Conditions: Hypercholesterolemia Dyslipidemias
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 40
Healthy volunteers: no

Brief summary:
Open-label study will titrate doses of intravenous atorvastatin and monitor respective LDL-C levels in hypercholesterolemic patients previously controlled on oral atorvastatin.

Detailed description:

Arms:
arm 1: Cohort 1 = Baseline daily dose of 10 mg oral atorvastatin during lead-in, then IV study drug for up to 15 days arm 2: Cohort 2 = Baseline daily dose of 20 mg oral atorvastatin during lead-in, then IV study drug for up to 15 days arm 3: Cohort 3 = Baseline daily dose of 40 mg oral atorvastatin during lead-in, then IV study drug for up to 15 days arm 4: Cohort 4 = Baseline daily dose of 20 mg oral atorvastatin during lead-in, then SC study drug for up to 15 days

Interventions: intervention 1: Atorvastatin injection
Intervention descriptions: intervention 1: statin (i.e., 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor) for injection

Protocol document:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
 
PHASE II, DOSE-RANGING STUDY TO EVALUATE THE EFFICACY DOSE 
RESPONSE AND PHARMACOKINETICS OF INTRAVENOUS 
ATORVASTATIN IN HYPERCHOLESTEROLEMIC PATIENTS 
PREVIOUSLY CONTROLLED WITH ORAL ATORVASTATIN 
Study Number: CPI-1103-002 
 
 
Protocol Version 
 
Version Number:  
03 
Final:  
 
04 SEPTEMBER 2019   
Amendment:   
Replacing protocol amendment, version 02, dated 11Mar2019 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are 
privileged or confidential and may not be disclosed unless such disclosure is required by applicable 
laws and regulations. In any event, persons to whom the information is disclosed must be informed 
that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you which is 
indicated as privileged or confidential. 
 
 
 
 
 


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RESPONSIBLE PERSONNEL 
Sponsor - Medically Responsible Person 
 Sponsor’s Coordinating Office 
 
  
Todd Rice, MD 
 Leo Pavliv, R.Ph 
Director, Medical Affairs 
 Executive VP, Operations and Chief 
Development Officer 
Cumberland Pharmaceuticals Inc. 
 Cumberland Pharmaceuticals Inc. 
2525 West End Avenue, Suite 950 
 2525 West End Avenue, Suite 950 
Nashville, TN 37203 
 Nashville, TN 37203 
USA 
 USA 
 
  
Tel.: 
615-255-0068  
 Tel.: 
615-255-0068  
Fax.: 866-438-2372 
 Fax.: 866-438-2372 
 
 lpavliv@cumberlandpharma.com 
 
  
 
  
Sponsor’s Clinical Operations  
  
 
  
Jerry Fox, DVM 
  
Senior Manager, Clinical Affairs 
  
Cumberland Pharmaceuticals Inc. 
  
2525 West End Avenue, Suite 950 
  
Nashville, TN 37203 
  
USA 
  
 
  
Tel.: 
615-255-0068  
  
Fax.: 866-438-2372 
  
jfox@cumberlandpharma.com 
  
 
  
 
 
 
 




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1 INVESTIGATOR’S STATEMENT 
I have read and agree to the Protocol CPI-1103-002, Amendment 03, “Phase II, dose-ranging study 
to evaluate the efficacy dose response and pharmacokinetics of intravenous atorvastatin in 
hypercholesterolemic patients previously controlled with oral atorvastatin”. I am aware of my 
responsibilities as an Investigator under the guidelines of Good Clinical Practice (GCP), local 
regulations (as applicable) and the study protocol. I agree to conduct the study according to these 
guidelines and to appropriately direct and assist the staff under my control, who will be involved 
in the study. 
Principal Investigator 
Signature: 
Gregory Tracey, MD 
Date of Signature 
Frontage Clinical Services 
200 Meadowland Parkway 
Secaucus, NJ   07094 
(201) 678-0288 
Sponsor Signature 
Signature: 
Todd Rice, MD 
Date of Signature 
Director, Medical Affairs 
Signature: 
Leo Pavliv, R.Ph 
Date of Signature 
Executive Vice President, Operations & Chief Development Officer 
4/Sep/19


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2 SYNOPSIS 
Name of Sponsor: 
Cumberland Pharmaceuticals 
Inc. 
Finished Product: 
Atorvastatin injection 
Active Ingredient: 
Atorvastatin Calcium 
Title of Study: Phase II, dose-ranging study to evaluate the efficacy dose response and 
pharmacokinetics of intravenous atorvastatin in hypercholesterolemic patients previously 
controlled with oral atorvastatin 
Study Center: Frontage Clinical Services, Inc. 
Expected Study Duration: 9 months 
Phase of Development: II 
Objectives: 
• To propose intravenous doses of atorvastatin injection that adequately replace each dose level 
of oral atorvastatin 
• To describe the pharmacokinetic profile of atorvastatin injection administered by the 
intravenous route   
• To explore the pharmacokinetic profile of atorvastatin administered by the subcutaneous 
route  
• To assess the safety of the study drug administered by either the intravenous or 
subcutaneous route   
Methodology:  Cohorts of thirteen subjects, composed from each of the commercially-
prescribed levels of daily oral atorvastatin dosing (10, 20, and 40 mg), are treated for 15 days 
with open-label injectable atorvastatin.  Dosing for each cohort is adjusted, if necessary as 
determined by the Sponsor based on either the Day 8 or Day 15 LDL-C values.  Any cohort that 
does not remain below 125% of baseline LDL-C may be repeated at a dose level to be determined 
by the protocol. 
Pharmacokinetic profiles are summarized for multiple doses via the intravenous or subcutaneous  
routes and for a single dose via a subcutaneous route (sub-study).   
Safety is assessed by standard adverse event reporting and monitoring of serum levels of liver 
and muscle enzymes.  
Number of subjects (planned):  Approximately 40 in the main study; estimated 26 in the sub-
study 


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Name of Sponsor: 
Cumberland Pharmaceuticals 
Inc. 
Finished Product: 
Atorvastatin injection 
Active Ingredient: 
Atorvastatin Calcium 
Main criteria for inclusion: 
1. Adult between 18 and 65 years, inclusive.  
2. On a stable dose of oral atorvastatin for at least 5 weeks prior to investigational 
treatment.   
3. LDL-C value taken immediately at baseline is > 75% and < 125% of LDL-C taken one 
week prior.  
Main criteria for exclusion:  
1. A history of myopathy or rhabdomyolysis 
2. Any hepatic impairment in the Investigator’s judgement, including active gall bladder or 
biliary disorders 
3. Screening aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater 
than two times the upper limit of normal 
4. Uncontrolled hypothyroidism or diabetes mellitus  
5. Alcohol consumption of more than two drinks per day, on average 
Investigational Medicinal Product (IMP), dose and mode of administration: 
Subjects taking 10 mg daily of oral atorvastatin at baseline start by receiving replacement 
treatment with 2 mg of intravenous atorvastatin daily.  Based on monitoring of LDL-C levels, 
dosing in that group and subsequent groups may be adjusted in order to target an intravenous or 
subcutaneous dose for each baseline oral-dose level that controls LDL-C.    
 
A sub-study collects pharmacokinetic data following a single subcutaneous dose of atorvastatin 
injection.     
Duration of treatment: 15 days (+1 day for the sub-study) 
Criteria for evaluation: 
 
SAFETY EVALUATION 
• Adverse events 
• Changes in creatine phosphokinase, ALT and AST 
 
EFFICACY EVALUATION 
• Changes in LDL-C and high-density lipoprotein cholesterol (HDL-C) 
 


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3 TABLE OF CONTENTS 
1 
INVESTIGATOR’S STATEMENT ............................................................................. 3 
2 
SYNOPSIS .................................................................................................................. 4 
3 
TABLE OF CONTENTS ............................................................................................. 6 
LIST OF FIGURES ........................................................................................................................ 9 
LIST OF TABLES .......................................................................................................................... 9 
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 10 
5 
INTRODUCTION ..................................................................................................... 12 
5.1 
Background Information ....................................................................................... 12 
5.2 
Stage of Development ........................................................................................... 13 
5.3 
Subject Population ................................................................................................. 13 
5.4 
Trial Rationale ....................................................................................................... 13 
5.5 
Risk-Benefit Assessment ....................................................................................... 13 
6 
STUDY OBJECTIVES .............................................................................................. 14 
7 
STUDY ENDPOINTS ............................................................................................... 14 
8 
STUDY DESCRIPTION ........................................................................................... 15 
8.1 
Study Design ......................................................................................................... 15 
8.2 
Randomization and Blinding Conditions and Methods ......................................... 16 
8.3 
Drugs and Dosages ................................................................................................ 17 
8.3.1 
Identification and Description of Test Agent ..................................................... 17 
8.3.2 
Investigational Medicinal Product (IMP) Preparation and Dosing Instructions 17 
8.3.2.1 
Intravenous Route .......................................................................................... 17 
8.3.2.2 
Subcutaneous Route (Sub-study) ................................................................... 17 
8.3.2.3 
Study Drug Product ....................................................................................... 18 
8.3.2.4 
Dose ............................................................................................................... 18 
8.3.3 
Drug Accountability Procedures ........................................................................ 18 
8.4 
Selection of Study Population ............................................................................... 19 
8.4.1 
Main Study_Screening Phase ............................................................................ 19 
8.4.2 
Main Study_Lead-in Phase ................................................................................ 20 
8.4.2.1 
Inclusion Criteria_Lead-in Phase ................................................................... 20 
8.4.2.2 
Exclusion Criteria_Lead-in Phase ................................................................. 20 
8.4.3 
Main Study_Treatment Phase ............................................................................ 21 
8.4.3.1 
Inclusion Criteria_Treatment Phase ............................................................... 21 


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8.4.3.2 
Exclusion Criteria_Treatment Phase .............................................................. 22 
8.4.4 
Sub-study: Subcutaneous Pharmacokinetics ..................................................... 22 
8.4.4.1 
Sub-study Inclusion Criteria .......................................................................... 23 
8.4.4.2 
Sub-study Exclusion Criteria ......................................................................... 23 
8.5 
Prior and Concomitant Therapy ............................................................................ 23 
8.5.1 
Excluded Medications/Procedures/Therapy ...................................................... 23 
8.5.2 
Dietary and Fasting Requirements .................................................................... 23 
9 
STUDY PROCEDURES ........................................................................................... 24 
9.1 
Study Overview ..................................................................................................... 24 
9.2 
Schedule of Time and Events ................................................................................ 24 
9.3 
Key Study Procedures ........................................................................................... 30 
9.3.1 
Clinical Laboratory Assessments ...................................................................... 30 
9.3.2 
LDL-C, Point of Care ........................................................................................ 30 
9.3.3 
Drug, Alcohol, and Viral Screening ................................................................... 31 
9.3.4 
Pharmacokinetic Assessments ........................................................................... 31 
9.3.4.1 
Pharmacokinetics for Oral Dosing ................................................................. 32 
9.3.4.2 
Pharmacokinetics for Intravenous Dosing ..................................................... 33 
9.3.4.3 
Pharmacokinetics for Subcutaneous Dosing (Sub-Study) ............................. 33 
9.3.5 
Pharmacodynamic Assessments ........................................................................ 34 
9.3.6 
Dose Assignments ............................................................................................. 34 
9.3.6.1 
Lead-in Period Dosing ................................................................................... 34 
9.3.6.2 
Intravenous Dosing ........................................................................................ 34 
9.3.6.2.1 
Initial Cohort (10 mg PO Atorvastatin) ...................................................... 35 
9.3.6.2.2 
Dose Adjustments ....................................................................................... 35 
9.3.6.2.3 
Subsequent Cohorts (20, 40, and 80 mg PO Atorvastatin) ......................... 36 
9.3.6.3 
Subcutaneous Dosing (Sub-Study) ................................................................ 37 
9.4 
Measurements and Evaluations ............................................................................. 37 
9.4.1 
Description of Screening Visit ........................................................................... 37 
9.4.2 
Description of Lead-in Period ........................................................................... 38 
9.4.3 
Eligibility Confirmation and Treatment Assignment ........................................ 40 
9.4.4 
Description of Treatment Period........................................................................ 40 
9.4.4.1 
Day 1 .............................................................................................................. 40 
9.4.4.2 
Days 2, and 4 through Day 7 ......................................................................... 41 
9.4.4.3 
Day 3 .............................................................................................................. 41 
9.4.4.4 
Day 8 .............................................................................................................. 41 
9.4.4.5 
Days 9 through 14 .......................................................................................... 41 
9.4.4.6 
Day 15 ............................................................................................................ 41 


