRs that are increasing in severity, or ISRs that lead to temporary dose interruption or 
permanent discontinuation of study drug. 
• An ISR is defined as a local reaction at or near the site of injection.  “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (e.g., as may 
occur with swelling or hematoma).  A systemic reaction which includes the injection site 
(e.g., generalized urticaria, other distinct entities or conditions like lymphadenopathy that 
may be near the injection site) is not considered an ISR 


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Adverse events of special interest must be recorded in the eCRF. 
8.3 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
• Death. 
• A life-threatening adverse event. 
Note: An adverse event or adverse reaction is considered “life-threatening” if, in view of either 
the Investigator or Sponsor, its occurrence places the patient at immediate risk of death. It does 
not include an event that, had it occurred in a more severe form, might have caused death. 
• Hospitalization or prolongation of existing hospitalizations. 
Note: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will not 
be recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent, or elective treatment of a preexisting condition 
that did not worsen from Baseline. However, unexpected complications and/or prolongation 
of hospitalization that occur during elective surgery should be recorded as adverse events and 
assessed for seriousness. Admission to the hospital for social or situational reasons (i.e., no 
place to stay, live too far away to come for hospital visits, respite care) will not be considered 
inpatient hospitalizations.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
• An important medical event. 
Note: Important medical events that do not meet any of the above criteria may be considered 
an SAE when, based upon appropriate medical judgment, they may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency. 
8.4 
Serious Adverse Event Reporting - Procedures for Investigators 
Initial reports 
All SAEs occurring from the time of informed consent until completion of the follow-up period 
must be reported to Medpace Clinical Safety within 24 hours of the knowledge of the occurrence. 
After the 30-day reporting window, any SAE that the Investigator considers related to study drug 
must be reported to Medpace Clinical Safety or the Sponsor/designee. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria and 
it is not possible to access the EDC system, send an email to Medpace Safety at medpace-


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safetynotification@medpace.com or call the Medpace SAE reporting line (phone number listed 
below), and fax/email the completed paper SAE form to Medpace (contact information listed in 
Section 8.7) within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available. 
Follow-up reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation (e.g., 
patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or email. If it is 
not possible to access the EDC system, refer to the procedures outlined above for initial reporting 
of SAEs. 
8.5 
Pregnancy Reporting 
If a patient becomes pregnant during the study or within the safety follow-up period, the 
Investigator is to stop dosing with study drug(s) immediately and the patient should be withdrawn 
from the study. Early termination procedures should be implemented at that time.  
A pregnancy is not considered to be an adverse event or SAE; however, it must be reported to 
Medpace Clinical Safety within 24 hours of knowledge of the event. Medpace Clinical Safety will 
then provide the Investigator/site the Exposure In Utero (EIU) form for completion. The 
Investigator/site must complete the EIU form and fax/email it back to Medpace Clinical Safety.  
If the female partner of a male patient becomes pregnant while the patient is receiving study drug 
or within the safety follow-up period, the Investigator should notify Medpace Clinical Safety as 
described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the EIU form should be completed and faxed/emailed to 
Medpace Clinical Safety. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
8.6 
Expedited Reporting 
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSAR) that are fatal or life-threatening as soon as possible to the Food and 
Drug Administration (FDA), Health Canada, and to the Central Ethics Committee, and in any case 
no later than 7 days after knowledge by the Sponsor/designee of such a case. Relevant follow-up 
information will subsequently be communicated within an additional 8 days.  
All other SUSARs will be reported to the FDA, Health Canada, and to the Central Ethics 
Committee, as soon as possible but within a maximum of 15 days of first knowledge by the 
Sponsor/designee.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation.  


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The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to IMP. 
8.7 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
• Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgement should always be applied. 
In cases of a discrepancy in the drug accountability, overdose will be established only when 
it is clear that the patient has taken additional dose(s) or the Investigator has reason to suspect 
that the patient has taken additional dose(s).  
• Misuse: Refers to situations where the medicinal product is intentionally and inappropriately 
used not in a way that is not in accordance with the protocol instructions or local prescribing 
information and may be accompanied by harmful physical and/or psychological effects.  
• Abuse: Is defined as persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
• Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product by a healthcare professional, patient, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors; cases of patients missing doses of 
investigational product are not considered reportable as medication error. 
• Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution. A Special Situations 
Report form will only be completed if a complaint is associated with an adverse drug 
reaction.  
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to Medpace Clinical Safety (contact information listed below) within 
24 hours of knowledge of the event. All adverse events associated with these Special Situations 
Report forms should be reported as adverse events or SAEs as well as recorded on the adverse 
event eCRF and/or the SAE report form. Details of the symptoms and signs, clinical management, 
and outcome should be provided, when available. 
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE reporting line – USA: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-570-5196 
email: medpace-safetynotification@medpace.com 
8.8 
Injection Site Assessment 
The SC injection site may be marked and mapped for later observation. Visual assessment of the 
injection site will be conducted by an Investigator (or designee) at the times indicated in the 


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Schedule of Procedures in Appendix A. Categorical scales will be used to score injection site 
reaction severity, pain, induration, erythema and edema. If a local reaction around the injection 
site occurs, photographs may be obtained.  
8.9 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including clinical 
safety chemistry; hematology; coagulation parameters including fibrinogen; cytokine; 
complement activation; urinalysis; and serology) at the times indicated in the Schedule of 
Procedures in Appendix A. Clinical laboratory analytes are listed in Appendix B. 
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
8.10 
Vital Signs 
Sitting BP, heart rate, respiration rate, and oral body temperature will be assessed at the times 
indicated in the Schedule of Procedures in Appendix A. Vital signs may also be performed at other 
times if judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of vital signs is required. 
All measurements will be performed singly and repeated once if outside the relevant clinical 
reference range. 
Patients must be sitting for at least 5 minutes before vital signs measurements.  
8.11 
12-Lead Electrocardiograms 
Resting 12-lead ECGs will be performed in triplicate and recorded  using the automatic data 
generated by the ECG as the source data. Recordings are to occur after the patient has been supine 
and at rest for at least 5 minutes at the times indicated in the Schedule of Procedures in 
Appendix A.  
Additional 12-lead ECGs may be performed at other times if judged to be clinically appropriate or 
if the ongoing review of the data suggests a more detailed assessment of ECGs is required. The 
Investigator (or designee) will perform a clinical assessment of each 12-lead ECG. 
8.12 
Physical Examinations 
A full physical examination or symptom-directed physical examination will be performed at the 
time points specified in the Schedule of Procedures in Appendix A. 
8.13 
Pharmacokinetic Assessments 
Blood samples will be collected by venipuncture or cannulation at the times indicated in the 
Schedule of Procedures in Appendix A. Procedures for collection, processing, and shipping of PK 
blood samples will be detailed in a separate document. 
Plasma concentrations of CIVI 007 will be determined using validated analytical procedures. 
Specifics of the analytical methods will be provided in a separate document. 


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8.14 
Pharmacodynamic Assessments 
Blood samples will be collected by venipuncture or cannulation at the times indicated in the 
Schedule of Procedures in Appendix A. Procedures for collection, processing, and shipping of PD 
blood samples will be detailed in a separate document. 
Concentrations of PCSK9, apolipoproteins, circulating lipids (LDL-C, triglycerides, HDL-C, 
non-HDL-C [calculation], lipoprotein(a), and total cholesterol), and inflammatory biomarkers, 
will be determined using validated analytical procedures in serum or plasma. Specifics of the 
analytical methods will be provided in a separate document. 