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9.4.4.7 
Withdrawal ..................................................................................................... 42 
9.4.5 
SUB-STUDY to Evaluate Subcutaneous Pharmacokinetics ............................. 42 
9.4.6 
Follow-up Call ................................................................................................... 43 
9.4.7 
Rescreening ....................................................................................................... 43 
10 
SUBJECT DISCONTINUATION ............................................................................. 43 
10.1 
Subject Discontinuation ......................................................................................... 43 
10.2 
Procedures for Subject Discontinuation ................................................................ 44 
10.3 
Study or Site Termination ...................................................................................... 44 
11 
ADVERSE EVENTS................................................................................................. 45 
11.1 
Definitions ............................................................................................................. 45 
11.1.1 
Adverse Event Definitions ................................................................................ 45 
11.1.2 
Adverse Event Assessment Definitions ............................................................. 47 
11.2 
Collection, Recording and Reporting of Adverse Events ...................................... 48 
11.3 
Follow-up of Adverse Events ................................................................................ 49 
12 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 49 
12.1 
Sample Size Determination ................................................................................... 49 
12.2 
Subject Population(s) for Analysis ........................................................................ 49 
12.3 
Statistical Methods ................................................................................................ 50 
12.3.1 
General Considerations...................................................................................... 50 
12.3.2 
Efficacy Analyses .............................................................................................. 50 
12.3.3 
Pharmacokinetics ............................................................................................... 51 
12.3.4 
Demographics and Baseline Characteristics...................................................... 51 
12.3.5 
Prior/Concomitant Medications ......................................................................... 52 
12.3.6 
Safety Analyses ................................................................................................. 52 
12.4 
Interim Analysis ..................................................................................................... 52 
13 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 52 
13.1 
Confidentiality ....................................................................................................... 52 
13.2 
Source Documents ................................................................................................. 53 
13.3 
Case Report Forms ................................................................................................ 53 
13.4 
Records Retention ................................................................................................. 53 
14 
STUDY MONITORING, AUDITING, AND INSPECTING ................................... 53 
14.1 
Study Monitoring Plan .......................................................................................... 53 
15 
ETHICAL CONSIDERATIONS ............................................................................... 54 


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15.1 
Informed Consent .................................................................................................. 54 
15.2 
Protocol Compliance ............................................................................................. 54 
15.3 
Financial Disclosure .............................................................................................. 55 
15.4 
Study Files ............................................................................................................. 55 
16 
REFERENCES .......................................................................................................... 55 
 
LIST OF FIGURES 
Figure 8–1 
Investigational Labeling........................................................................................ 17 
Figure 9-1 
Study Overview .................................................................................................... 25 
 
LIST OF TABLES 
Table 9–1 
Schedule of Events ................................................................................................ 26 
Table 9–2 
Clinical Lab Analytes ............................................................................................ 30 
Table 9–3 
Allowable Time Windows for Pharmacokinetic Draws........................................ 31 
Table 9-4 
Intravenous Dosing by Lead-in Cohort................................................................. 35 


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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation Definition or Term 
AE 
Adverse Event 
AUCinf 
area under the curve to infinity 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BUN 
Blood urea nitrogen 
oC 
Celsius, degrees 
CBC  
Complete Blood Count 
CFR 
Code of Federal Regulations 
CK 
Creatine Kinase 
Cl 
Clearance 
Cmax 
maximum serum concentration 
CMP 
Comprehensive metabolic profile (serum biochemistry profile) 
CPI 
Cumberland Pharmaceuticals Inc. 
CRF 
Case Report Form 
dL  
deciliter 
eCRF 
Electronic Case Report Form 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
Hepatitis Virus B 
HCV 
Hepatitis Virus C 
HDL-C 
high density lipoprotein cholesterol 
HIV 
Human Immunodeficiency Virus 
HMG-CoA 
3-hydroxy-3-methylglutaryl-coenzyme A 
ICH 
International Conference on Harmonization  
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IV 
intravenous 
Kel 
elimination rate constant 
kg  
kilogram 
LDH 
Lactate dehydrogenase 
LDL-C 
low density lipoprotein cholesterol  
Mg 
milligram 


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Abbreviation Definition or Term 
MI 
myocardial infarction 
mL 
milliliter 
mmHg 
millimeters of mercury 
N 
Number 
NPO 
Nil per os (nothing by mouth) 
NOAEL 
no observed adverse effect level 
PK 
pharmacokinetics 
PO 
Per os (by mouth) 
q.d.  
Once daily 
SAE 
Serious Adverse Event/Experience 
SC 
Subcutaneous 
SCr 
Serum creatinine 
T1/2 
elimination half-life 
TEAE 
Treatment-emergent adverse event 
ULN 
upper limit of normal 
VDss 
Volume of distribution at steady state 
WD 
withdrawn 
 


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5 INTRODUCTION 
This study is to be performed in accordance with Good Clinical Practice (GCP), the ethical 
principles that have their origin in the Declaration of Helsinki, Title 21 of the Code of Federal 
Regulations Parts 50, 56 and 312, and the International Conference on Harmonization E6. 
5.1 Background Information 
Cumberland Pharmaceuticals Inc. is developing atorvastatin injection for use in patients where an 
injectable route of atorvastatin administration is preferred.  
Oral atorvastatin is currently approved for a number of indications, including the treatment of 
hyperlipidemia and the reduction of risk of myocardial infarction, stroke, revascularization 
procedures and angina (Lipitor Package Insert 2018).  Atorvastatin injection is initially under study 
for treatment of hypercholesterolemia in patients where the intravenous (IV) or subcutaneous (SC) 
route is preferable to the oral route. 
Statins, i.e., 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are a 
class of drugs to treat patients with hypercholesterolemia and for secondary prevention of coronary 
artery disease and stroke.  Statins are among the most potent cholesterol lowering drugs available, 
yet only commercially available in oral formulations. 
An injectable formulation of atorvastatin would allow for continuation of atorvastatin therapy in 
patients whenever enteral administration is not possible.  There is evidence that abrupt 
discontinuation of statin therapy in patients with acute vascular disease results in adverse outcomes 
like cardiac events and higher mortality (Endres 2008, Daskalopoulou 2008, Schouten 2007). 
Patients that may potentially benefit from injectable statin administration include: (1) individuals 
on an established statin regimen who are hospitalized and listed as nil per os (NPO) such as those 
who are intubated, sedated, unconscious, or perioperative; (2) classes of acutely vulnerable patients 
such as those experiencing stroke, acute coronary syndrome, and certain types of myocardial 
infarction (MI) who may obtain protective effects from immediate statin administration; and (3) 
patients at high-risk of vascular events prior to and immediately following surgery.  
Atorvastatin injection is being developed by Cumberland Pharmaceuticals Inc. (CPI). The current 
formulation of atorvastatin injection is a 10 mg/mL (40 mg/4mL) liquid for injection, available in 
a glass vial. 
Several Cumberland-sponsored nonclinical studies of atorvastatin injection have been conducted.  
No adverse trends were seen in a repeat-dose canine toxicity study, a rabbit-ear venous irritation 
study, or hemolysis and flocculation studies with human plasma/serum.  The highest doses of 


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atorvastatin injection caused elevated liver enzymes, a result consistent with high dose oral 
atorvastatin. The dog toxicity study determined a no observed adverse effect level (NOAEL) of 20 
mg/kg/day atorvastatin injection.  
In a Phase 1 clinical trial in healthy volunteers, a preliminary pharmacokinetic profile for the parent 
compound and the two active metabolites was established for the intravenous delivery route.  No 
major safety concerns were identified.   
The current study is intended to further define the pharmacodynamic properties of atorvastatin and 
metabolites when delivered intravenously or subcutaneously, and to propose a dosing regimen to 
meet efficacy and safety objectives in changing from an oral to an injectable route.  A single dose 
of atorvastatin will also be given by the subcutaneous route in a sub-study and initial 
pharmacokinetic data will be collected for subjects enrolling under Amendments 1 or 2 of the study 
protocol.  In Protocol Amendment 3, dated 04Sep2019, subjects taking oral atorvastatin change to 
a subcutaneous route for the treatment phase rather than an intravenous route.        
5.2 Stage of Development  
This is a Phase II study to determine the efficacy dose response and pharmacokinetics of injectable 
atorvastatin in hypercholesterolemic subjects. 
5.3 Subject Population 
Subjects already taking statins to control elevated low-density lipoprotein cholesterol (LDL-C), or 
subjects not taking statins that currently have elevated LDL-C.      
5.4 Trial Rationale 
This study is designed to propose non-inferior intravenous and subcutaneous doses of atorvastatin 
injection to temporarily replace stable, oral doses of 10, 20, and 40 mg.  As expected and confirmed 
by the Phase I results, the systemic ratios of parent compound to active metabolites are altered 
with intravenous dosing as compared to oral.  The pharmacokinetic profiles of each are further 
studied in this trial at the level of the individual patient to support both the dosing regimen and the 
safety profile of atorvastatin when administered parentally.        
5.5 Risk-Benefit Assessment 
Atorvastatin was first approved by the Food and Drug Administration (FDA) in December 1996 
as an oral tablet under the trade name Lipitor®.  Expected risks associated with the administration 
of atorvastatin injection can in part be anticipated because of the longstanding and widespread use 
of oral atorvastatin. The most commonly reported adverse reactions in subjects treated in clinical 


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trials with Lipitor, when having a higher incidence than with placebo and regardless of causality 
were nasopharyngitis, arthralgia, diarrhea, pain in extremity and urinary tract infection (Lipitor 
Package Insert 2018).  Although rare, cases of rhabdomyolysis have been reported with use of 
Lipitor and other drugs in the class.  This marks a serious potential risk with the drug class and one 
that needs to be monitored during statin treatment.  Lipitor is indicated for extended dosing; 
however, this study will evaluate a two-week treatment period with atorvastatin injection.  The 
Phase 1 study with atorvastatin injection did not detect any additional risks with the formulation 
or intravenous administration route.                
6 STUDY OBJECTIVES 
The objectives of this study apply to hypercholesterolemic patients currently being maintained on 
a stable dose of oral atorvastatin: 
• To propose intravenous doses of atorvastatin injection that adequately replace each dose 
level of oral atorvastatin 
• To describe the pharmacokinetic profile of atorvastatin injection administered by the 
intravenous route   
• To explore the pharmacokinetic profile of atorvastatin administered by the subcutaneous 
route  
• To assess the safety of the study drug when administered either intravenously or 
subcutaneously 
7 STUDY ENDPOINTS 
• To support a dose of atorvastatin injection that adequately replaces oral atorvastatin, the 
following primary endpoint will be evaluated for each of the three, labelled oral doses of 
atorvastatin (10, 20, and 40 mg daily); endpoints are assessed using the subjects’ levels of 
(LDL-C) and high-density lipoprotein cholesterol (HDL-C):  
o Eleven or more subjects in a dosing cohort of thirteen with a Day 15 LDL-C not 
more than 125% of their baseline LDL-C. 
Secondary endpoints that contribute to the same objective are as follows:  
o Eleven or more subjects in a dosing cohort of thirteen with a Day 15 HDL-C not 
less than 75% of their baseline HDL-C. 


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o The mean change in LDL-C at Day 15 for each treatment cohort (N=13) 
• To compare the pharmacokinetic profile of atorvastatin administered by the intravenous 
route to that of oral administration, the following parameters of atorvastatin, 2-hydroxy 
atorvastatin and 4-hydroxy atorvastatin will be calculated for each of the three final IV 
treatment cohorts (See Study Design for description of the three cohorts):  
o Maximum serum concentration (Cmax) 
o Area under the curve to infinity (AUCinf) 
o Area under the curve to 24 hours (AUC0-24) 
o Elimination half-life (T1/2) 
o Volume of distribution at steady state (VDss) 
o elimination rate constant (Kel) 
o Clearance (Cl) 
• To explore the pharmacokinetic profile of atorvastatin administered by the subcutaneous 
route, the following parameters of atorvastatin, 2-hydroxy atorvastatin and 4-hydroxy 
atorvastatin will be calculated for each of the three final treatment cohorts (See Study 
Design for description of the three cohorts):  
o Cmax  
o AUCinf   
o AUC0-24 
o T1/2 
o VDss 
o Kel 
o Cl/F 
o Cl 
• 
To assess the safety of the study drug, the following will be evaluated:  
o Adverse events 
o Mean change (baseline to Day 15) for creatine phosphokinase (CPK), alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) in each dosing 
cohort. 
 
8 STUDY DESCRIPTION 
8.1 Study Design 
• Phase II, open-label, single-center dose-ranging study. 


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• Three treatment cohorts of 13 subjects each are planned, potentially for each of the routes 
of administration (intravenously and subcutaneously).  The different cohorts are composed 
of subjects taking three of the four commercially-prescribed levels of daily oral dosing:  
10, 20, and 40 80 mg.  Subjects are treated with daily doses of injectable atorvastatin 
intended to be non-inferior to the efficacy of their stable oral dose during the Lead-in 
Period.   
• Enrollment of subjects into any one of the cohorts that does not prove to meet the primary 
endpoint, or otherwise shows a lack of efficacy, is terminated as soon as this determination 
is made, and a new cohort intended for 13 subjects is opened at an adjusted dose with 
intentions to meet the primary endpoint.  See Section 9.3.6.2.2.    
• Subjects remain on the replacement treatment with atorvastatin for injection for 15 days, 
followed by a one-week follow-up period. 
• Assessments include the following:  
o Pharmacokinetic (PK) profile evaluation .of both the oral and IV dosing and, 
starting with Amendment 3, the SC dosing regimen. 
o Cholesterol (LDL-C) levels to assess efficacy 
o Safety assessment, including markers of rhabdomyolysis 
• Sub-study (Amendments 1 and 2 only):  If remaining on oral atorvastatin in the follow-
up period, subjects that individually meet the study objective (Day 15 LDL-C < 125% of 
baseline level) may substitute a daily oral dose of atorvastatin for a subcutaneous dose of 
the same volume as the intravenous dose to which they were assigned.  Plasma levels of 
atorvastatin and the two metabolites are measured for a 24-hour period to assess the 
pharmacokinetic parameters of the subcutaneous route.       
• Schedules of assessments are summarized in Table 9-1A and Table 9-1B depending on the 
medication history of the subject when they entered the study.  
8.2 Randomization and Blinding Conditions and Methods 
This is an unblinded study.  All subjects will be openly assigned atorvastatin injection and their 
daily dose will be known by the Investigator and the subject.  


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8.3 Drugs and Dosages 
8.3.1 Identification and Description of Test Agent 
Atorvastatin injection is available for investigational use only. Atorvastatin injection is packaged 
as a clear, colorless to slightly yellow liquid in a glass vial containing 40 mg atorvastatin in a total 
volume of 4 mL (10mg/mL). Atorvastatin injection contains the following inactive ingredients: 
hydroxypropyl beta cyclodextrin, L-cysteine monohydrochloride monohydrate, dibasic sodium 
phosphate, sodium hydroxide and water for injection. Ingredients in the formulation meet current 
Pharmacopeia standards. A copy of the vial investigational label is included as Figure 8-1. 
Figure 8–1 
Investigational Labeling 
Atorvastatin Injection, 40 mg (40 mg/4 mL) 
Lot:  
Store at room temperature.  
Instructions: Use as directed 
Caution: New Drug – Limited by United States Law to 
Investigational Use 
Cumberland Pharmaceuticals Inc., Nashville, TN 
   
For subjects that were taking oral atorvastatin prior to their study involvement, it will continue to 
be obtained according to the subject’s standard methods.  Oral atorvastatin will be supplied by the 
study for subjects that were not taking it prior to study involvement.   
8.3.2 Investigational Medicinal Product (IMP) Preparation and Dosing 
Instructions 
8.3.2.1 Intravenous Route 
Atorvastatin injection is administered intravenously over 5 - 10 seconds into an antecubital or 
forearm vein.  Following the Investigator’s standard technique and equipment for preparing the 
injection site, the open-label study drug is administered without dilution.  The dose is determined 
as directed in Section 8.3.2.4.  If any IV tubing is utilized, normal saline is used to flush the line 
immediately following the injection of IMP to clear the line of any residual drug and ensure 
complete dosing.  The location of the injection is captured in the source documents, but not the 
CRF.   
8.3.2.2 Subcutaneous Route 
Atorvastatin injection is administered subcutaneously as an injection into the abdominal area.  The 
Investigator’s center uses their standard technique and equipment to prepare the injection site and 


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to administer the injection.  The location of the injection is captured in the source documents, but 
not the CRF.    
8.3.2.3 Study Drug Product  
Atorvastatin injection is administered at its full 10 mg/mL strength without dilution.  For doses of 
10 mg or less, 1.0 mL or insulin syringes are used so that small volumes can be drawn up and 
administered accurately.   
A new vial of Atorvastatin injection (40 mg/4 mL) is used each calendar day.  Sterile technique is 
utilized to draw individual subject doses; the same 10 mL vial can be used to dose multiple subjects 
on the same calendar day, but partially-used vials must not be used on a subsequent day.  Drug 
accountability is documented at the level of each 40 mg vial of Atorvastatin injection.          
8.3.2.4 Dose  
The daily dose of IMP to be administered to each subject by both the intravenous route and the 
subcutaneous route is provided by the sponsor when the enrollment decision is made by the 
Investigator.  It is based on the stable dose of oral atorvastatin taken by the subject during the lead-
in phase.  The initial dose for patients entering the treatment phase on 10 mg of daily oral 
atorvastatin is 2 mg IV daily.  Corresponding initial target doses for the other levels of oral dosing 
are listed in Table 9-4.  Dose adjustments for all follow the guidance listed in Section 9.3.6.2.2.  In 
all cases, the Investigator will adhere to the dosing assignment documented by the Sponsor for 
each individual subject.    
8.3.3 Drug Accountability Procedures 
Atorvastatin injection, labeled for investigational use, will be provided by Cumberland 
Pharmaceuticals Inc.  The investigator is required to keep complete and accurate records of the 
receipt, dispensation, disposal and return of all clinical trial drugs provided during the conduct of 
the study.  
For subjects entering the study already taking oral atorvastatin, the product will continue to be 
obtained according to the subjects’ standard methods through the lead-in and follow-up periods.  
Accountability is not formally documented in these cases; however, in determining each subject’s 
eligibility, the Investigator assures to the best of his or her knowledge that the subject has been on 
a stable dose of oral atorvastatin.  
Subjects that were not taking oral atorvastatin when entering the study are provided it by the study 
at the assigned dose.  Drug accountability for these subjects is calculated during the five-week 
lead-in period so that compliance for that patient is understood and eligibility can be confirmed.          


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8.4 Selection of Study Population 
Eligible subjects ultimately enter a baseline lead-in period where they take daily oral atorvastatin 
prior to converting to the investigational atorvastatin injection in the treatment phase.  There are 
two main classifications of patients, and two sub-classifications, that may be eligible for screening 
and entry into the lead-in phase and the specific eligibility criteria differ for each:  
a) Subjects that are taking a daily statin prior to their study involvement 
i. 
Subjects taking oral atorvastatin 
ii. 
Subjects taking a statin other than atorvastatin 
b)   Subjects that are not taking a daily statin prior to their study involvement 
Determination of study eligibility will be made by the Investigator on the basis of the inclusion 
and exclusion criteria listed below. 
8.4.1 Main Study Screening Phase 
After a subject provides written consent to participate in the study, they may enter the screening 
phase by meeting one of the two following groups of inclusion criteria, depending on their pre-
study medication history.    
a) Subjects that are already taking a statin prior to their study involvement:  
1a.   Male or female, between 18 and 65 years of age, inclusive. 
2a.  Have been taking a commercially-labelled (U.S.), daily, stable dose of an oral statin 
for at least 28 days prior to consent.  
3a.  Point-of-care* LDL-C level > 65 mg/dL (measured on CardioChek® PA Analyzer, 
or equivalent) 
4a.  Ability to make daily office visits, including weekends, during the two-week 
treatment period. 
b) Subjects that are not taking a statin prior to their study involvement: 
1b.  
Male or female, between 18 and 65 years of age, inclusive. 
2b.  
No statin use in the 6 weeks prior to consent 
3b.  
Point-of-care* LDL-C level > 120 mg/dL (measured on CardioChek® PA Analyzer, 
or equivalent) 
4b.  Ability to make daily office visits, including weekends, during the two-week 
treatment period. 


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*If there are occurrences where the point-of-care analyzer gives an error message rather than a 
numerical result, it may be possible to substitute LDL-C from the local laboratory.  See Section 
9.4.1. 
8.4.2 Main Study_Lead-in Phase 
After a subject has completed the screening phase assessments, they may enter the lead-in phase 
by meeting the following eligibility criteria.   
Please note that the structure of the Lead-in Phase is different depending on the pre-study 
medication history of the individual patient, as described in Section 9.4.2. 
8.4.2.1 Inclusion Criteria_Lead-in Phase 
1. Female subjects must have a negative pregnancy test at screening AND  
• be surgically sterile (with documentation of hysterectomy, bilateral oophorectomy, 
bilateral salpingectomy, bilateral tubal ligation/tubal occlusion),  
• OR be post-menopausal (no menstruation for a minimum of 12 months), As 
evaluated by Investigator, 
• OR if of child-bearing potential, must be using an acceptable method of 
contraception such as an IUD, implant or contraceptive injection, or two forms of 
the following (e.g., diaphragm, cervical cap, patch or vaginal hormonal 
contraceptive, condom, spermicide, or sponge) for the last three months. All 
females must agree to continue to use their method of birth control for the duration 
of the study and for a minimum of one complete menstrual cycle. 
8.4.2.2 Exclusion Criteria_Lead-in Phase 
1. A history of myopathy or rhabdomyolysis or an Investigator assessment that subject may 
have experienced myopathy with previous statin use  
2. Screening AST or ALT > 2x the upper limit of normal (ULN) 
3. Any hepatic impairment in the Investigator’s judgement, including active gall bladder or 
biliary disorders.  Previous cholecystectomy is allowable if the subject is stable. 
4. Positive status for Human Immunodeficiency Virus (HIV) virus, Hepatitis B Virus (HBV) 
or Hepatitis C Virus (HCV).  
5. Alcohol consumption of more than two drinks per day, on average.  Or any abuse of alcohol 
or non-prescribed drugs based on Investigator opinion and/or study screening.    


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6. Current known unstable angina or uncontrolled cardiac arrhythmias or a known cardiac 
event in the three months before screening (e.g., myocardial infarction, cerebral vascular 
event, percutaneous coronary intervention, coronary bypass surgery, etc.)  
7. Uncontrolled hypothyroidism or diabetes mellitus, as determined by Investigator opinion 
based on subject health or medication records, and/or verbal report.   
8. Uncontrolled hypertension (e.g., systolic pressure >160 mmHg or diastolic pressure>110 
mmHg) 
9. Concurrent treatment with cyclosporine and strong CYP3A4 inhibitors (e.g., 
clarithromycin, itraconazole, HIV protease inhibitors, etc.) 
10. Poor venous access for intravenous injections or blood draws 
11. Pregnant, nursing, or planning to become pregnant. 
12. A history of allergy or hypersensitivity to oral atorvastatin 
13. Have taken investigational drugs within 30 days before IMP administration. 
14. Inability to understand the requirements of the study. 
15. Be otherwise unsuitable for the study, in the opinion of the Investigator. 
8.4.3 Main Study_Treatment Phase 
Subjects are eligible to enter the Treatment Phase and receive IMP after completing the Lead-in 
period and meeting one of the two following groups of inclusion criteria, depending on their pre-
study medication history, and not meeting any exclusion criteria. 
8.4.3.1 Inclusion Criteria_Treatment Phase 
a) Subjects that were already taking oral atorvastatin prior to their study involvement:  
1a.   LDL-C value from Lead-in End Visit is > 75% and < 125% of Screening Visit LDL-
C measured by the point-of-care tests*.  
2a.  Female subjects must have a negative pregnancy test at screening AND, if of child-
bearing potential, must be using an acceptable method of contraception such as an 
IUD, implant or contraceptive injection, or two forms of the following (e.g., 
diaphragm, cervical cap, patch or vaginal hormonal contraceptive, condom, 
spermicide, or sponge) for the last three months. All females must agree to continue 


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to use their method of birth control for the duration of the study and for a minimum 
of one complete menstrual cycle.  
b) Subjects that were NOT taking oral atorvastatin prior to their study involvement (includes 
subjects not taking any statin and those taking statins other than atorvastatin) 
1b.   LDL-C value from Lead-in End Visit is > 75% and < 125% of Lead-in Interim Visit 
LDL-C measured by the point-of care tests*.   
2b.  Female subjects must have a negative pregnancy test at screening AND, if of child-
bearing potential, must be using an acceptable method of contraception such as an 
IUD, implant or contraceptive injection, or two forms of the following (e.g., 
diaphragm, cervical cap, patch or vaginal hormonal contraceptive, condom, 
spermicide, or sponge) for the last three months. All females must agree to continue 
to use their method of birth control for the duration of the study and for a minimum 
of one complete menstrual cycle.  
*If there are occurrences where the point-of-care analyzer gives an error message rather 
than a numerical result, it may be possible to substitute LDL-C from the local laboratory.  
See Section 9.4.2. 
8.4.3.2 Exclusion Criteria_Treatment Phase 
1. 
Clinically-significant elevation of ALT, AST, or CK during the Lead-in Period, as 
determined by the Investigator.   
2. 
Known compliance for oral atorvastatin <90% during the Lead-in Period.  
3. 
Failure to complete the pharmacokinetic blood draws (See Section 9.3.4.1) during 
the Lead-in Period.   
8.4.4 Sub-study: Subcutaneous Pharmacokinetics 
Please note that the Sub-study is no longer active or available under Protocol Amendment 
3.   
A subject must first meet all the eligibility criteria in Sections 8.4.1, 8.4.2 and 8.4.3 to qualify for 
the Sub-study. 
In addition, the following criteria must be met:   


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8.4.4.1 Sub-study Inclusion Criteria 
1. Ability to present to clinic for IMP dosing and PK assessment timepoints. 
2. Approval to participate granted by sponsor based on review of each subject’s Day 15 LDL-
C level, baseline dose of oral atorvastatin and current enrollment numbers.      
8.4.4.2 Sub-study Exclusion Criteria 
1. Study Day 15 LDL-C > 125% of baseline LDL-C 
2. Cohort to which subject belongs has three or more subjects with Day 15 LDL-C > 125% 
of baseline LDL-C 
8.5 Prior and Concomitant Therapy 
8.5.1 Excluded Medications/Procedures/Therapy 
Concomitant medications and treatments that may directly or indirectly affect cholesterol levels 
are not to be initiated, discontinued, or otherwise changed during the lead-in and treatment phases 
of the study.  Subjects that enter screening on a statin other than atorvastatin will replace that drug 
with oral atorvastatin during the Lead-in Period.     
Use of St. John’s Wort or grapefruit juice is prohibited 24 hours prior to IMP administration and 
throughout the conduct of the study.  
Caution should be used with concurrent use of fibrate products or lipid-modifying doses            (≥1 
g/day) of niacin as this may increase the risk of adverse skeletal muscle effects while taking 
atorvastatin.  Patients on digoxin should be monitored appropriately (Lipitor Package Insert 2018). 
8.5.2 Dietary and Fasting Requirements 
During the study, subjects maintain the dietary practices that they followed prior to study 
participation.  Changes in nutritional or dietary behavior during the study, if deemed significant by 
the Investigator, are recorded in the Case Report Forms.      
All lipid panel lab draws will be performed in a fasting state. 