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9 
STATISTICS 
9.1 
Analysis Populations 
The Intent-to-Treat (ITT) Population will include all patients who are randomized to the study and 
will be used to assess efficacy. 
The Per-Protocol Population will include all patients who are randomized to the study and do not 
have any major protocol deviations. 
The Safety Analysis Population will include all patients who receive any amount of study drug. 
9.2 
Statistical Methods 
9.2.1 
Analysis of Primary Safety/Tolerability Data 
Analysis of safety will be descriptive.  
The number and percentage of patients who experience 1 or more adverse events will be 
summarized by dose, relationship to study drug, and severity by descriptive statistics. Adverse 
events will be coded using Medical Dictionary for Regulatory Activities terminology. Listings of 
patients with SAE or discontinuations due to an adverse event will be presented. 
Laboratory parameters will be summarized by dose using descriptive statistics; data listings of 
clinically significant abnormalities will be presented. Individual results of vital signs will be listed 
and summarized. Observed values and changes from baseline in vital signs will be summarized by 
dose. Individual results of quantitative safety ECG parameters from the 12-lead safety ECGs will 
be listed. Observed values and changes from baseline in quantitative ECG parameters will be 
summarized by dose. Abnormal ECGs will be summarized for each dose level. Physical 
examination findings will be listed. 
Where appropriate, safety findings will be graded using the CTCAE version available at the time 
of analysis. 
9.2.2 
Secondary and Exploratory Efficacy Analysis 
The PCSK9, LDL-C, and exploratory lipid/PD endpoints will be listed and summarized using 
descriptive statistics by treatment group over the study period to describe absolute and percent 
changes from baseline.  
The presentation of results will be the observed data and include the estimated means by treatment 
group, their standard errors, and the estimated differences in means between the patient treatments 
and corresponding 95% confidence intervals and p-values.  
The treatment comparisons between each active dose versus placebo will be tested following a 
fixed sequence step-down procedure to control the multiplicity.  
Analysis of the secondary efficacy endpoints will be repeated with the Per Protocol Population. 
Further details will be specified in the Statistical Analysis Plan (SAP). 
9.2.2.1 
Secondary efficacy analysis 
The secondary endpoints of the study will be analyzed using analysis of covariance (ANCOVA) 
models to compare the mean percent change from baseline in LDL-C and PCSK9 28 days after 
the first injection and 28 and 56 days after the second injection of study drug between treatment 


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groups with placebo. This ANCOVA model will include treatment as a factor and baseline level 
as a covariate. 
9.2.2.2 
Pharmacokinetic analysis 
Plasma concentrations of CIVI 007 will be determined for patients randomized to active drug; 
samples for placebo patients will not be analyzed unless required (e.g., to help explain anomalous 
results). Plasma concentrations of CIVI 007 will be listed. Individual and mean CIVI 007 plasma 
concentration-time profiles for each treatment cohort will also be presented graphically. 
Where possible, plasma PK parameters of CIVI 007 after each dose will be calculated using 
standard non-compartmental methods and will be listed and summarized using descriptive 
statistics. 
Where sufficient data are available, CIVI 007 fold increase in exposure will be examined between 
the dose cohorts. The PK parameters may be analyzed for dose proportionality using a variance 
model approach or analysis of variance model as appropriate.  
Pharmacokinetic analysis will use actual times as recorded on the eCRF. Other details and data 
handling procedures will be detailed in the SAP. 
9.2.3 
Interim Analysis 
No formal interim analyses are planned for this study other than descriptive analyses required for 
the SRC to review accumulating safety information. Interim safety reviews and lipid analyses 
(sponsor only) will initially occur when approximately 12 patients have received their first study 
drug injection and have two weeks of follow-up data available. Subsequent analyses will occur 
with the accrual of each 12 new patients who have two week follow-up data available with a final 
review when the last 12 patients have two week follow-up data available. 
Guidelines for interim study stoppage by the SRC will be based on safety parameters and the 
cumulative evidence of treatment group imbalances as follows: 
• Clinically relevant signs or symptoms of similar nature occur in 3 or more patients in a 
treatment group that, in the opinion of the Investigator, warrants stopping based on concerns 
of patient safety.  
• Two or more patients experiencing a non-cardiovascular SAE or 4 or more patients experience 
severe AEs.   
• There is evidence of clinically significant increases in the following: 
o liver tests, defined as 3 × ULN (confirmed with repeat testing) in either ALT or  
AST; or 2 × ULN in either ALP or bilirubin, in 3 or more patients in a treatment 
group. 
o confirmed platelet count decreases to <140,000 mm3  
o confirmed increases in serum creatinine of 0.3 mg/dL above baseline 
9.2.4 
Sample Size Determination 
Approximately 48 patients (12 patients per active treatment group, 12 patients per placebo 
treatment) will be randomized into 1 of 4 treatment groups. 


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The sample size chosen for this study was not based on power calculations. However, the number 
of patients in each part of the present study is common in early clinical studies and is considered 
sufficient to achieve the objectives of the study without exposing undue numbers of patients to 
study drug. 


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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the Clinical Research Associate (CRA) 
during monitoring visits. The CRAs will verify data recorded in the EDC system with source 
documents. All corrections or changes made to any study data must be appropriately tracked in an 
audit trail in the EDC system. An eCRF will be considered complete when all missing, incorrect, 
and/or inconsistent data have been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure username and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Medical Dictionary for Regulatory Activities (latest version) for medical history and adverse 
events 
• World Health Organization Drug Dictionary for prior and concomitant medications 
• CTCAE (current version) 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
10.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 


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destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  
10.3 
End of Study 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last patient in the study. 
 


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve human patients. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study patients are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and 
that the clinical study data are credible. 
11.2 
Institutional Review Board 
The Institutional Review Board (IRB) will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of patients. The study will only be conducted at sites 
where IRB approval has been obtained. The protocol, IB, ICF, advertisements (if applicable), 
written information given to the patients, safety updates, annual progress reports, and any revisions 
to these documents will be provided to the IRB by the Investigator. 
Federal regulations and ICH Guidelines require that approval be obtained from an IRB prior to 
participation of patients in research studies. Prior to study onset, the protocol, any protocol 
amendments, ICFs, advertisements to be used for patient recruitment, and any other written 
information regarding this study to be provided to a patient or patient’s legal guardian must be 
approved by the IRB. 
No drug will be released to the site for dosing until written IRB authorization has been received 
by the Sponsor. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements.   
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB, and/or regulatory agencies. 
A copy of the signed ICF will be given to the subject. 
11.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. Before 
the enrollment of any patient in this study, the Sponsor or their designee will review with the 
Investigator and site personnel the following documents: protocol, Investigator’s Brochure, eCRFs 


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and procedures for their completion, informed consent process, and the procedure for reporting 
SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
11.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition. The records should be 
retained by the Investigator according to specifications in the ICH guidelines, local regulations, or 
as specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.   
11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor and share their 
proposed publication with Medpace and the Sponsor at least 60 days prior to submitting for 
publication, upon which, the Sponsor has 60 days to review and propose edits or additional delay. 
The Sponsor reserves the right to deny publication rights until mutual agreement on the content, 
format, interpretation of data in the manuscript, and journal selected for publication are achieved. 


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11.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 


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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendment to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB within 5 working days. 


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13 
REFERENCES 
1. 
Investigator’s Brochure for CIVI 007. Version 2, 2018. 
2. 
Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density 
lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, 
epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis 
Society Consensus Panel. Eur Heart J. 2017;38(32):2459-72.  
3. 
Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of LDL-lowering therapy 
among men and women: meta-analysis of individual data from 174,000 patients in 27 randomised 
trials. Lancet. 2015;385(9976):1397-405. 
4. 
Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, et al. Efficacy and 
safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the 
ODYSSEY ALTERNATIVE randomized trial. Journal of Clinical Lipidology. 2015;9(6):758-69. 
5. 
Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. 
ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Journal of the American 
College of Cardiology. 2002;40(3):567-72.  
6. 
Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. 
Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: 
guidance for clinicians to prevent coronary heart disease: consensus statement of the European 
Atherosclerosis Society. Eur Heart J. 2013;34(45):3478–90. 
7. 
Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade thematic review 
series: new lipid and lipoprotein targets for the treatment of cardiometabolic diseases. J Lipid 
Res. 2012;53(12):2515-24.  
8. 
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. 
Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 
2017;376(18):1713-22. 
9. 
Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. Cardiovascular efficacy 
and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376(16):1527-39. 
10. 
Havulinna AS, Sysi-Aho M, Hilvo M, Kauhanen D, Hurme R, Ekroos K, et al. Circulating 
ceramides predict cardiovascular outcomes in the population-based FINRISK 2002 cohort. 
Arterioscler Thromb Vasc Biol. 2016;36(12):2424-30. 
11. 
Irwin S. Comprehensive observational assessment: Ia. A systematic, quantitative procedure for 
assessing the behavioral and physiologic state of the mouse. Psychopharmacologia. 
1968;13(3):222-57. 
12. 
van Poelgeest EP, Swart RM, Betjes MG, Moerland M, Weening JJ, Tessier Y, et al. Acute 
kidney injury during therapy with an antisense oligonucleotide directed against PCSK9. Am J 
Kidney Dis. 2013;62(4):796-800. 
13. 
Yu RZ, Gunawan R, Post N, Zanardi T, Hall S, Burkey J, et al. Disposition and pharmacokinetics 
of a GalNAc3-conjugated antisense oligonucleotide targeting human lipoprotein (a) in monkeys. 
Nucleic Acid Ther. 2016;26(6):372-80. 
14        Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on 
the Management of Blood Cholesterol. A Report of the American College of 
 
 


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Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. JACC 2019; 
73: e285-350. 
 