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9 STUDY PROCEDURES 
9.1 Study Overview  
A schematic of the overview of the study is shown below in Figure 9-1.  Three types of patient 
populations, categorized by statin use prior to study participation, are all potentially eligible for 
the study as shown below, and their progression through the screening and lead-in periods follows 
the pathway determined by their pre-study use of statins: 
• Patients taking oral atorvastatin prior to the study 
• Patients taking statins other than atorvastatin prior to the study 
• Patients not taking any statins prior to the study.    
The study consists of a screening visit that determines a subject’s eligibility to enter a lead-in phase 
where they will start or continue taking daily oral atorvastatin.  Specific eligibility requirements 
are dependent on their pre-study statin use.   
During the Lead-in Period, daily dosing of oral atorvastatin allows the determination of baseline 
LDL-C levels and also provides PK data from steady-state oral administration that will be 
compared to that from the intravenous administration.      
The treatment period consists of an open-label treatment of 15 daily intravenous or subcutaneous 
doses of atorvastatin injection.  A 7-day follow up period follows and concludes with a phone call 
from the Investigator or designee to the subject to collect information on any possible adverse 
events or changes in concomitant treatments.   
Subjects eligible for the Sub-study and willing to participate receive a subcutaneous injection of 
atorvastatin on Day 22 and complete PK sampling the following day.  The follow-up phone call, 
as noted above, is completed on Day 29.    
9.2 Schedule of Time and Events 
A detailed schedule of events is found below which lists the assessments required by the study at 
the corresponding timepoints.  The type of statin use of the individual subject prior to study 
involvement determines which schedule to follow:  
• Table 9-1A is to be followed for patients that entered the study having been taking a daily 
oral dose of atorvastatin.  
• Table 9-1B is followed for patients that are not taking oral atorvastatin on their entry into 
the study.  Two sub-classifications of patients comprise this group:  
o Patients that were not taking ANY statin at the time of study entry, and 


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o Patients that were taking a statin other than atorvastatin at the time of study entry.   
 
Figure 9-1 
Study Overview 
 


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Table 9–1A 
Schedule of Events  
 
 
 
 
For subjects that ARE taking oral atorvastatin at study entry 
 
Study Phase 
Screen 
-ing 
Lead-in  
Treatment 
Follow-up 
call 
Optional 
SUB-STUDY 
Study Day 
Day -3 to 
0 from LI 
Day 0 
LI End Visit 
(Screening visit 
+ 7 to 10 days) 
AND 
(0 to -2 days 
before Day 1) 
Day 
1 
Day 
2 
Day 
3 
Days 
4–7 
Day 
8 
Days 
9-14 
Day 
15/ 
WD** 
Day 22 
Day 22  
+ 2 days 
 
Day 29  
+ 3 days 
(Phone call) 
LDL-C, Point of care 
X* 
X† 
 
 
 
 
 
 
 
 
 
 
LDL-C, Local laboratory 
 
 
 
 
 
 
X 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test, if needed 
X 
X 
 
 
 
 
 
 
X 
 
 
 
Drug, Alcohol, Viral screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC, CMP, lipid profile 
X   
X‡ 
 
 
 
 
 
 
X 
 
 
 
Basic Metabolic Panel 
 
 
 
 
X 
 
X 
 
 
 
 
 
Vital Signs 
X 
 
X‖ 
 
 
 
 
 
 
 
 
 
Review of Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
PK Blood Draws    
 
X§ 
 
 
 
 
 
 
X⁋ 
 
XΔ 
 
Daily oral atorvastatin 
dosing (standard of care). 
X 
 
 
 
 
 
 
 
Resume on 
Day 16, if in  
sub-study 
 
Daily IV or SCIMP 
 
 
X 
 
 
 
Single injection SC 
 
 
 
 
 
 
 
 
 
 
X 
 
Con Med monitoring 
X 
               X 
Adverse Event monitoring 
 
X 
X 


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* Point of care LDL-C is the first procedure done after the subject gives consent.  If the value does not meet eligibility, the subject screen fails and receives no other 
assessments.  Otherwise, the subject continues into the full screening phase.    
† On LI End Visit, the Point of Care LDL-C is performed first and, if the subject does not qualify for treatment, they are a screen fail and no other assessments are 
done.   
‡ The CMP, including liver enzymes and CK results must be reviewed by an Investigator before the subject is deemed eligible for treatment. The LDL result from 
this panel will not weigh in on the eligibility determination.  Only the point of care result from LI End Visit determines eligibility.   
§ PK sampling (oral PK) is performed at the Lead-in End visit.  Samples are taken per Section 9.3.4.1. The pre-dose sample serves as the Hour 24 level.   
‖ On Day 1, vitals are measured twice: 1) between 30 and 0 minutes before the start of IMP, and 2) 15 (+ 5) minutes after the start of IMP  
⁋ PK sampling (Multi-dose PK) is performed on subjects that complete a Day 15 visit.  Samples are taken per Section 9.3.4.2. The pre-dose sample serves as the 
Hour 24 level. 
Δ PK sampling (SC PK) is performed On Day 22 for those subjects participating in the sub-study.  A subcutaneous injection of IMP is administered on a day that 
oral atorvastatin is withheld, then samples are taken per Section 9.3.4.3. 
** If a subject withdraws (WD) from the treatment period before Day 15, the following assessments should be completed:  Physical exam, CBC, CMP, lipid 
profile, vital signs.  Withdrawn subjects do not have PK blood draws and are not eligible for the SC sub-study.     
 


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Table 9-1B 
Schedule of Events  
 for subjects NOT taking oral atorvastatin at study entry 
Study Phase 
Screen 
-ing 
Lead-in 
Treatment 
Follow-
up call 
Optional 
SUB-STUDY 
Study Day 
Day -3 
to 0 
from LI 
Day 0 
LI 
Day 
0 
 
LI Interim 
Visit   
(LI Day 28 
+/-2 days) 
LI End Visit 
(Interim visit + 
7 to 10 days 
AND 
0 to -2 days 
before Day 1) 
Day 
1 
Day 
2 
Day 
3 
Days 
4–7 
Day 
8 
Days 
9-14 
Day 
15 
Day 22 
Day 22 
+ 2 days 
Day 29 
+ 3 days 
(Phone call)
LDL-C, Point of care 
X* 
 
X 
X† 
 
 
 
 
 
 
 
 
 
LDL-C, Local 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test, if 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
Drug, Alcohol, Viral 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC, CMP, lipid profile 
X   
 
 
X‡ 
 
 
 
 
 
 
X 
 
 
Basic Metabolic Panel 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Vital Signs 
X 
 
 
 
X‖ 
 
 
 
 
 
 
 
 
Review of Eligibility 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
PK Blood Draws    
 
 
 
X§ 
 
 
 
 
 
 
X⁋ 
 
XΔ 
 
Dispense oral 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Daily oral atorvastatin 
dosing 
 
X 
 
 
 
 
 
 
 
Resume 
on Day 
16, if in  
sub-study 
 
Drug accountability 
 
 
X 
X 
 
 
 
 
 
Daily IV or SC IMP 
 
 
 
 
X 
 
 
Single injection SC 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Con Med monitoring 
X 
               X 


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* Point of care LDL-C is the first procedure done after the subject gives consent.  If the value does not meet eligibility, the subject screen fails and receives no other 
assessments.  Otherwise, the subject continues into the full screening phase.     
† On LI End Visit, the Point of Care LDL-C is performed first and, if the subject does not qualify for treatment, they are a screen fail and no other assessments are done.   
‡ The CMP, including liver enzymes and CK results must be reviewed by an Investigator before the subject is deemed eligible for treatment. The LDL result from this 
panel will not weigh in on the eligibility determination.  Only the point of care result from LI End Visit determines eligibility.   
§ PK sampling (oral PK) is performed at the Lead-in End visit.  Samples are taken per Section 9.3.4.1. The pre-dose sample serves as the Hour 24 level.   
‖ On Day 1, vitals are measured twice: 1) between 30 and 0 minutes before the start of IMP, and 2) 15 (+ 5) minutes after the start of IMP  
⁋ PK sampling (Multi-dose PK) is performed on subjects that complete a Day 15 visit.  Samples are taken per Section 9.3.4.2. The pre-dose sample serves as the Hour 24 
level. 
Δ PK sampling (SC PK) is performed On Day 22 for those subjects participating in the sub-study.  A subcutaneous injection of IMP is administered on a day that oral 
atorvastatin is withheld, then samples are taken per Section 9.3.4.3. 
** If a subject withdraws (WD) from the treatment period before Day 15, the following assessments should be completed:  Physical exam, CBC, CMP, lipid profile, vital 
signs.  Withdrawn subjects do not have PK blood draws and are not eligible for the SC sub-study.    
Adverse Event 
 
X 
X 


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9.3 Key Study Procedures 
9.3.1 Clinical Laboratory Assessments 
Blood sample collection for routine laboratory assessments will be performed within protocol-
specified time periods and according to the site’s standard practices for drawing and processing 
samples. The analytes listed here in Table 9-2 are measured by the site’s local laboratory and 
evaluated by the investigator for safety monitoring with respect to reference ranges provided by 
that lab: 
Table 9–2a. Clinical Lab Analytes to be Measured at Screening, Lead-in End Visit and Day 
15  
Complete blood count (CBC) with differential 
Hematocrit 
Neutrophils, absolute count 
Hemoglobin 
Lymphocytes, absolute count 
Total white blood cell count 
Monocytes, absolute count 
Platelet count 
Eosinophils, absolute count 
 
Basophils, absolute count 
Comprehensive Metabolic Panel (CMP) 
Sodium 
Albumin 
Potassium 
Total protein 
Chloride 
Aspartate aminotransferase (AST) 
Total carbon dioxide (serum biocarbonate) 
Alanine aminotransferase (ALT) 
Glucose 
Alkaline phosphatase (ALP) 
Blood urea nitrogen (BUN) 
Total bilirubin 
Serum creatinine (SCr)  
Creatine Kinase (CK) 
Calcium 
Lactate Dehydrogenase (LDH) 
Lipid Profile 
Low-density lipoprotein cholesterol (LDL-C) 
Total cholesterol 
High-density lipoprotein cholesterol (HDL-C) 
Triglycerides 
b. Clinical Lab Analytes to be Measured at Day 3 and Day 8  
Basic Metabolic Panel  
Blood urea nitrogen (BUN) 
Aspartate aminotransferase (AST) 
Serum creatinine (SCr)  
Alanine aminotransferase (ALT) 
Creatine Kinase (CK) 
Alkaline phosphatase (ALP) 
LDL-C (Day 8 only) 
 
9.3.2 LDL-C, Point of Care 
A point-of-care analytical device (CardioChek® PA Analyzer, or equivalent) is used for the 
measurement of LDL-C levels when immediate results are required in order to make study-related 


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decisions.  Table 9-1A and Table 9-1B designated the timepoints where a point-of-care LDL-C is 
measured.  In each occurrence, a skin lancet is used to collect 1-2 drops of blood from the subject’s 
finger.  The instructional manual for the device will be followed for the assessment and LDL-C 
values will be documented, as required, in the source and/or the CRF.     
9.3.3 Drug, Alcohol, and Viral Screening 
During the screening visit, all subjects receive a urine drug screen and a saliva alcohol (ethanol) 
test.  Subjects confirmed or suspected, in the Investigator’s opinion, as abusing alcohol or non-
prescription drugs are not eligible for the study. 
Serology is performed to detect active infections of HIV, HBV, and HCV; positive subjects are not 
eligible to participate in the study treatment.          
9.3.4 Pharmacokinetic Assessments 
Allowable time windows for PK draws are shown below in Table 9-3.  Sampling taken outside of 
the allowable windows still contribute to building the pharmacokinetic profile, but minor 
deviations are captured in the Case Report Form (CRF).    
Blood samples are taken by either direct venipuncture or via an indwelling catheter; however, 
samples must not be taken from the same catheter or any device used for administering the study 
drug.      
Pharmacokinetic blood samples are collected for analyzing atorvastatin and metabolite 
concentrations in plasma.  
 