15. 
Yu RZ, Grundy JS, Henry SP, Kim TW, Norris DA, Burkey J, et al. Predictive dose-based 
estimation of systemic exposure multiples in mouse and monkey relative to human for antisense 
oligonucleotides with 2’-o-(2-methoxyethyl) modifications. Mol Ther Nucleic Acids. 
2015;4:e218. 
16         U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER).   July 
2009. Guidance for Industry: Drug-Induced Liver Injury-  Premarketing Clinical Evaluation. 
 


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APPENDICIES
 
Appendix A:  Schedule of Procedures 
Footnotes are on the next page. 
 
Procedure/Visit 
Screeninga 
Treatment Periodb 
Follow-up Periodc 
Up to 
Day -21 
Day 1d 
Day 8 
Day 15 
 
Day 
22 
Day 29 
Day 36 
Day 43 
Day 
57 
Day 85 or ET 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical history and demographics 
X 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
 
 
 
 
 
 
 
 
X 
Symptom-directed physical examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signse, heightf, and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSH/Serum/Urine pregnancy testh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical safety chemistry panel, coagulation, and 
hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Screen/ TSH, HbA1c, and serologyi 
X 
 
 
 
 
 
 
 
 
 
Fasting lipid panelj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting apolipoproteins & beta quant LDL-Ck 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
hsCRP, PCSK9, and fibrinogen 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Study drug/Placebo administration 
 
X 
 
 
 
X 
 
 
 
 
Sample for antidrug antibodies 
 
X 
 
X 
 
X 
 
X 
X 
X 
Sparse PK, cytokine and complement activation 
samplingl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGm 
X 
X 
 
X 
 
X 
 
 
X 
X 
Concurrent statin PKn 
 
X 
 
 
 
X 
 
 
X 
 
Adverse events (including injection site reactions) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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a  All eligible patients will partake in the Screening Visit up to 21 days prior to Day 1. 
b,c Study assessments will be completed within 3 days of the given time point for all study visits other than Day 1. Extended follow-up beyond day 85 for below baseline LDL-C 
will assess the fasting lipid panel and occur monthly for up to 3 months or until LDL-C returns to within 80% of its baseline level. Those visits will also record AEs and concomitant 
medication. 
d  The Investigator will query the participant on Day 1 to determine if there have been any changes in the participant’s health that would affect eligibility or require an update to 
his/her medical/surgical history.  
e  Vital signs include pulse rate, blood pressure, respiration rate, and temperature. Blood pressure should be obtained in a seated position after the participant has been sitting  or at 
least 5 minutes. Blood pressure at the Screening Visit should be obtained in both arms, and the arm with the highest value should be used for ongoing monitoring throughout the 
rest of the study. If an automated assessment is performed, the same machine should be used for the participant throughout the study whenever possible. Care should be taken to 
ensure an appropriate cuff size is utilized. 
f  Height will be measured only at the participant’s Screening Visit. 
g  A urine microscopic examination will be performed when the dipstick result is abnormal (i.e., positive for blood, leukocyte esterase, or nitrites). 
h  Pregnancy tests are for women of childbearing potential only. A serum pregnancy test will be performed at screening. Urine pregnancy test will be conducted at all other visits. 
Unscheduled serum pregnancy testing will be performed for confirmation of positive urine pregnancy testing. FSH tests are for all postmenopausal women who are not surgically 
sterile; FSH testing will be performed once at screening.   
i  Drugs of abuse along with thyroid-stimulating hormone, HbA1c, and serology (HBsAg, HBV, HCV, and HIV) will be measured at the participant’s Screening Visit. Serology 
testing will be HBsAg, HCV, and HIV, with confirmatory testing for positive HCV and HIV Ab screens. 
j  The fasting lipid panel includes LDL-C, non–HDL-C, TC, TGs, HDL-C, and VLDL-C. Fasting will be defined as no food or caloric beverage for at least 10 hours (±2 hours) prior 
to sample collection. Patients will be permitted to have water. LDL-C will be estimated. 
k  Fasting apolipoproteins include apoB, apoA1, and Lp(a). Beta quant LDL is beta-quantification measurement of LDL-C. Fasting will be defined as no food or caloric beverage 
for at least 10 hours (±2 hours) prior to sample collection. Patients will be permitted to have water. 
l  PK, cytokine panel, and complement activation sampling will be performed on dosing days and at each study visit during the Follow-up Period. For each of the dosing days, 
samples will be drawn at pre-dose (-1 hour), 3 hours (±1 hour) post-dose, and at 8 hours (±1 hour) post-dose. 
m Patients should be at rest for at least 5 minutes lying quietly in a fully supine position prior to each triplicate 12-lead ECG. The triplicate measurements should be taken approximately 
one minute apart.  ECGs on Days 1 and 29 should be performed twice: the first should be pre-dose (-1 hour) and the second at 2.5 hours post-dose (±0.5 hours) which is about 30 
min prior to the 3-hour PK draw. 
n Statin PK blood sample will be taken for measurement of their steady state levels/major components when validated assays are available for such measurements. 
apo = apolipoprotein; CV = cardiovascular; ECG = electrocardiogram; ET = Early Termination; HbA1c = hemoglobin A1c; HBV = hepatitis B virus; HCV = hepatitis C virus;  
HDL-C = high-density lipoprotein cholesterol; HIV = human immunodeficiency virus; hsCRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein cholesterol; 
Lp(a) = lipoprotein(a); non–HDL-C = non–high-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9; PK = pharmacokinetic(s); TC = total 
cholesterol; TG = triglyceride; TSH = thyroid-stimulating hormone; VLDL-C = very low-density lipoprotein cholesterol. 


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Appendix B:  Clinical Laboratory Analytes 
 
Clinical Safety Chemistry Panel 
Aspartate aminotransferase 
Inorganic phosphate 
Alanine aminotransferase 
Glucose 
Alkaline phosphatase 
BUN  
Gamma glutamyl transferase (GGT) 
Bilirubin (direct) 
Sodium 
Bilirubin (total) 
Potassium 
Creatinine 
Chloride 
Total protein 
Calcium 
Albumin 
Creatine Kinase (CK) 
Cystatin C 
eGFR (CKD-EPI) 
 
 
 
Endocrinology 
Thyroid-stimulation hormone 
Follicle-stimulating hormone [1](females only) 
Urine pregnancy test (females only) 
Serum pregnancy test (human chorionic 
gonadotropin) (females at screening only) 
Hemoglobin A1c 
[1] Follicle-stimulating hormone in peri-menopausal women who have not had a menstrual period for ˂12 
months at Screening. 
 
Hematology 
Hematocrit 
Hemoglobin 
Mean cell volume 
Mean cell hemoglobin concentration 
Mean cell hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
[1]  
Manual microscopic review is performed only if white blood cell count and/or differential values are out of 
reference range. 
 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [1] 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Spot Urine: Albumin, Creatine, Protein, Albumin-
to-Creatine Ratio (UACR), and Protein-to-
Creatine Ratio (UPCR). 
[1]  Microscopy is performed only as needed based on positive dipstick test results for hematuria or proteinuria. 


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Serology 
Hepatitis B surface antigen (HBsAg) 
Hepatitis C antibody 
HIV antibodies 
HBV 
 
Drug Screen 
Drugs of abuse in urine: 
 
• 
Tetrahydrocannabinol (THC) 
• 
Cocaine 
• 
Heroin 
• 
Amphetamines 
• 
Methamphetamine 
• 
Phencyclidine (PCP) 
• 
Ecstasy 
• 
Barbiturates 
• 
Methadone 
• 
Oxycodone 
• 
Alcohol 
 
 
Cytokine Panel 
IL-1β 
IL-2 
IFNγ 
IL-6 
TNFα 
IL-12 
 
MCP-1 
 
Coagulation 
Activated partial thromboplastin time (aPTT) 
International normalized ratio (INR) 
Prothrombin time (PT) 
 
 
Pharmacodynamic Assessments 
PCSK9 
 
Lipid profile: 
Apolipoproteins: 
• Low-density lipoprotein cholesterol 
(β quantification and estimated by Friedewald 
equation) 
• Apolipoprotein B 
• Apolipoprotein A-I 
 
• Very low-density lipoprotein cholesterol 
 
• High-density-lipoprotein cholesterol 
 
• Total cholesterol 
 
• Triglycerides 
 
• Non-high-density lipoprotein cholesterol 
(calculated) 
 
• Lipoprotein (a) 
 
 
Complement Activation 
C3a  
Split product Bb 
C5a  
 
 


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Inflammatory/ Other Biomarkers 
C-reactive protein 
Fibrinogen 
Concurrent Statin PK 
Atorvastatin parent; ortho- para- hydroxy 
metabolite concentrations 
Other statin PK levels based on availability of 
validated assays 
 
 


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Appendix C:  2018 Guideline on the Management of Blood Cholesterol 
 
 Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood 
cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines [published online ahead of print November 10, 2018]. Circulation. DOI: 10.1161/CIR.0000000000000625. 
 