If blood samples are obtained from an indwelling catheter rather than direct venipuncture, the 
catheter must be kept patent with saline flushes.  A blood sample of approximately 1 mL will be 
drawn and discarded prior to each saved collection.   
 
The samples are frozen in a -20°C freezer within 120 minutes of being drawn. 
The actual sample collection date and time is entered in the eCRFs.  Any issues with the sampling 
process will be noted. 
Table 9–3 
Allowable Time Windows for Pharmacokinetic Draws 
Route being studied Target time of blood draw 
Allowable time window  
Oral  
(screening period) 
Pre-dose 
-60 to -1 minutes before a dose 
of oral atorvastatin is taken 


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Hour 0.5 
+ 5 minutes 
Hours 1, 2, 4, 6, and 8 
+ 10 minutes 
Intravenous or 
Subcutaneous  
(Day 15) 
Prior to the IV or SC dose 
-60 to -1 minutes before the 
dose of IV or SC atorvastatin is 
taken 
Immediately after the IV or SC 
dose 
3 to 7 minutes following the end 
of the administration 
Hour 0.5 
+ 5 minutes 
Hours 1, 2, 4, 6, and 8 
+ 10 minutes 
Subcutaneous  
 (Day 22) 
Hour 0.5 
+ 5 minutes 
Hours 1, 2, 4, 6, 8 
+ 10 minutes 
Hour 24 
+ 60 minutes 
 
9.3.4.1 Pharmacokinetics for Oral Dosing 
Samples will be drawn from all participating subjects at the Lead-in End Visit in order to define 
the steady-state pharmacokinetic profile of the respective, stable dosing regimen on oral 
atorvastatin.   
The subject is directed to refrain from taking their daily oral dose of atorvastatin at home, but then 
to bring the dose to the clinic for the PK visit.  The visit is scheduled such that the dose is taken in 
the clinic at a time of day as close as possible to the time that the subject typically takes their oral 
dose.   
At the oral PK visit, samples are drawn and processed per the procedure detailed above in Section 
9.3.4 at the following times; allowable windows are listed in Table 9-3:  
• 
Within 60 minutes prior to taking the oral dose of atorvastatin.   
• 
At the following times after taking the oral dose:  
o 30 minutes  
o 1 hour  
o 2 hours 
o 4 hours 
o 6 hours 
o 8 hours 
Levels of atorvastatin and metabolites measured from the pre-dose timepoint are imputed as the 
Hour 24 levels since the subject is on daily, constant dosing.   


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9.3.4.2 Pharmacokinetics for Multi-dose Intravenous or Subcutaneous Dosing 
(Treatment Phase) 
Subjects receive their last dose of injectable atorvastatin at their Day 15 visit.  Following the 
sampling and processing procedure detailed in Section 9.3.4, samples are drawn at the following 
times relative to their last injectable dose; allowable windows are listed in Table 9-3:  
• 
Within 60 minutes prior to the start of the dose.     
• 
At the following times after completing the dose:  
o Immediately after completion (IV dose only; subjects taking the SC dose under 
Amendment 03 omit this timepoint.) 
o 30 minutes 
o 1 hour  
o 2 hours 
o 4 hours 
o 6 hours 
o 8 hours 
    
9.3.4.3 Pharmacokinetics for Subcutaneous Dosing (Sub-Study) 
Subjects must first meet the eligibility criteria listed in Section 8.4.4 before participating in the 
subcutaneous PK sub-study.  The Investigator ensures the subject has given and documented their 
consent to participate in the sub-study before performing related procedures.    
As a result of the review of real-time, open-label LDL-C values, the sponsor informs the 
Investigator as to which subject(s) qualify for the sub-study.  This determination is made following 
the subject’s Day 15 visit and the subsequent reporting of the LDL-C level from the visit.  The 
Investigator inquires of the subject’s ability and continued consent to participate in the sub-study 
(Inclusion Criteria).  
Eligible subjects that have consented to the sub-study will have resumed taking daily oral 
atorvastatin at their lead-in dose since Day 16.  They then return to the study center on Day 22 + 
2 days after being instructed by the Investigator to refrain from taking their daily oral dose of 
atorvastatin at home on the day of the visit.       
Subjects receive a subcutaneous dose of atorvastatin injection (Section 8.3.2.2), then samples are 
drawn at the following times after the time of the SC dose; allowable windows are listed in Table 
9-3:  
o 30 minutes 
o 1 hour  


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o 2 hours 
o 4 hours 
o 6 hours 
o 8 hours 
o 24 hours 
 
9.3.5 Pharmacodynamic Assessments 
The main efficacy objectives of the study are assessed through the lipid profile measured at 
Lead-in End Visit, Day 8 and Day 15.  (See Tables 9-1A and 9-1B). 
9.3.6 Dose Assignments 
Subjects are assigned to one of three lead-in cohorts based on their daily dose of oral statin on 
which they entered the study, if applicable, and their screening value for LDL-C.  Lead-in cohorts 
are categorized by the amount of daily, oral atorvastatin the corresponding subject will take (10, 
20, or 40 mg).  Following the completion of the Lead-in Period, subjects are assigned a daily 
intravenous or subcutaneous (Amendment 3) dose on which they remain during their complete 
treatment period, including the sub-study, if they participate.  The dose for each cohort is 
determined by the sponsor and may be adjusted while the study is ongoing based on the continual 
monitoring and evaluation of safety and efficacy parameters.   
9.3.6.1 Lead-in Period Dosing 
Subjects that pass screening and enter the Lead-in Period are assigned an oral dose by the sponsor.  
Subjects enter one of the three possible Lead-in cohorts:  10, 20, and 40 mg.  The sponsor will 
communicate the dosing assignment for each individual subject to the Investigator in writing.   
9.3.6.2 Intravenous Dosing 
The goal of the intravenous dosing and any associated dose adjustments is to fill all three cohorts 
and meet the primary study endpoint for each while utilizing the lowest possible daily dose of 
intravenous atorvastatin injection.   
 
Primary study endpoint (See Section 7):  Eleven or more subjects in a dosing cohort of thirteen 
with a Day 15 LDL-C not more than 125% of their baseline LDL-C. 


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9.3.6.2.1 Initial Cohort (10 mg PO Atorvastatin) 
Subjects belonging to the 10-mg per os (PO) baseline cohort group (those that were taking 10 mg 
oral atorvastatin per day during Lead-in) are the first to be enrolled on the study.  As shown below 
in Table 9-4, the initial subject in the 10 mg cohort is assigned to 2 mg IV atorvastatin injection as 
their daily dose.  Subsequent subjects from the 10 mg PO Lead-in group are enrolled and treated 
with 2 mg IV daily while LDL-C values from their Day 8 and Day 15 study visits are reported and 
compared to baseline values in real time.    
Table 9–4 
Intravenous Dosing by Lead-in Cohort 
Lead-in Daily Dose of 
Oral Atorvastatin 
Initial Targeted, Daily 
Intravenous Dose  
Maximum Daily Intravenous 
Dose, after escalations 
10 mg 
2 mg 
5 mg 
20 mg 
4 mg 
10 mg 
40 mg 
8 mg* 
20 mg 
*Targeted starting doses for the cohort are shown; however actual starting doses may be adjusted pending findings from earlier cohorts.   
 
LDL-C values are monitored by the sponsor in real time and, if consistent and significant trends 
are seen to suggest that a cohort is not receiving an adequate dose, a dose adjustment for the cohort 
is warranted.  Ongoing subjects in the treatment period of the affected cohort at the time of the 
decision to adjust the dose are contacted by the Investigator and directed to immediately 
discontinue the intravenous dosing and withdraw from the treatment period.  The subjects are then 
not eligible for the sub-study.   
9.3.6.2.2 Dose Adjustments 
Following are two criteria that may initiate a dose adjustment: 
• 
Three or more subjects have a Day 8 and/or a Day 15 LDL-C > 125% of their baseline 
LDL-C.  The dose is then increased for subsequent subjects.   
• 
Three or more subjects have a Day 8 and/or Day 15 LDL-C < 75% of their baseline 
LDL-C AND the mean of the lowest available post-treatment values is < 85% of the 
mean of the baselines 
In all scenarios, additional enrollment into the cohort is immediately stopped if the dose for the 
cohort is adjusted following an open-label review by the sponsor’s clinical and medical teams.  
Enrollment into that cohort is then re-started at a new dose with the intention to enroll thirteen 
subjects.  Doses will be adjusted by an amount not to exceed 25% of the preceding dose for that 
cohort.   


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The final dose will not exceed the maximum for that group as listed in Table 9-4.  The maximum 
intravenous or subcutaneous dose to be administered to any cohort level will not exceed 50% of 
the oral dose for that same cohort.  Prior to increasing a dose, the sponsor’s medical monitor 
reviews a listing of serum biochemical values from all subjects in the current cohort and determines 
if there are any concerns of safety issues.  Subsequent investigational treatment can proceed at the 
increased dose once any safety concerns have been eliminated.    
In the opposite scenario, where three or more subjects report an LDL-C < 75% of their baseline 
LDL-C and the mean of the lowest available post-treatment values is < 85% of the mean of the 
baselines, the dose will be decreased following review of all treated subjects from that baseline 
group. 
If subsequent dose adjustments are needed, the guidelines above continue to be followed.         
Once a full cohort of 13 subjects have been enrolled and treated and the primary study objective 
has been met, the current dose is considered the established dose for that cohort and the next cohort 
initiates enrollment.     
9.3.6.2.3 Subsequent Cohorts (20and 40 mg PO Atorvastatin) 
Once two or more subjects from the 10 mg Lead-in group complete the study, the other cohorts 
can be opened to enrollment.   
LDL-C results from completed subjects in the 10 mg PO atorvastatin cohort provide information 
on the dose-response efficacy for the injectable route for atorvastatin that is helpful toward dosing 
the other Lead-in groups.   
The targeted initial dose for each of the subsequent Lead-in cohorts is listed in Table 9-4.  However, 
any adjustments that were ultimately required for the dosing of the 10 mg PO cohort suggest that 
a similar adjustment is needed from the targeted doses for the other cohorts.  Therefore, the starting 
dose for each subsequent cohort is adjusted accordingly by the sponsor prior to dosing the first 
enrolled subject of that treatment cohort.   
With the activation of Protocol Amendment 3, dated 04Sep2019, one additional cohort is to be 
enrolled:  Ten subjects that qualify for treatment following a lead-in period taking 20 mg oral 
atorvastatin are assigned to a daily dose of subcutaneous atorvastatin for the 15-day treatment 
phase.   
 


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9.3.6.3 Subcutaneous Dosing (Sub-Study) 
Those subjects that are participating in the sub-study resume their Lead-in daily oral dose of 
atorvastatin beginning on Day 16.   Their oral dose is withheld on the day of their Day 22 Visit 
while they return to the clinic for a subcutaneous injection given as close as possible to the time 
of day at which they take their oral dose.  The dose amount administered is the same as that which 
was taken intravenously during the treatment period.   
Subjects that are not participating in the sub-study resume their standard of care treatment, if any, 
for hypercholesterolemia while they await their Day 22 follow-up call.   
9.4 Measurements and Evaluations   
9.4.1 Description of Screening Visit 
Before the initiation of study-specific screening assessments, the subject or legal authorized 
representative must be given a complete explanation of the purpose and conduct of the study.  
Subsequently, the subject or legal authorized representative must sign and receive a copy of an 
Informed Consent Form that was approved by the center’s governing Institutional Review Board 
(IRB).   
During this consenting process, the Investigator or designee has a preliminary discussion with the 
subject about participation in the sub-study.  The subject’s initial consent or refusal to participate 
in the sub-study is documented; however, this decision by the subject can be re-evaluated and 
changed prior to the end of the study treatment period.           
Subjects that enter the study taking oral statins remain on their prescribed dose during the screening 
process.     
After consent is obtained, the inclusion criteria in Section 8.4.1 are confirmed, including the 
measurement of LDL-C by the point-of-care test (CardioChek® PA Analyzer, or equivalent).  In 
the event that the point-of-care analyzer gives an error message rather than a numerical result at 
the Screening Visit, a blood sample may be submitted to the site’s local laboratory for the eligibility 
determination.  Subjects that do not meet the eligibility requirement are deemed screen failures; 
others continue to complete the full screening visit to determine the subject’s eligibility to enter 
the Lead-In Period and to document their baseline disease state.  Allowable time windows are 
described in Table 9-1A and Table 9-1B: 
• Collection of demographic data, including age, gender, race and ethnicity 


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• Review and documentation of medical history.  Resolved diseases or past procedures that 
are not significant to the disease under study should be captured only if they occurred or 
were present in the previous five years. Other history (diagnoses, major signs or symptoms) 
should be recorded in the CRF regardless of time reference.   
• A serum and/or urine pregnancy test is performed on all women. 
• A serum FSH and estradiol test may be performed by Investigator on subjects to confirm 
postmenopausal status. 
• Serology for HIV, HBV, and HCV.  
• Urine Drug Screen and Saliva Alcohol Test 
• A baseline physical examination is performed on all significant body systems.    
• Blood samples are analyzed for hematology and serum biochemical levels, including a 
lipid profile.  Labs are drawn and processed according to standard local processes and 
analyzed at the Investigator’s local clinical laboratory. Analytes to be measured are listed 
in Table 9-2a. 
• Vital signs are measured to include heart rate, respiration rate, body temperature, and seated 
blood pressure. 
9.4.2 Description of Lead-in Period 
Subjects that meet all screening requirements enter the Lead-in Period.  The Investigator notifies 
the sponsor that a subject is eligible for Lead-in and the sponsor assigns a dose of oral atorvastatin:  
a. Subjects already on oral atorvastatin stay on their current dose.   
b. Subjects not on oral atorvastatin are prescribed and dispensed oral atorvastatin at the 
assigned dose.     
During the Lead-in Period, oral atorvastatin is to be taken in the morning.  Subjects are also 
instructed to bring their medication vials to their study visits so that drug compliance can be 
calculated.  Finally, subjects are instructed to refrain from taking a dose at home on the morning 
of their Lead-in End Visit.     
The remainder of the Lead-in Period transpires according to one of two schedules depending on 
the pre-study medication history of the individual subject:   


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a. Subjects that were already taking oral atorvastatin prior to their study involvement (See 
Table 9-1A):   
• There is no Lead-in Interim Visit.  
• The Lead-in End Visit occurs 7 to 10 days after the Screening Visit. 
• A point-of-care LDL-C value is obtained and compared to the value from the screening 
visit as per Inclusion Criterion 1a in Section 8.4.3.1.  If the comparison between values 
meets eligibility, the Lead-In End Visit continues including the oral pharmacokinetic 
assessments per Section 9.3.4.1.     
• In the event that the point-of-care analyzer gives and error message rather than a 
numerical result at the Lead-in End Visit, a blood sample may be submitted to the site’s 
local laboratory and be compared to the Screening LDL-C value, also measured by the 
local lab.  Values taken by one method may not be compared to values taken by the 
other method.   
• Other assessments are completed as per Table 9-1A.    
b. Subjects that were not taking oral atorvastatin prior to their study involvement (See Table 
9-1B):   
• Subjects are dispensed oral atorvastatin at the dose assigned by the sponsor and 
instructed to initiate their daily dosing on Lead-in Day 0, as defined by the Investigator.   
• Twenty-eight (+/- two) days following the first dose of oral atorvastatin (defined as 
Lead-in Day 0), the subject returns to the clinic for a Lead-in Interim Visit that includes 
a point-of-care LDL-C measurement and a review of drug compliance.  Any 
compliance other than 100% prompts re-training of the subject.  The subject is 
reminded to refrain from taking their oral atorvastatin at home on the day of the Lead-
in End Visit.    
• The Lead-in End Visit occurs 7 to 10 days after the Lead-in Interim Visit: 
• A point-of-care LDL-C value is obtained and compared to the value from the Lead-in 
Interim Visit as per Inclusion Criterion 1b in Section 8.4.3.1.  If the comparison 
between values meets eligibility, the Lead-In End Visit continues including the oral 
pharmacokinetic assessments per Section 9.3.4.1.  


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• In the event that the point-of-care analyzer gives an error message rather than a 
numerical result at the Lead-in Interim Visit, a blood sample may be submitted to the 
site’s local laboratory and be available for comparison to a LDL-C value measured by 
the local lab at the Lead-in End Visit.  Values taken by one method may not be 
compared to values taken by the other method.   
• Other assessments are completed as per Table 9-1B.     
9.4.3 Eligibility Confirmation and Treatment Assignment 
The Investigator reviews all eligibility criteria that are assessed in the subject’s history and 
screening period, then confirms whether the subject will enter study treatment.  All subjects are 
assigned to open-label atorvastatin injection; however, the Investigator must obtain from the 
Sponsor the daily amount of IMP to be administered to each individual subject.  This daily dose 
will be provided by the sponsor in writing based on 1) the oral dose of atorvastatin taken during 
the Lead-in Period, and 2) the most recent dosing assignment given by the protocol or medical 
review committee (See Section 9.3.6).  
The Day 1 Visit occurs within two days following the Lead-in End Visit and the subject is 
instructed to continue their daily oral atorvastatin but to refrain from taking it on Treatment Day 
1.   
9.4.4 Description of Treatment Period 
The subject presents to the clinic for daily outpatient visits during the 15-day treatment period. 
The subject is monitored in the clinic for a minimum of approximately 15 minutes after any 
injection to ensure there are no issues with bleeding or other adverse reactions.   
Spontaneously-reported adverse events are recorded in addition to any changes in concomitant 
treatments.     
9.4.4.1 Day 1 
Vitals are taken between 30 and 0 minutes before the start of the first IMP injection.  
The Investigator’s standard technique and equipment are used to prepare the injection site and 
delivering the injection.  If any IV tubing is utilized, normal saline is used to flush the line 
immediately following the injection of IMP.   
Vital sign measurements are repeated at 15 (+ 5) minutes after the time of the IMP administration.   


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9.4.4.2 Days 2, and 4 through Day 7 
The subject returns to the clinic each day at the approximate same time of day for an outpatient 
visit.  The subject receives an injection of atorvastatin at the same amount and by the same route 
and method as at the Day 1 visit.   
9.4.4.3 Day 3 
Blood is drawn prior to the daily injection of study drug and submitted to the site’s local laboratory 
to measure the analytes listed in Table 9-2b.  Levels of liver and muscle enzymes are reviewed 
against baseline values to assess safety.    
9.4.4.4 Day 8 
Prior to administration of the daily injection of atorvastatin, a blood sample is collected, processed 
and analyzed at the Investigator’s local laboratory to provide an LDL-C level.  Additionally, the 
analytes listed in Table 9-2b are measured.  Levels of liver and muscle enzymes are reviewed 
against baseline values to assess safety.   
LDL-C levels are transmitted to the sponsor as soon as available.   
9.4.4.5 Days 9 through 14  
The subject returns to the clinic each day at the approximate same time of day for an outpatient 
visit.  The subject receives an injection of atorvastatin at the same amount and by the same method 
as at the Day 1 visit       
9.4.4.6 Day 15 
Unless withdrawn early from the treatment period (See Section 9.4.4.7), the subject presents to the 
clinic on Study Day 15 for their final injection with atorvastatin.   
Prior to administration, blood samples are drawn for analysis of hematology and serum 
biochemical levels, including a lipid profile.  Labs are drawn and processed according to standard 
local processes and analyzed at the Investigator’s local clinical laboratory.  Analytes to be 
measured are listed in Table 9-2a.  The Investigator reviews reported values in comparison to those 
reported at the screening and treatment visits and any changes that are deemed undesirable and 
clinically significant are reported as adverse events.  Subjects with clinically-significant changes 
in lab values are monitored at unscheduled visits until values return to normal or until a cause other 
than the study drug is determined.   
LDL-C and HDL-C levels are transmitted to the sponsor as soon as available.   


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Samples for Pharmacokinetic profiling of intravenous atorvastatin are taken per Section 9.3.4.2. 
A urine pregnancy test is administered for all women of child-bearing potential.    
Subjects that entered the study taking oral atorvastatin are directed to resume taking their oral 
atorvastatin on the day following the Day 15 (or withdrawal) visit at the same dose level as that 
taken during the Lead-in Period. 
Subjects that did not enter the study taking oral atorvastatin but continue to participate in the Sub-
study are dispensed oral atorvastatin at the same dose as that taken during the Lead-in Period.  
Patients that are in the Sub-study are directed to refrain from taking their oral dose at home on the 
day of their Day 22 Visit.    
9.4.4.7 Withdrawal  
Subjects may be withdrawn from the treatment on any day during the 15-day period by subject, 
Investigator or sponsor decision.  Withdrawn subjects are not eligible to participate in the sub-
study that would immediately follow their treatment period.    
If the sponsor determines that a cohort will not meet the primary endpoint (eleven or more subjects 
in a dosing cohort of thirteen with a Day 15 LDL-C not more than 125% of their baseline LDL-
C), any subjects currently being treated in that cohort are to be withdrawn.  In such a case, there is 
no benefit to the subject or the study data for the subject to continue taking an investigational drug 
at a non-efficacious dose.  The Investigator is notified by the sponsor in writing that the cohort is 
closed.    
For patients that were taking oral atorvastatin prior to the study, the investigator contacts the 
subject and instructs them to resume taking their normal dose of oral atorvastatin on the day 
following their last injected dose.  Other subjects return to their standard of care treatment.  The 
subject returns to the clinic as previously planned according to the daily visit schedule but does 
not receive an injection of study drug or undergo pharmacokinetic sampling.  Labs are drawn and 
processed according to standard local processes and analyzed at the Investigator’s local clinical 
laboratory.  Analytes to be measured are listed in Table 9-2a.  Also, a urine pregnancy test is 
administered for all women of child-bearing potential.  Following the visit, the subject enters the 
follow-up period and receives a phone call 6-8 days later.    
9.4.5 SUB-STUDY to Evaluate Subcutaneous Pharmacokinetics 
Please note that the Sub-study is no longer active or available under Protocol Amendment 
3.   


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Participation in the sub-study is initially discussed between the Investigator and subject during the 
original consenting process for the main study.  The subject’s decision regarding participation is 
discussed again at the end of the 15-day treatment period.  Any change to their consent is 
documented by both the subject and the Investigator or designee.  
Final approval for an individual subject to participate in the sub-study is made by the sponsor 
following review of their Day 15 LDL-C levels.  The Investigator is immediately made aware of 
this decision and informs the subject to confirm their participation and schedule of events.     
Subjects participating in the sub-study proceed according to the process described in Section 
9.3.4.3.  Subjects that decline participation or are not eligible per sponsor decision continue to be 
monitored until their Follow-up call.      
9.4.6 Follow-up Call 
The Investigator or designee contacts all subjects 7 days (+ 2 days) after their last exposure to 
study drug.  For subjects participating in the sub-study, this occurs at approximately Study Day 
29.  Subjects that do not participate in the sub-study receive follow-up contact at approximately 
Study Day 22.  
A phone call is the desired method of communication; however, alternate methods can be utilized 
by the Investigator if deemed appropriate and effective. 
During the contact, the subject is asked about any changes in their medical condition or 
concomitant medications and responses are recorded and/or monitored further as appropriate.   
9.4.7 Rescreening 
Individual subjects may be rescreened one time each if the Investigator obtains sponsor approval.  
This applies to subjects that previously screen fail, lead-in fail and those that initiate investigational 
treatment.  In such cases, the subject will begin with a new screening visit.        
10 SUBJECT DISCONTINUATION  
10.1 Subject Discontinuation 
Subjects will be encouraged to complete the study; however, they may voluntarily discontinue at 
any time and for any reason.  Also, the sponsor directs the Investigator to withdraw subjects if they 
belong to a treatment cohort that will not meet the primary endpoint (See Section 9.4.4.7).  The 
Investigator will describe in the CRF the reason for discontinuation.   


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A subject may be removed from the study for the following additional reasons; in each case, the 
decision to discontinue should be confirmed following consultation between the Investigator and 
Sponsor: 
• Adverse event (AE): If a subject experiences an AE for which continued study participation 
presents an unacceptable consequence or risk to the subject, the subject may be 
discontinued.  
• Subject non-compliance: A subject’s past, current, or anticipated inability to comply with 
study visits, clinical trial medication or other processes required by the protocol may lead 
to the decision to discontinue the subject from the study.  
• Enrollment violation: If it is realized after the initiation of investigational treatment that a 
subject did not meet all eligibility requirements, the Sponsor and Investigator will discuss 
whether it is safe, ethical, and scientifically sound to keep the subject in the study or to 
discontinue the subject.   
• Concurrent Treatment: If a subject initiates a procedure or medication that may interfere 
with their study conduct or for which study involvement may pose a significant risk to the 
prescribed therapy, the subject may be discontinued.  
• Other reasons: Following discussion between the Sponsor and Investigator, subjects may 
be discontinued from the study for reasons other than those listed above. 
10.2 Procedures for Subject Discontinuation 
If a subject is discontinued or withdrawn for any reason prior to completion of the full treatment 
period, a withdrawal visit plus follow-up, as described above should be performed.   Following the 
visit, reasonable efforts should be made to monitor the subject for AEs, as appropriate.  
Subjects that do not complete the full treatment period do not undergo the Day 15 PK assessments.  
They are also not eligible to participate in the sub-study.    
Subjects that are discontinued may be replaced, as needed. The decision will be made on a case-
by-case basis by the study sponsor.   
10.3 Study or Site Termination 
If conditions arise during the study that indicate that the study should be halted or that the study 
center should be terminated, this action may be taken after appropriate consultation among the 
Sponsor, Investigator, Medical Monitor, and Study Monitor.   