SAP_001.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol Title: 
A Placebo-controlled, Randomized, Phase 2a, Study to 
Assess the Safety, Tolerability, Pharmacodynamics and 
Pharmacokinetics of CIVI 007 in Patients on a 
background of Stable Statin Therapy 
Protocol Number: 
CIVI 007-2-01 
Protocol Version/Date: 
Version 1.0 / 01 July 2019 
Version 2.0 / 09 Sept 2019 
Version 3.0 / 14 Nov 2019 
 
Investigational Product: CIVI 007 
 
 
Sponsor: 
CiVi Biopharma, Inc.  
200 Four Falls Corporate Center 
Suite 107 
West Conshohocken, PA 19428 
USA
 
 
SAP Version/Date: 
Version 2.0 / 19 February 2020 
 
CONFIDENTIAL 
The information in this document is proprietary and confidential in nature and may not be used, 
divulged, published, or otherwise disclosed to others except to the extent that disclosure would 
be required by law and for the purpose of evaluating and/or conducting a clinical study for CiVi 
Biopharma, Inc. (CiVi, hereinafter).  You are allowed to disclose the contents of this document 
only to your Institutional Review Board or Independent Ethics Committee and study personnel 
directly involved with conducting this SAP.  Persons to whom the information is disclosed must 
be informed that the information is confidential and proprietary to CiVi and that it may not be 
further disclosed to third parties. 
 
 


CiVi Biopharma, Inc. 
Protocol: CIVI 007-2-01 
Protocol Title: 
Protocol Number: 
SAP Version/Date: 
CONFIDENTIAL 
SIGNATURE PAGE 
Statistical Analysis Plan 
Version 2.0, 19 February 2020 
A Placebo-controlled, Randomized, Phase 2a, Study to 
Assess the Safety, Tolerability, Pharmacodynamics and 
Pharmacokinetics of CIVI 007 in Patients on a background 
of Stable Statin Therapy 
CIVI 007-2-01 
Version 2.0 / 19 February 2020 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
Signature 
Date 
Page 2 of 21 
PPD


CiVi Biopharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: CIVI 007-2-01 
 
Version 2.0, 19 February 2020 
Page 3 of 21 
 
VERSION HISTORY 
Version 
Version Date 
Description 
1.0 
09 July 2019 
Original signed version 
2.0 
19 February 2020 
Updated per Amendment 1 and 
Amendment 2
 
 
 
 


CiVi Biopharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: CIVI 007-2-01 
 
Version 2.0, 19 February 2020 
Page 4 of 21 
 
TABLE OF CONTENTS 
1 
Introduction ............................................................................................................................ 8 
2 
Study Overview...................................................................................................................... 8 
2.1 
Study Objectives ............................................................................................................. 8 
2.1.1 
Primary Objective .................................................................................................... 8 
2.1.2 
Secondary Objectives ............................................................................................. 8 
2.1.3 
Exploratory Objectives ............................................................................................ 8 
2.2 
Study Design .................................................................................................................. 8 
2.2.1 
Overview ................................................................................................................. 8 
2.2.2 
Randomization and Blinding .................................................................................. 10 
2.2.3 
Study Drug ............................................................................................................ 10 
2.2.4 
Sample Size Determination ................................................................................... 10 
2.3 
Study Endpoints ........................................................................................................... 10 
2.3.1 
Primary Safety/Tolerability Endpoints ................................................................... 10 
2.3.2 
Secondary Endpoints ............................................................................................ 11 
2.3.3 
Exploratory Endpoints ........................................................................................... 11 
2.3.4 
Safety Variables .................................................................................................... 12 
3 
Statistical Methodology ........................................................................................................ 12 
3.1 
General Considerations ................................................................................................ 12 
3.1.1 
Analysis Day .......................................................................................................... 12 
3.1.2 
Analysis Visits ....................................................................................................... 12 
3.1.3 
Definition of Baseline ............................................................................................. 12 
3.1.4 
Summary Statistics ................................................................................................ 13 
3.2 
Analysis Populations .................................................................................................... 13 
3.2.1 
Intent-to-Treat (ITT) Population ............................................................................. 13 
3.2.2 
Per-Protocol (PP) Population ................................................................................ 13 
3.2.3 
Safety Analysis Population .................................................................................... 13 
3.2.4 
Pharmacokinetic Population .................................................................................. 13 
3.3 
Subject Data and Study Conduct ................................................................................. 13 
3.3.1 
Subject Disposition ................................................................................................ 13 
3.3.2 
Protocol Deviations ............................................................................................... 13 
3.3.3 
Analysis Populations ............................................................................................. 13 
3.3.4 
Demographic and Baseline Characteristics .......................................................... 13 
3.3.5 
Medical History ...................................................................................................... 14 
3.3.6 
Concomitant Medications ...................................................................................... 14 
3.3.7 
Study Exposure and Compliance .......................................................................... 14 
3.4 
Efficacy and Pharmacodynamics Assessments ........................................................... 15 
3.4.1 
Secondary Efficacy Endpoints Analyses ............................................................... 15 
3.4.2 
Exploratory Efficacy Endpoints Analyses .............................................................. 16 


CiVi Biopharma, Inc. 
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Statistical Analysis Plan 
Protocol: CIVI 007-2-01 
 
Version 2.0, 19 February 2020 
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3.5 
Pharmacokinetic Assessment ...................................................................................... 16 
3.5.1 
Handling Missing Data or Concentration Below the Lower Limit of Quantification 17 
3.5.2 
Pharmacokinetic Concentrations ........................................................................... 17 
3.5.3 
Pharmacokinetic Parameters ................................................................................ 18 
3.6 
Safety Assessment ....................................................................................................... 18 
3.6.1 
Adverse Events (AEs) ........................................................................................... 18 
3.6.2 
Clinical Laboratory Tests ....................................................................................... 19 
3.6.3 
Vital Signs ............................................................................................................. 20 
3.6.4 
Electrocardiograms ............................................................................................... 21 
3.6.5 
Physical Examinations .......................................................................................... 21 
3.6.6 
Other Safety Assessments .................................................................................... 21 
4 
Interim Analysis ................................................................................................................... 21 
5 
Programming Specifications ................................................................................................ 21 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Antidrug antibody
AE 
Adverse event
AESI 
Adverse event of special interest
ATC 
Anatomical therapeutic chemical
ALP 
Alkaline phosphatase
ALT 
Alanine aminotransferase
ANCOVA 
Analysis of covariance
AST 
Aspartate aminotransferase
AUC 
Area under the plasma concentration-time curve 
AUC0-∞ 
Area under the plasma concentration-time curve from time 0 
extrapolated to infinity
AUC0-24 
Area under the plasma concentration-time curve from time 0 
to 24 hours
AUC0-48 
Area under the plasma concentration-time curve from time 0 
to 48 hours
AUC0-168 
Area under the plasma concentration-time curve from time 0 
to 168 hours
AUC0-t 
Area under the plasma concentration-time curve from time 0 
to the time of last quantifiable concentration 
AUCextrap 
Extrapolation of area under plasma concentration 
BLQ 
Below the lower limit of quantification
BMI 
Body mass index
CRF 
Case report form
CL/F 
Apparent clearance
CSR 
Clinical Study Report
Cmax 
Maximum observed plasma concentration 
Ctrough 
Concentration observed at pre-dose
CTCAE 
Common Terminology Criteria for Adverse Events 
Ecrf 
Electronic Case Report Form
HbA1c 
Hemoglobin A1c
HDL-C 
High-density lipoprotein cholesterol
hsCRP 
High-sensitivity C-reactive protein
ITT 
Intent-to-treat
LDL 
Low-density lipoprotein
LDL-C 
Low-density lipoprotein cholesterol
LLOQ 
Lower limit of quantitation
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-Effect Model Repeated Measure
NCA 
Non-compartmental analyses
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamic(s)
PK 
Pharmacokinetic(s)
PP 
Per-Protocol
Q4W 
Every 4 weeks
SAE 
Serious adverse event
SAP 
Statistical Analysis Plan


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Version 2.0, 19 February 2020 
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Abbreviation 
Definition 
SC 
Subcutaneous(ly)
SD 
Standard deviation
SRC 
Safety Review Committee
TEAE 
Treatment-emergent adverse event
TG 
Triglyceride
TSH 
Thyroid-stimulating hormone
ULN 
Upper limit of normal
VLDL 
Very low density lipoprotein
VLDL-C 
Very low density lipoprotein-Cholesterol
Vz/F 
Apparent volume of distribution during the terminal phase
WHO 
World Health Organization
 
 


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Statistical Analysis Plan 
Protocol: CIVI 007-2-01 
 
Version 2.0, 19 February 2020 
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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods and pharmacokinetic (PK) methodology to be implemented for the analysis of data 
from the study with CiVi Biopharma, Inc. protocol number CIVI 007-2-01.  The SAP will be 
finalized prior to database lock.  Any deviations from the SAP after database lock will be 
substantiated by sound statistical/PK rationale and will be documented in the final Clinical Study 
Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective of the study is to assess the safety and tolerability of CIVI 007 following 
multiple subcutaneous (SC) doses in patients on a background of a stable dose of statin 
therapy. 
2.1.2 Secondary Objectives 
The secondary objective is to assess the pharmacodynamic (PD) effect of CIVI 007 on total 
plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein 
cholesterol (LDL-C) levels in the study population. 
2.1.3 Exploratory Objectives 
The exploratory objectives include the following: 
 
To assess the effect of CIVI 007 on other lipid and lipoproteins including triglycerides (TG), 
high density lipoprotein cholesterol (HDL-C), non-HDL-C, very low-density lipoprotein 
cholesterol (VLDL-C), total cholesterol, apolipoproteins B, A-I and lipoprotein(a) 
 
To assess the effect of CIVI 007 on high-sensitivity C-reactive protein (hsCRP) 
 
To collect antidrug antibody (ADA) samples for potential future assessments of 
immunogenicity  
 
To further inform the population pharmacokinetic (PK) model of CIVI 007 with sparse PK 
sampling in patients on a background of statin therapy 
2.2 Study Design 
2.2.1 Overview 
This is a Phase 2a, randomized, double-blind (investigator/subject), sponsor-open, parallel-
group, multicenter study to evaluate the early clinical profile (safety, tolerability, 
pharmacodynamics and pharmacokinetics) of CIVI 007 in patients on a background of statin 
therapy with or without ezetimibe.  Patients are required to be on standard of care treatment for 
high blood cholesterol consistent with 2018 ACC/AHA guidelines that includes a stable dose of 
statin therapy (with or without ezetimibe) for at least 4 weeks prior to the Screening Visit.  The 
study will enroll approximately 48 patients who will be randomized to 1 of 3 active treatment 
groups or the placebo reference group (12 patients per active treatment group and 12 in the 
placebo treatment group) across approximately 7 sites in the United States. 


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All potentially eligible patients will partake in the Screening Visit up to 21 days prior to Day 1.  
The Screening Visit will be their first study visit.  Laboratory values can be retested once during 
screening for LDL-C that is in the range of 65-69 mg/dL, or for triglycerides in the range of 401- 
450 mg/dL. 
The Treatment Period will be approximately 28 days from Day 1 to Day 29; each treatment 
group will receive 2 administrations of study drug.  Eligible patients will be randomized on Day 1 
in a 1:1:1:1 ratio to one of the following treatment groups: 
 
Group 1: 
mg CIVI 007 administered SC on Days 1 and 29 
 
Group 2:
mg CIVI 007 administered SC on Day 1 followed by 
 mg CIVI 007 
administered SC on Day 29 
 
Group 3: 
mg CIVI 007 administered SC on Days 1 and 29 
 
Group 4: Placebo for CIVI 007 administered SC on Days 1 and 29 
The Follow-up Period will be approximately 8 weeks and begin following the last dose of study 
drug, unless extended follow-up is required based on the Day 85 LDL-C assessment or other 
Investigator determined safety considerations.  
Extended follow-up visits will be conducted on a monthly basis for up to 3 months if Day 85 
LDL-C levels are <80% of their baseline level; extended follow-up will end within the 3-month 
period if LDL-C levels are ≥80% of baseline.  Extended follow-up visits (frequency and 
assessments will be at the discretion of the Investigator) to monitor Investigator determined 
safety considerations may extend beyond 3 months, if deemed appropriate by the Investigator, 
and will continue until there are no safety observations requiring further follow-up.  The total 
duration of the study for each patient will be approximately 3 to 6.5 months, depending on the 
length of the screening, and follow up periods. 
The study design is graphically summarized below: 
 
Patients will be routinely monitored for safety, tolerability and pharmacodynamic effects.  The 
schedule of procedures and clinical laboratory analytes are detailed in Appendices of the 
protocol: measurements will be taken as detailed in Appendix A (schedule) and Appendix B 
(clinical laboratory analytes). 
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2.2.2 Randomization and Blinding 
Approximately 48 patients will be assigned randomly to placebo,
mg CIVI 007,
mg CIVI 
007 followed by
mg CIVI 007 or 
mg CIVI 007 in a 1:1:1:1 allocation ratio.  
Throughout the study, study treatment will be administered in a double-blinded fashion for the 
Investigator, clinical staff and patients.  Only where required will key site staff (such as 
pharmacist) be unblinded throughout the study. 
The following controls will be employed to maintain the double-blind execution of the study: 
 
The placebo solution will be identical in appearance to the CIVI 007 solution. 
 
The Investigator and other members of staff involved with the study will remain blinded. 
 
Lipid levels after randomization will be blinded to the study site. 
 
Appropriate firewalls will exist to prevent communication between the unblinded SRC and 
personnel involved in study execution. 
2.2.3 Study Drug 
CIVI 007 and placebo are sterile solutions to be administered by SC injection.  Placebo for CIVI 
007 will be commercially available sterile saline for injection.  An unblinded pharmacist will 
prepare the study drug for blinded administration by the investigator site as detailed in the 
protocol’s Pharmacy Manual. 
Dosing is to be in the morning following an overnight fast: 
 
CIVI 007 is to be administered SC into the abdomen (or thigh or upper arm, if necessary) 
from a solution at 150 mg/mL. 
 
Doses of CIVI 007 are 
mg Q4W x2, 
mg on Day 1 followed by
 mg on Day 29 and 
mg Q4W x2. 
 
Placebo is to be administered SC into the abdomen (or in thigh or upper arm, if necessary) 
on Day 1 and Day 29.  The volume of injection will be randomly assigned to match the 
active CIVI 007 dose. 
2.2.4 Sample Size Determination 
Approximately 48 patients (12 patients per active treatment group, 12 patients per placebo 
treatment) will be randomized into 1 of 4 treatment groups. 
The sample size chosen for this study was not based on power calculations.  However, the 
number of patients in each part of the present study is common in early clinical studies and is 
considered sufficient to achieve the objectives of the study without exposing undue numbers of 
patients to study drug. 
2.3 Study Endpoints 
2.3.1 Primary Safety/Tolerability Endpoints 
The primary safety/tolerability endpoints for this study are as follows: 
 
incidence and severity of any drug-related AE 
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Version 2.0, 19 February 2020 
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 
incidence of clinically significant laboratory abnormalities, based on drug-induced 
changes from baseline in haematology, clinical safety chemistry, and urinalysis test 
results. 
2.3.2 Secondary Endpoints 
The secondary efficacy endpoints include the following changes from baseline measured 
approximately 28 days after the first and 28 and 56 days after the last injection of study drug: 
 
The percent change in PCSK9 and LDL-C 
2.3.3 Exploratory Endpoints 
The exploratory endpoints include the following: 
2.3.3.1 
Lipid/Pharmacodynamic (PD) Endpoints 
PD endpoints are the absolute and % changes from baseline (except where indicated) in the 
levels of the following in serum or plasma over the time course of the treatment period and 
follow-up: 
 
PCSK9 (absolute only) 
 
LDL-C (absolute only) 
 
VLDL-C 
 
triglycerides 
 
HDL-C 
 
Non-HDL-C 
 
total cholesterol 
 
lipoprotein (a) 
 
apolipoproteins B and A-I 
 
hsCRP 
2.3.3.2 
Pharmacokinetic (PK) Endpoints 
The following PK parameters will be calculated for CIVI 007, where possible: 
 
Cmax 
 
time of the maximum observed plasma concentration (Tmax) 
 