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Conditions that may warrant termination of the study include, but are not limited to, the following: 
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study 
• A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product 
A study conducted at a single study site or a single study site in a multicenter study may also 
warrant termination under the following conditions: 
• Failure of the Investigator to enroll subjects into the study at an acceptable rate 
• Failure of the Investigator to comply with pertinent regulations of appropriate regulatory 
authorities 
• Submission of knowingly false information from the research facility to the Sponsor, Study 
Monitor, or appropriate regulatory authority 
• Insufficient adherence to protocol requirements 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
the International Conference on Harmonization (ICH) sixth efficacy publication (E6) on Good 
Clinical Practice, Section 4.12, ICH E6 4.13, ICH E6 5.20, and ICH E6 5.21. 
11 ADVERSE EVENTS 
Information about AEs, whether spontaneously reported by the subject, discovered by the 
Investigator by questioning/review of records or detected through physical examination, 
laboratory test or other means, will be collected and recorded on the adverse event form and 
followed-up as appropriate. Information about serious adverse events should be reported to the 
Sponsor within 24 hours of obtaining knowledge of the event.  
11.1 Definitions 
11.1.1 Adverse Event Definitions 
Adverse events are defined according to ICH Harmonized Tripartite Guideline E2A. 
Adverse event (AE) 


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Any untoward medical occurrence in a patient or clinical trial subject administered a trial product 
whether it has a causal relationship with the study treatment or not.  
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
None of the following are considered an AE: 
• Pre-planned procedure (documented as concomitant illness on the CRF at screening) unless 
the condition for which the procedure was planned has worsened from the first trial related 
activity after the subject has signed the informed consent form. 
• Pre-existing conditions found as a result of screening procedures. 
Serious adverse event (SAE) 
An AE that meets any of the following criteria:  
• results in death  
• is immediately life-threatening (this refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it was more severe)  
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability or incapacity 
• is a congenital anomaly or birth defect 
• is judged medically important in the opinion of the Investigator (this refers to an event that 
may not be immediately life-threatening or result in death or hospitalization, but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed). 
Non-serious adverse event 
Any adverse event that does not meet the definition of an SAE. 
Unexpected adverse event 


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An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed.  
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug but are not specifically mentioned as 
occurring with the particular drug under investigation. 
11.1.2 Adverse Event Assessment Definitions 
Anticipated 
Anticipated events include known consequences of an underlying disease or the condition under 
investigation, events anticipated from any background regimen, events common in the study 
population, or re-emergence or worsening of a condition relative to pretreatment baseline. 
Severity 
The maximum severity of an adverse event is assessed by the investigator using the following 
guidelines:  
Mild: Transient symptoms, no interference with the subject’s daily activities. 
Moderate: Marked symptoms, moderate interference with the subject’s daily activities. 
Severe: Considerable interference with the subject’s daily activities. 
Relationship/Relatedness 
The causal relationship between an adverse event and the trial product is assessed by the 
investigator using the following definitions: 
Related:  No reasonable support to believe that the event was caused by something other than 
the study drug.  
Probably Related:  There is good reason to assume a causal relationship. 
Unlikely Related:  A causal relationship is doubtful but cannot be fully dismissed.   
Not related:  The Investigator cannot suggest any reasonable relationship between the event 
and the study drug.   
Outcome 
The outcome of an adverse event is assessed by the investigator using the following definitions: 


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Recovered: Fully recovered, or by medical or surgical treatment the condition has returned to 
the level observed at the subject’s study baseline.   
Recovering: The condition is improving and the subject is expected to recover from the event. 
This term should only be used when the subject has completed the trial. 
Ongoing:  The subject’s condition has not improved and the symptoms are unchanged. 
Fatal:  The event resulted in death.  
Unknown: The subject’s condition is unknown. This term should only be used when no other 
definition is possible e.g., the subject is lost to follow-up. 
11.2 
Collection, Recording and Reporting of Adverse Events 
All events meeting the definition of an adverse event must be collected and reported from the first 
trial-related activity after the subject signs the informed consent and until last subject 
contact/visit/end of post-treatment follow-up period.  
At each contact with the trial center, the subject must be asked about adverse events in an objective 
manner like: “Have you experienced any problems since the last contact?” 
Adverse events according to the definition, either observed by the investigator or reported by the 
subject, must be recorded by the investigator and evaluated.  Adverse events must be recorded in 
the case report forms. For serious adverse events, the SAE form must also be filled in. 
The investigator should record the diagnosis, if available. If no diagnosis is available, the 
investigator should record each sign and symptom as individual adverse events.  
Serious Adverse Events 
The investigator must report initial information on all serious adverse events within 24 hours of 
obtaining knowledge of the event.  
Furthermore, the investigator must complete and transmit, as applicable, the adverse event and 
SAE forms within five days of obtaining knowledge of the SAE. The monitor must be informed 
accordingly. 
The Investigator will inform the health authorities and IRBs in accordance with local requirements 
in force and the International Conference on Harmonization (ICH) guidelines for GCP and the 
European Union (EU) Directive 2001/20/EC / Food and Drug Administration (FDA) Title 21 Code 
of Federal Regulations, Part 312.32 (5). 


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Adverse Events Starting after Trial Completion 
Adverse events occurring after trial completion, which the investigator considers to be related to 
the investigational medicinal product must be reported to the sponsor.     
11.3 
Follow-up of Adverse Events 
Follow-up of Non-Serious Adverse Events 
All adverse events classified as non-serious adverse events that are both severe and related or 
probably related to the investigational medicinal product should be followed until the event has 
recovered or, in cases where recovery is not expected, until the event is stabilized and well defined 
and understood by the investigator.     
Follow-up of Serious Adverse Events 
All serious adverse events should be followed until resolved, or until stabilized and understood or 
a non-IMP reason is determined to be the most probable cause.   
12 STATISTICAL METHODS AND DATA ANALYSIS 
12.1 
Sample Size Determination 
The clinical goal of replacing stable oral dosing of atorvastatin with temporary intravenous or 
subcutaneous dosing is to maintain constant LDL-C levels during and following the replacement 
therapy window.   Therefore, the target mean change in LDL-C is zero.  Utilizing the standard 
biological variabilities of LDL-C and an associated, estimated standard deviation of 0.15, a sample 
size of 13 would provide 80% power to show that the mean change in LDL-C after switching to 
intravenous or subcutaneous dosing is less than 10% of baseline levels if the true mean change for 
the group is zero.  A mean change in LDL-C of up to 10% is not considered to be clinically 
significant over a short, two-week period.      
12.2 
Subject Population(s) for Analysis 
The safety population consists of all subjects who were enrolled and received at least a partial dose 
of IMP; no treated subjects will be excluded from the safety analysis population.  
For the efficacy analyses, subjects will be stratified by their lead-in dose of oral atorvastatin.  
Defined by each of the three lead-in cohorts (10, 20, and 40 mg oral atorvastatin), the completed 
groups of thirteen subjects that 1) finish the two-week treatment period with intravenous 
atorvastatin, 2) provide a Day 15 LDL-C level, and 3) took the final targeted dose for that cohort 
comprise the three intravenous efficacy populations.  


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With the activation of Protocol Amendment 3, dated 04Sep2019, one additional efficacy 
population is defined.  Ten subjects that qualify for treatment following a lead-in period taking 20 
mg oral atorvastatin are assigned to a daily dose of subcutaneous atorvastatin for the 15-day 
treatment phase.  Efficacy and pharmacokinetic outputs are calculated individually for this 
population.         
12.3 Statistical Methods 
To assess efficacy endpoints related to changes in cholesterol, the expected biological variabilities 
of LDL-C (9%) and HDL-C (7%) in a standard population (Marcovina 1994) were factored into 
the statistical calculations.  Additional data are available in the literature to understand the rate of 
cholesterol changes when statin dosing is inadequate.  A population that discontinued their stable 
dosing of statins showed significant elevations of LDL-C after 5 days (Fadini 2015).  A dosing 
duration of 15 days was chosen to allow adequate time to detect changes in LDL-C resulting from 
inadequate intravenous dosing.  
In the evaluation of all pharmacokinetics except for the single-dose subcutaneous PK of the sub-
study, levels of atorvastatin and metabolites measured from the pre-dose timepoint are imputed as 
the Hour 24 levels since the subject will have been on at least a two-week period of daily, constant 
dosing, and the pre-dose value will essentially be the Hour 24 level from the previously 
administered dose.  This imputation will relieve subjects from making an extra clinic visit.  
12.3.1  General Considerations 
Data collected in this study will be presented using summary tables and subject data listings. 
Continuous variables will be summarized using descriptive statistics, specifically n (number of 
subjects), mean, median, standard deviation (SD), minimum and maximum. Categorical variables 
will be summarized by frequencies and percentages. 
Statistical calculations will be done using SAS software (Version 9.3 or higher, SAS Institute, 
Cary, North Carolina, USA). 
Baseline is considered the last assessment prior to the date and time of first dose of study drug. 
Change from Baseline is defined as:  post baseline assessment value – baseline assessment value. 
12.3.2 Efficacy Analyses 
Efficacy will be determined by evaluating the final cohorts for each dosing level and the ability 
to meet the targets of the following:  


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• 11 of 13 subjects with a Day 15 LDL-C not more than 125% of their baseline LDL-C 
• 11 of 13 subjects with a Day 15 HDL-C not less than 75% of their baseline HDL-C 
• The mean change at Day 15 in LDL-C for each treatment cohort 
The dose required to meet the targets for each cohort will be listed by subjects and summarized. 
A dosing cohort will be considered successful if eleven or more subjects have a Day 15 HDL-C 
not less than 75% of their baseline HDL-C and if eleven or more subjects have a Day 15 LDL-C 
not more than 125% of their baseline LDL-C.  
12.3.3 
Pharmacokinetics 
Plasma concentrations will be listed at each time point by subject, and summarized by treatment 
at each time point using descriptive statistics (n, mean, standard deviation, coefficient of variation, 
median, minimum and maximum values).  PK calculations will be performed based on actual time 
of blood sample collection, using non-compartmental methods with WinNonlin Version 6.3.1 or 
higher (Certara Corporation, Princeton, New Jersey, USA). PK parameters will be listed by subject 
and summarized by cohort. In addition to the descriptive statistics listed above, geometric means 
will be reported for the PK parameters. 
All plasma concentrations below the lower limit of quantitation (BLOQ) for the assay that occur 
prior to the first or after the last quantifiable timepoint will be treated as “0” in the PK analyses 
and summary statistics.  Plasma concentrations that are BLOQ but occur between quantifiable 
timepoints will be set to missing. 
The PK endpoints will be listed and summarized for each dosing route and cohort. The arithmetic 
means, geometric means, medians, minimums and maximums, CV% will be displayed.  
Plots of mean concentration levels and individual subject concentrations versus time will also be 
prepared. 
12.3.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all subjects using descriptive 
statistics. The current medical condition and/or other significant medical history will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA) Version 18.1, or higher. Conditions 
will be listed, including reported term, System Organ Class (SOC) and Preferred Term (PT). 


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12.3.5 
Prior/Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Enhanced Dictionary (September 2014 or later). Prior medications will be those that start 
and end prior to first dose of study drug. Concomitant medications will be those that have a known 
end date after the first dose of study drug or have a missing end date. Medications will be listed 
by subject including Anatomical Therapeutic Class (ATC) classification, preferred term and 
reported term; the start and end dates (or ongoing status). Medications taken by subjects from 15 
days prior to Screening until the end of treatment will be included in the listing. 
12.3.6 
Safety Analyses 
The safety and tolerability of Atorvastatin IV and SC will be assessed by the evaluation of 
treatment-emergent adverse events (TEAEs), study discontinuation information, laboratory test 
results, vital signs and physical examination findings.  
Safety variables will be tabulated and presented for all subjects in the Safety Population. Data will 
be summarized by route and cohort. Adverse events will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) for preferred term and system organ class, and will be listed 
by subject. Treatment-emergent AEs (TEAEs) will be summarized by treatment, where treatment-
emergent is defined as any event with a start date on or after the date and time of the first dose date 
and time of study drug. All TEAEs will be summarized by relationship to study drug and by 
intensity. 
Deaths, SAEs, and AEs resulting in study discontinuation will be listed. 
12.4 
Interim Analysis 
No interim analyses are planned. 
13 STUDY MANAGEMENT AND DATA COLLECTION 
13.1 Confidentiality 
All information regarding the nature of the proposed investigation provided by the Sponsor or 
Study Monitor to the Investigator (with the exception of information required by law or regulations 
to be disclosed to the IRB, the subject, or the appropriate regulatory authority) must be kept in 
confidence by the Investigator. 
The anonymity of participating subjects must be maintained. Subjects will be identified by an 
assigned subject number on CRFs and other study documents submitted to the Study Monitor. 
Documents that will not be submitted to the Study Monitor and that identify the subject (e.g., the 


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signed informed consent document) must be maintained in strict confidence by the Investigator, 
except to the extent necessary to allow auditing by the appropriate regulatory authority, the Study 
Monitor, or Sponsor representatives. 
13.2 Source Documents 
Source data are contained in source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. The Monitor, representatives of the 
Sponsor and the applicable regulatory authority will be allowed access to source documentation. 
13.3 Case Report Forms 
CRF forms will be available for data entry by the site through Medrio, a web-based, electronic 
data entry and reporting platform. Cases will be monitored remotely and on-site by the sponsor 
according to a written Monitoring Plan and data will be retrieved by the monitor for data analysis 
by the sponsor.       
13.4 Records Retention 
According to 21CFR312.62, all CRFs, as well as supporting documentation and administrative 
records, must be retained by the Investigator for a minimum of two years following notification 
that the appropriate regulatory authority has approved the product for the indication under study, 
notification that the entire clinical investigation will not be used in support of a marketing 
application, or notification that the marketing application was not approved. No study documents 
will be destroyed or moved to a new location without prior written approval from the Sponsor. If 
the Investigator relocates, retires, or withdraws from the clinical study for any reason, all records 
required to be maintained for the study should be transferred to an agreed upon designee, such as 
the Study Monitor, another Investigator, or the institution where the study was conducted. 
14 STUDY MONITORING, AUDITING, AND INSPECTING 
14.1 Study Monitoring Plan 
The investigator will permit study-related monitoring, audits and inspections by the IRB, the 
Sponsor and any applicable regulatory authority.  