AUC0-t 
 
concentration observed at pre-dose (Ctrough) (Day 29 only) 
Additional exploratory PK parameters, which may include but are not limited to the following, 
may be calculated:  
 
area under the plasma concentration-time curve from time 0 extrapolated to infinity 
(AUC0-∞) 
 
area under the plasma concentration-time curve from time 0 to 168 hours (AUC0-168) 


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 
percentage of AUC0-∞ that is due to extrapolation (%AUCextrap) 
 
apparent terminal elimination rate constant (λz) 
 
apparent plasma terminal elimination half-life (t1/2) 
 
apparent total plasma clearance (CL/F) 
 
apparent volume of distribution during the terminal phase (Vz/F) 
2.3.4 Safety Variables 
The safety variables include adverse events, safety laboratory parameters (including clinical 
safety chemistry, hematology, coagulation parameters including fibrinogen, complement 
activation, cytokines and urinalysis), 12-lead ECGs, physical examinations, and vital signs.  
Samples will also be collected for the potential future assessment of anti-drug antibodies. 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day 
Analysis day will be calculated from the date of first dose of study drug.  The day of the first 
dose of study drug will be Day 1, and the day immediately before Day 1 will be Day -1.  There 
will be no Day 0. 
3.1.2 Analysis Visits 
Scheduled visits will be assigned to analysis visits as recorded on the case report form (CRF).  
Unscheduled and early termination visits will be assigned to analysis visits according to the 
following visit windows: 
Analysis Visit 
Target Analysis Day 
Low Analysis Day 
High Analysis Day 
Day 8 
8 
2
11
Day 15 
15 
12
18
Day 22 
22 
19
25
Day 29 
29 
26
32
Day 36 
36 
33
39
Day 43 
43 
40
46
Day 57 
57 
47
71
Day 85 
85 
72 
85 or End of Study (if Last 
Observation > Day 85)
Within an analysis visit window, the measurement from the visit closest to the defined target 
analysis day will be used.  If there is more than one measurement with equal distance to the 
defined target analysis day, the latter will be used.  If no visits occur within a visit window, the 
measurement for this visit will be treated as missing. 
3.1.3 Definition of Baseline  
Baseline for all efficacy and safety variables will be defined as the last scheduled value obtained 
prior to the first dose of study drug.  If the measurement at this visit is missing, the last 
measurement prior to the first dose of study drug will be used as baseline.  The scheduled 
baseline visit for all efficacy and safety variables is Day 1 pre-dose. 


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3.1.4 Summary Statistics 
Categorical data will generally be summarized with counts and percentages of patients.  The 
denominator used for the percentage calculation will be clearly defined.  Continuous data will 
generally be summarized with descriptive statistics including n (number of non-missing values), 
mean, median, standard deviation, minimum, and maximum. 
3.2 Analysis Populations 
3.2.1 Intent‐to‐Treat (ITT) Population 
The ITT Population will include all patients who are randomized to the study and will be used to 
assess efficacy. 
3.2.2 Per‐Protocol (PP) Population 
The PP Population will include all patients who are randomized to the study and do not have 
any major protocol deviations. 
A list of patients with major protocol deviations leading to exclusion from the PP Population will 
be finalized prior to unblinding the randomized treatment assignments. 
3.2.3 Safety Analysis Population 
The Safety Analysis Population will include all patients who receive any amount of study drug. 
3.2.4 Pharmacokinetic Population 
The Pharmacokinetic Population will include all patients who receive any amount of 
investigational product and have at least one measurable CIVI 007 concentration.  
3.3 Subject Data and Study Conduct 
3.3.1 Subject Disposition 
Counts and percentages of patients who were screened (signed informed consent), 
discontinued early during screening (screen failures), and randomized will be summarized in 
total based on all screened patients.  Reasons for early discontinuation will also be summarized. 
Counts and percentages of patients who were randomized, discontinued early from the study, 
and completed the study will be summarized by treatment and in total based on all randomized 
patients.  Reasons for early discontinuation will also be summarized. 
3.3.2 Protocol Deviations 
Protocol deviations will be defined in the Protocol Deviation Plan.  Counts and percentages of 
patients with CSR reportable protocol deviations by deviation category will be summarized by 
treatment and in total based on all randomized patients. 
3.3.3 Analysis Populations 
Counts and percentages of patients in each analysis population will be summarized by 
treatment and in total based on all randomized patients. 
3.3.4 Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 


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 
Age (years) and age categories (<65 years, ≥65 years) 
 
Sex 
 
Childbearing potential 
 
Race 
 
Ethnicity 
 
Baseline Height (cm) 
 
Baseline Weight (kg) 
 
Baseline Body mass index (BMI) (kg/m2) and Baseline BMI categories (<30 kg/m2, ≥30 
kg/m2)  
 
Baseline PCSK9 (mg) 
 
Baseline fasting LDL-C (mg/dL) 
 
Background statin therapy 
Demographic and baseline characteristics will be summarized with descriptive statistics or 
counts and percentages of patients as appropriate by treatment and in total for all randomized 
patients and each defined analysis population if the analysis population composition is different 
than all randomized patients. 
3.3.5 Medical History 
Medical history will be coded to system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology version 22.0 (or the most recent 
version available).  Counts and percentages of patients with medical history by system organ 
class and preferred term will be summarized by treatment and in total based on all randomized 
patients. 
3.3.6 Concomitant Medications 
Concomitant medications will be coded to anatomical therapeutic chemical (ATC) class and 
preferred term using the World Health Organization (WHO) Drug Dictionary version 2019G B3 
(or the most recent version available).  For summary purposes, medications will be considered 
prior medications if they stopped prior to the first dose of study drug and concomitant 
medications if they were taken at any time after the first dose of study drug (i.e. started prior to 
the first dose of study drug and were ongoing or started after the first dose of study drug). 
Counts and percentages of patients taking concomitant medications by ATC class and preferred 
term will be summarized by treatment and in total based on the Safety Analysis Population.  The 
use of any prior medication or concomitant medication will be listed for all randomized subjects. 
3.3.7 Study Exposure and Compliance 
Days of exposure to study will be calculated as date of last visit – date of first dose of study drug 
+ 1.  Days of exposure to study will be summarized by treatment based on the Safety Analysis 
Population with descriptive statistics and with counts and percentages of patients with exposure 
in the following categories: 
 
<= 14 days 
 
15 - 28 days 
 
29 - 56 days 
 
57 - 84 days 
 
>= 85 days 


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The total number of injections administered will be calculated for each patient.  A contingency 
table will be provided to display the number and percentage of patients in each treatment group 
with the number of injections.  
3.4 Efficacy and Pharmacodynamics Assessments 
PCSK9 will be collected at Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, Day 43, Day 57 and 
Day 85 or early termination.  Fasting lipid panel (including LDL-C, non-HDL-C, total cholesterol, 
triglycerides, HDL-C, and VLDL-C) will be collected at each study visit.  Fasting apolipoproteins 
(including apolipoproteins B and A-I, and lipoprotein (a)) and β-Q LDL-C will be collected at 
Day 1, Day 8, Day 15, Day 29, Day 36, Day 43, Day 57 and Day 85 or early termination.  
All the secondary and exploratory efficacy endpoints will be summarized descriptively and 
analyzed by planned treatment based on ITT Population.  All the individual data will be listed. 
3.4.1 Secondary Efficacy Endpoints Analyses 
The PCSK9 and LDL-C will be listed and summarized using descriptive statistics by treatment 
group over the study period to describe absolute and percent changes from baseline.  
The secondary endpoints of the study will be analyzed using analysis of covariance (ANCOVA) 
models to compare the mean percent change from baseline in LDL-C and PCSK9 
approximately 28 days after the first injection (Day 29) and approximately 28 and 56 days after 
the second injection of study drug (Day 57 and Day 85) between treatment groups with placebo.  
This ANCOVA model will include treatment as a factor and baseline level as a covariate.  The 
missing values will be imputed by last observation carried forward (LOCF) method.   
Normality will be tested for the model residuals and the p-value from the Shapiro-Wilk test will 
be provided.  If the residuals of this model are not normal, then non-parametric analyses 
(Wilcoxon rank- sum test) will be explored to compare the difference in median percent 
change between treatment groups.   
The presentation of results will be the observed data and include the estimated means by 
treatment group, their standard errors, and the estimated differences in means between the 
patient treatments and corresponding 95% confidence intervals and p-values.   
The SAS sample code is listed: 
***********************************************************************  
  TREATMENT: 0 (Placebo), 1 (CIVI 007 
mg Q4W x2),  
             2 (CIVI 007 
mg on Day 1 followed by 
mg on Day 29), or 
             3 (CIVI 007 
mg Q4W x2) 
  BASE: Baseline PCSK9 or LDL-C 
  CHG: Change from baseline to the specified visit in PCSK9 or LDL-C 
**********************************************************************;  
proc glm;  
  class TREATMENT;  
  model CHG = TREATMENT BASE / p;  
  lsmeans TREATMENT / stderr pdiff cl;  
  estimate "CIVI 007 
mg Q4W x2: Placebo" TREATMENT -1 0 0 1;  
  estimate "CIVI 007 
mg on Day 1 followed by 
mg on Day 29: Placebo"    
           TREATMENT -1 0 1 0; 
  estimate "CIVI 007 
mg Q4W x2: Placebo" TREATMENT -1 1 0 0;  
run; 
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The treatment comparisons between each active dose versus placebo will be tested following a 
fixed sequence step-down procedure to control the multiplicity.  
Analysis of the secondary efficacy endpoints will be repeated with the PP Population. 
Mixed-Effect Model Repeated Measure (MMRM) method may be used to test the robustness of 
the results with baseline value, treatment and visit as factors, and treatment by visit interaction.  
An unstructured covariance matrix will be used (TYPE=UN).  The treatment difference will be 
estimated from the MMRM.  No imputation will be performed.  The SAS sample code is listed: 
***********************************************************************  
  USUBJID: Unique subject identifier 
  TREATMENT: 0 (Placebo), 1 (CIVI 007 
mg Q4W x2),  
             2 (CIVI 007 
mg on Day 1 followed by 
mg on Day 29), or 
             3 (CIVI 007 
mg Q4W x2)  
  BASE: Baseline PCSK9 or LDL-C 
  VISIT: Visits 
  CHG: Change from baseline to the specified visit in PCSK9 or LDL-C 
**********************************************************************;  
proc mixed;   
  class USUBJID TREATMENT VISIT;   
  model CHG = TREATMENT BASE VISIT TREATMENT*VISIT;   
  Repeated VISIT / TYPE=UN sub=USUBJID;   
  lsmeans VISIT*TREATMENT / cl pdiff slice=VISIT;   
run;   
3.4.2 Exploratory Efficacy Endpoints Analyses 
The exploratory lipid/PD endpoints are listed in the section 2.3.3.1 excluding hsCRP.  All the 
endpoints will be listed and summarized using descriptive statistics by treatment group over the 
study period to describe absolute and percent changes from baseline.  
For continuous variables, the ANCOVA model specified for the secondary efficacy endpoints 
analysis will be used.  The missing values will be imputed by LOCF method.  For certain 
efficacy endpoints like the percent change in triglycerides, logarithmic transformation may be 
performed prior to fitting the ANCOVA model.   
For certain efficacy endpoints, the MMRM method may be used to test the robustness of the 
results with baseline value, treatment and visit as factors, and treatment by visit interaction.  An 
unstructured covariance matrix will be used (TYPE=UN).  The treatment difference will be 
estimated from the MMRM.  No imputation will be performed. 
3.5 Pharmacokinetic Assessment 
Sparse PK sampling will be conducted for all consenting patients.  Sampling will be performed 
on dosing days, and at each study visit during the Treatment and Follow-up Periods.  For each 
of the dosing days, a PK sample will be drawn pre-dose (-1 hour), 3 hours (± 1 hour) post-dose, 
and at 8 hours (± 1 hour) post-dose. 
The population PK model created based on data from the ongoing Phase 1 study will be refined 
to evaluate the relationship of CIVI 007 PK to demographics and background statin therapy.  
The model will be periodically refined as new and broader datasets emerge to include the 
covariates of special populations, concomitant medications, and disease state. 
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3.5.1 Handling Missing Data or Concentration Below the Lower Limit of Quantification 
For non-compartmental analyses (NCA), missing or concentration below the lower limit of 
quantification (BLQ) data will be handled based on the current knowledge of the study drug. 
If the actual sampling time is missing, but a valid concentration value has been measured, the 
concentration value will be flagged and the scheduled time point may be used for the calculation 
of PK parameters. 
In cases of missing pre-dose values on Day 1, the missing components will be assumed as 
zero.  In cases of a missing pre-dose value on Day 29, the individual minimum observed 
concentration during the dosing interval will be used as pre-dose concentration values.  For the 
other cases, the missing data will not be imputed. 
The following rules will be used to handle BLQ data for individual plot and PK parameter 
calculation: 
• 
If BLQ values occur in a profile before the first measurable concentration, it is assigned 
as zero for Day 1 and as LLOQ for Day 29.  
• 
If BLQ values occur between measurable concentrations or after the last measurable 
concentration, it is treated as missing.  
The following rules will be used to handle BLQ data for mean plot and concentration summary: 
• 
Mean concentration at any individual time point are only calculated if at least half (50%) 
of the patients have valid values (i.e., measurable and not missing) at this time point for each 
treatment.  
• 
In cases where a mean value is not calculated due to the criterion above not met, the 
value will be set to missing 
• 
BLQ will be set as zero. The only exception is that the pre-dose BLQ on Day 29 will be 
set as LLOQ 
• 
Missing values are excluded from the calculation of these means. 
3.5.2 Pharmacokinetic Concentrations 
Plasma concentrations for CIVI 007 will be summarized over scheduled time using descriptive 
statistics.  Actual sampling times that are outside the scheduled sampling time window will be 
excluded from summary statistics but will still be used in the calculation of PK parameters.  
Individual plasma concentration data versus actual time points will be listed.  
For each of the dosing days, the sampling time windows are as follows: 
 
Pre-dose: -1 hour,  
 
3 hours post-dose:  ±1 hour, and  
 
8 hours post-dose: ±1 hour. 
For each study visit, the sampling time window is ±3 days. 
Individual concentrations of CIVI 007 will be plotted on a linear and semi-log scale against 
actual sampling time points for each treatment.  Mean (±SD) CIVI 007 concentration will be 
plotted on a linear and semi-logarithmic scale against nominal time points by treatment. 


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3.5.3 Pharmacokinetic Parameters 
Where possible, standard non-compartmental analyses will be used to calculate the PK 
parameters of interest for CIVI 007 in section 2.3.3.2.  The actual collection times will be used 
for PK parameter calculation.  The Linear Up Log Down method (equivalent to the Linear 
Up/Log Down option in WinNonlin® Professional) will be used in the computation of AUCs. 
The elimination constant rate, λz, will not be presented for patients who do not exhibit a terminal 
elimination phase in their concentration-time profiles. In order to estimate λz, linear regression of 
concentration in logarithm scale versus time will be performed using at least 3 data points.  
Uniform weighting will be selected to perform the regression analysis to estimate λz. 
Generally, λz will not be assigned if one of the following happens: 
1. Tmax is one of the 3 last data points, 
2. The adjusted regression coefficient (R-squared) is less than 0.80, 
3. The estimated λz indicates a positive slope, or 
4. The terminal elimination phase is not linear (as appears in a semi-logarithmic scale) based on 
visual inspection. 
If the λz is not assigned, the values of associated PK parameters will not be calculated.  In the 
cases where AUCextrap exceeds 20%, the λz will be assigned and the λz and the corresponding 
λz-related PK parameters will be flagged but still included to the summary statistics with an 
explanatory footnote. 
Pharmacokinetic parameters of CIVI 007 will be listed and summarized using descriptive 
statistics. 
Where sufficient data are available, CIVI 007 fold-increase in exposure will be examined 
between the dose cohorts.  The PK parameters may be analyzed for dose proportionality using 
analysis of variance model, as appropriate. 
3.6 Safety Assessment 
Safety data will be summarized descriptively by actual treatment received (and in total for selected 
analyses) based on the Safety Analysis Population.  All the individual data will be listed. 
3.6.1 Adverse Events (AEs) 
AEs will be monitored and documented from the time of screening until completion of the Day 
85 Visit, early termination visit or extended Follow-up, whichever is later.  All AEs will be coded 
to system organ class and preferred term using MedDRA terminology version 22.0 (or the most 
recent version available).   
Treatment-emergent adverse events (TEAEs) are defined as AEs that worsen in severity or 
relationship to study drug or start on or after the time of start of first study drug administration. 
Adverse events of special interest (AESIs) include CTCAE Version 5.0 Grade 2 or higher ALT 
measurements, and injection site reactions (ISRs). 
An overview of AEs will be provided including counts and percentages of patients (and event 
counts) with the following: 
 
Any AEs (overall and by maximum severity) 


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 
Any drug related AEs (overall and by maximum severity) 
 
Any AEs of special interest (ALT and injection site reactions) 
 
Any serious AEs (SAEs) 
 
Any AEs leading to discontinuation of study treatment 
 
Any AEs leading to discontinuation of study 
 
Any AEs leading to death 
The primary endpoint is the incidence and severity of any drug-related AEs.  The number and 
percentage of patients who experience 1 or more drug-related (possibly, probably, or definitely 
related) AEs will be presented by system organ class and preferred term by overall and by 
maximum severity.  In addition, summaries will be provided by system organ class, preferred 
term, and maximum severity. 
Listings of patients with drug-related AEs will be presented. 
Counts and percentages of patients (and event counts) will also be presented by system organ 
class and preferred term for each of the categories in the overview. 
Listings will be presented for all AEs, specifically for AESIs, SAEs and AEs leading to death. 
3.6.2 Clinical Laboratory Tests 
Clinical safety chemistry, hematology, coagulation, and urinalysis will be collected at each study 
visit.  Fibrinogen, cytokine and complement activation sampling will be collected at Day 1, 
Day 8, Day 15, Day 22, Day 29, Day 36, Day 43, Day 57 and Day 85 or early termination.  
hsCRP will be collected at Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, Day 43, Day 57 and 
Day 85 or early termination.  Thyroid-stimulating hormone (TSH), hemoglobin A1c (HbA1c), and 
serology will be collected in the Screening Visit. 
Observed values and changes from baseline will be presented at each scheduled visit and 
baseline by laboratory test.   
The primary endpoint is the incidence of clinically significant laboratory abnormalities, based on 
changes from baseline in hematology, clinical safety chemistry, and urinalysis test results.  The 
incidence of abnormalities will be summarized with counts and percentages of patients for 
selected parameters grading by Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0 if appropriate.   
Laboratory 
CTCAE Term 
Grade 1 
Grade 2
Grade 3
Grade 4 
Chemistry 
Alanine 
aminotransferase 
increased 
>ULN - 3.0 x ULN if 
baseline was 
normal; 
1.5 - 3.0 x baseline 
if baseline was 
abnormal 
>3.0 - 5.0 x ULN if 
baseline was 
normal; 
>3.0 - 5.0 x baseline 
if baseline was 
abnormal
>5.0 - 20.0 x ULN if 
baseline was 
normal; 
>5.0 - 20.0 x 
baseline if baseline 
was abnormal
>20.0 x ULN if 
baseline was 
normal;  
>20.0 x baseline if 
baseline was 
abnormal
Aspartate 
aminotransferase 
increased 
>ULN - 3.0 x ULN if 
baseline was 
normal;  
1.5 - 3.0 x baseline 
if baseline was 
abnormal 
>3.0 - 5.0 x ULN if 
baseline was 
normal;  
>3.0 - 5.0 x baseline 
if baseline was 
abnormal
>5.0 - 20.0 x ULN if 
baseline was 
normal;  
>5.0 - 20.0 x 
baseline if baseline 
was abnormal
>20.0 x ULN if 
baseline was 
normal;  
>20.0 x baseline if 
baseline was 
abnormal


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Laboratory 
CTCAE Term 
Grade 1 
Grade 2
Grade 3
Grade 4 
Blood bilirubin 
increased 
Total Bilirubin 
>ULN - 1.5 x ULN if 
baseline was 
normal;  
> 1.0 - 1.5 x 
baseline if baseline 
was abnormal
Total Bilirubin 
>1.5 - 3.0 x ULN if 
baseline was 
normal;  
>1.5 - 3.0 x baseline 
if baseline was 
abnormal
Total Bilirubin 
>3.0 - 10.0 x ULN if 
baseline was 
normal;  
>3.0 - 10.0 x 
baseline if baseline 
was abnormal
Total Bilirubin 
>10.0 x ULN if 
baseline was 
normal;  
>10.0 x baseline if 
baseline was 
abnormal
Alkaline 
phosphatase 
increased 
>ULN - 2.5 x ULN if 
baseline was 
normal; 
2.0 - 2.5 x baseline 
if baseline was 
abnormal 
>2.5 - 5.0 x ULN if 
baseline was 
normal; 
>2.5 - 5.0 x baseline 
if baseline was 
abnormal
>5.0 - 20.0 x ULN if 
baseline was 
normal; 
>5.0 - 20.0 x 
baseline if baseline 
was abnormal
>20.0 x ULN if 
baseline was 
normal; 
>20.0 x baseline if 
baseline was 
abnormal
Creatinine 
increased 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x 
baseline;  
>1.5 - 3.0 x ULN
>3.0 x baseline;  
>3.0 - 6.0 x ULN 
>6.0 x ULN 
CPK increased 
>ULN - 2.5 x ULN 
>2.5 x ULN - 5 x 
ULN
>5 x ULN - 10 x 
ULN
>10 x ULN 
Hyperkalemia 
Potassium 
>ULN - 5.5 mmol/L
Potassium 
>5.5 - 6.0 mmol/L
Potassium 
>6.0 - 7.0 mmol/L 
Potassium 
>7.0 mmol/L
Chronic kidney 
disease 
eGFR  
<LLN - 60 
ml/min/1.73 m2 or 
proteinuria 2+ 
present; urine 
protein/creatinine 
>0.5’. 
eGFR  
59 - 30 ml/min/1.73 
m2 
eGFR  
29 - 15 ml/min/1.73 
m2 
eGFR  
<15 ml/min/1.73 m2 
Hematology 
Anemia 
Hemoglobin (Hgb) 
<LLN - 10.0 g/dL; 
<LLN - 6.2 mmol/L; 
<LLN - 100 g/L
Hemoglobin (Hgb) 
<10.0 - 8.0 g/dL; 
<6.2 - 4.9 mmol/L;  
<100 – 80 g/L
Hemoglobin (Hgb) 
<8.0 g/dL;           
<4.9 mmol/L;       
<80 g/L
 
Hemoglobin 
increased 
Hemoglobin > ULN 
& 
Increase in >0 - 2 
g/dL 
Hemoglobin > ULN 
& 
Increase in >2 - 4 
g/dL
Hemoglobin > ULN 
& 
Increase in >4 g/dL 
 
White blood cell 
decreased 
<LLN - 3000/mm3; 
<LLN - 3.0 x 10e9 /L
<3000 - 2000/mm3; 
<3.0 - 2.0 x 10e9 /L
<2000 - 1000/mm3; 
<2.0 - 1.0 x 10e9 /L 
<1000/mm3;       
<1.0 x 10e9 /L
Platelet count 
decreased 
<LLN - 75,000/mm3; 
<LLN - 75.0 x 10e9 
/L 
<75,000 - 
50,000/mm3;   
<75.0 - 50.0 x 10e9 
/L
<50,000 - 
25,000/mm3;   
<50.0 - 25.0 x 10e9 
/L
<25,000/mm3; 
<25.0 x 10e9 /L 
For the other parameters, the incidence of abnormalities (as defined by normal ranges) prior to 
the first dose of study drug and after the first dose of study drug will be summarized with counts 
and percentages of subjects. 
3.6.3 Vital Signs 
Vital signs including supine blood pressure, supine heart rate, respiration rate, oral body 
temperature and weight will be measured at each study visit.  Height will be measured only at 
the participant’s Screening Visit.   
Observed values and changes from baseline in vital signs will be summarized.   


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3.6.4 Electrocardiograms 
12-lead ECGs will be performed in triplicate and measured at Screening, Day 1 pre-dose 
(- 1 hour), Day 1 post-dose (2.5 hours ±0.5 hour), Day 15, Day 29 pre-dose (-1 hour), Day 29 
post-dose (2.5 hours ±0.5 hour), Day 57 and Day 85 or early termination.   
Observed values and changes from baseline in quantitative ECG parameters (heart rate, PR 
interval, QRS Interval, QT interval, QTcB interval, QTcF interval and RR interval) and overall 
interpretation will be summarized by scheduled timepoint.  The number and percentage of 
patients with absolute QTc interval values in the pre-specified categories (>450, >480, and >500 
msec), and QTc interval change (>30 and >60 msec) will be summarized.  Triplicate 
measurements will be averaged prior to summary.   
3.6.5 Physical Examinations 
Physical examination findings will be listed. 
3.6.6 Other Safety Assessments 
ADA will be listed and summarized using descriptive statistics by treatment group.  All other 
safety data will be listed. 
4 INTERIM ANALYSIS 
No formal interim analyses are planned for this study other than descriptive analyses required 
for the Safety Review Committee (SRC) to review accumulating safety information.  The reviews 
and analyses will be defined in the SRC Charter. 
5 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.4 or higher.  All available data will be 
presented in subject data listings which will be sorted by subject and visit date as applicable.  
Detailed Programming Specifications will be provided in a separate document.