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The sponsor will adhere to a written Monitoring Plan in fulfilling the requirements of ICH/GCP 
guidelines and the CFR to monitor the execution of the study and the collection of data.  In general, 
the progress of the study will be monitored by using the following methods: 
• Periodic onsite visit(s) by the sponsor representative 
• Telephone communications among the Investigator, Clinical Monitor and/or Medical 
Monitor, as needed 
• Remote and on-site review by the sponsor representative of CRFs, clinical records and 
regulatory documents 
15 ETHICAL CONSIDERATIONS 
This study will be conducted according to the standards of ICH, GCP Guidelines, IRB regulations, 
any applicable government regulations and procedures. This protocol and any amendments will be 
submitted to a properly constituted IRB for approval of the study conduct. 
15.1 Informed Consent 
Written informed consent must be obtained from each subject (or the subject’s legal 
guardian/representative) before performing any Screening/Baseline Period evaluations. The 
signed informed consent document will be retained by the Investigator, and a signed copy will be 
given to the subject or subject’s legal guardian/representative. The informed consent document, 
which is prepared by the sponsor, must have been reviewed and approved by the Sponsor and the 
Investigator’s IRB before the initiation of the study. The document must contain the 20 elements 
of informed consent described in 21CFR50.25 and ICH E6 4.8. In addition, subjects of appropriate 
intellectual maturity should provide written informed assent, as determined by the institution’s 
IRB or local legal requirement. 
15.2 Protocol Compliance 
Investigators must follow the IRB-approved protocol. If the Investigator intends to deviate from 
the protocol, the IRB and Sponsor should be informed prior to the deviation.  
In cases where the Investigator decides to deviate from the protocol in order to avoid an apparent 
immediate risk to a specific subject, the Investigator may proceed with emergency and appropriate 
treatment at his discretion and the IRB and Sponsor will be notified as soon as possible afterward. 
In addition, the Investigator will document in the subject’s CRF the reasons for the protocol 
deviation and the ensuing events. 


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Substantive changes in the protocol include changes that affect the safety of subjects or changes 
that alter the scope of the investigation, the scientific quality of the study, the experimental design, 
dosages, assessment variable(s), the number of subjects treated, or the subject selection criteria. 
Such changes must be prepared as a protocol amendment by the Sponsor. A protocol amendment 
must receive IRB approval before implementation.   
In parallel with the IRB approval process, the protocol amendment will be submitted to the 
appropriate regulatory authority as an amendment to the regulatory submission under which the 
study is being conducted. If a protocol amendment requires changes in the informed consent 
document, the revised informed consent document prepared by the Investigator must be approved 
by the Sponsor, Study Monitor, and the IRB prior to its use in consenting potential subjects. 
15.3 Financial Disclosure 
Each clinical site investigator will provide the Sponsor with sufficient, accurate financial 
information in accordance with local and federal regulations to allow the sponsor to submit 
complete and accurate financial certification or disclosure statements to the appropriate regulatory 
health authorities. Investigators are responsible for providing information on financial interest 
during the study and for one year after completion of the study in accordance with FDA policy 
(Title 21 CFR – PART 54 FINANCIAL DISCLOSURE BY CLINICAL INVESTIGATORS 
Revised as of April 1, 2015). 
15.4 Study Files 
Documentation verifying the Investigator’s legal and regulatory authority and acceptable scientific 
background to conduct the trial will be available at both the site and the sponsor before shipments 
of IMP are sent to the investigative center.   
Following study initiation, the Investigator will maintain adequate records to re-create and justify 
the complete conduct of the trial at a later date. Document inventory will adhere to ICH/GCP and 
CFR requirements and will include those pertaining to the Investigator’s qualifications, inventory 
and handling details of investigational products, and detailed medical and study histories for all 
subjects.    
16 REFERENCES 
Daskalopoulou, SS, et. al. Discontinuation of statin therapy following an acute myocardial 
infarction: a population-based study.  Eur Heart J. 2008; 29:2083-91.  
 
Endres M, Laufs U. The medical case for the development of an intravenous statin formulation--
beyond ischemic stroke. Cerebrovasc Dis. 2008; 25(6): 593-4. 


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Fadini GP, et. al.  Short-term statin discontinuation increases endothelial progenitor cells without 
inflammatory rebound in type 2 diabetic patients. Vascular Pharmacol. 2015; 21-29.  
Marcovina SM, Gaur VP, Albers JJ.  Biological variability of cholesterol, triglyceride, low-and 
high-density lipoprotein cholesterol, lipoprotein(a), and Apolipoproteins A-1 and B. Clin Chem. 
1994; 40(4): 574-8.   
Lipitor [package insert]. New York, NY: Pfizer Inc; 2018. 
Schouten, O, et. al.  Effect of statin withdrawal on frequency of cardiac events after vascular 
surgery. Amer J Cardiol. 2007; 100(2); 316-20.  

SAP_001.pdf: 
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                Protocol No. CPI-1103-002 
Statistical Analysis Plan – Final 
 
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Confidential 
                                                                  
 
 
Statistical Analysis Plan 
 
 
 
Protocol No. CPI-1103-002, Version 3.0, 04 September 2019 
 
 
 
PHASE II, DOSE-RANGING STUDY TO EVALUATE THE 
EFFICACY DOSE RESPONSE AND PHARMACOKINETICS OF 
INTRAVENOUS ATORVASTATIN IN 
HYPERCHOLESTEROLEMIC PATIENTS PREVIOUSLY 
CONTROLLED WITH ORAL ATORVASTATIN 
 
 
 
 
Sponsor: 
Cumberland Pharmaceuticals Inc. 
2525 West End Avenue, Suite 950 
Nashville, TN 37203, USA 
 
Prepared by: 
Frontage Clinical Services, Inc. 
200 Meadowlands Parkway 
Secaucus, NJ 07094, USA 
Tel: (201) 678-0288 
Fax: (201) 552-2597 
 
Document status: 
Final Version 2.0 
Release date:           April 10, 2020 
 
 
 
 
 


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Statistical Analysis Plan – Final 
 
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Confidential 
                                                                  
Signature Page 
 
Authors: 
Ruth E. Swanton, MPH 
Director of Biostatistics 
Frontage Clinical Services, Inc. 
101 Carnegie Center, Suite 102 
Princeton, NJ 08540 
Signature:___________________________ 
 
Date:_______________________________ 
 
Ken Yin, PhD 
Director, Clinical Pharmacology 
Frontage Clinical Services, Inc. 
200 Meadowlands Parkway 
Secaucus, NJ 07094 
Signature:___________________________ 
 
Date:_______________________________ 
 
Frontage Representative: 
Annie Li, MD 
Associate Director, Project Management 
Frontage Clinical Services, Inc.  
200 Meadowlands Parkway 
Secaucus, NJ 07094 
Signature:___________________________ 
 
Date:_______________________________ 
 
Sponsor Representative: 
Jerry Fox, DVM 
Sr. Manager, Clinical Operations 
Cumberland Pharmaceuticals Inc. 
2525 West End Avenue, Suite 950 
Nashville, TN 37203 
Tel.: 615-255-0068  
Fax.: 866-438-2372 
Email: jfox@cumberlandpharma.com 
Signature:___________________________ 
 
Date:_______________________________ 
 


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Statistical Analysis Plan – Final 
 
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Confidential 
                                                                  
Table of Contents 
 
Glossary and Abbreviations .................................................................................................5 
1 
Introduction ...................................................................................................................7 
2 
Study Objectives ...........................................................................................................9 
3 
Study Endpoints ..........................................................................................................10 
4 
Study Design and Methods .........................................................................................11 
4.1 
Study Measurements .......................................................................................18 
4.1.1 
Efficacy Measurements ..................................................................18 
4.1.2 
Pharmacokinetic Measurements .....................................................18 
4.1.3 
Safety Measurements......................................................................18 
4.2 
Randomization ................................................................................................19 
4.3 
Blinding ...........................................................................................................19 
4.4 
Sample Size Justification ................................................................................19 
4.5 
Data Handling .................................................................................................19 
5 
Data Analysis ..............................................................................................................21 
5.1 
Analysis Populations .......................................................................................21 
5.2 
Study Subjects .................................................................................................21 
5.3 
Subject Demographics/Other Baseline Characteristics ..................................22 
5.4 
General Medical/Surgical History and Procedures/Non-Drug Therapies.......22 
5.5 
Prior and Concomitant Medications ...............................................................22 
5.6 
Efficacy Analysis ............................................................................................23 
5.7 
Pharmacokinetic Analysis ...............................................................................23 
5.7.1 
Plasma Concentrations ...................................................................23 
5.7.2 
Pharmacokinetic Parameters ..........................................................23 
5.7.3 
Relative Bioavailability Analysis ...................................................25 
5.7.4 
Exploratory Dose Response ...........................................................25 
5.8 
Safety Analysis ...............................................................................................25 
5.8.1 
Study Product Exposure .................................................................25 
5.8.2 
Adverse Events ...............................................................................25 
5.8.3 
Clinical Laboratory Assessments ...................................................26 
5.8.4 
Vital Signs Assessments .................................................................27 
5.8.5 
Physical Examinations....................................................................27 
5.9 
Interim Analysis ..............................................................................................27 
5.10 
Statistical Programming and Deliverables ......................................................27 
5.11 
Changes from Pre-Specified Analyses ............................................................27 
5.12 
Changes to the Planned Analysis ....................................................................27 
6 
Revision History .........................................................................................................28 


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                Protocol No. CPI-1103-002 
Statistical Analysis Plan – Final 
 
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Confidential 
                                                                  
Listing of Tables 
 
Table 1: Treatment Assignment – Main Study ..................................................................11 
Table 2: Treatment Assignment – Sub-study.....................................................................12 
Table 3A: Schedule of Study Procedures for Subject’s with Prior Oral Atorvastatin 
Use ..............................................................................................................................14 
Table 3B: Schedule of Study Procedures for Subject’s without Prior Oral 
Atorvastatin Use at Study Entry .................................................................................16 
Table 4: Pharmacokinetic Parameters ................................................................................24 
 
 
 


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Statistical Analysis Plan – Final 
 
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Confidential 
                                                                  
Glossary and Abbreviations 
Abbreviation 
Term 
AE(s) 
Adverse Event(s) 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC0-24 
Area under the plasma concentration-time curve from time 
zero to 24 hours 
AUCinf 
Area under the plasma concentration-time curve from time 
zero to infinity 
BLQ 
Below the lower limit of quantification 
CBC 
Complete blood count 
CI(s) 
Confidence Interval(s) 
CL(/F) 
(Apparent) clearance of drug from plasma 
Cmax 
Maximum plasma concentration 
CMP 
Comprehensive metabolic panel 
CPI 
Cumberland Pharmaceuticals Inc. 
CPK 
Creatine phosphokinase 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
eCRF 
Electronic Case Report Form 
h or hr 
Hour(s) 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human Immunodeficiency Virus 
HMG-CoA 
3-hydroxy-3-methylglutaryl-coenzyme A 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
IV 
Intravenous 
Kel 
Elimination rate constant 
Kg 
Kilogram(s) 
L 
Liter 
LDL-C 
Low-density lipoprotein cholesterol 
Ln 
Natural logarithm 


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Statistical Analysis Plan – Final 
 
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Confidential 
                                                                  
Abbreviation 
Term 
MedDRA 
Medical Dictionary for Regulatory Activities 
max  
Maximum 
mg 
Milligram(s) 
min 
Minimum 
mL 
Milliliter 
n or N 
Number of subjects 
OTC 
Over the counter 
PK 
Pharmacokinetic(s) 
PO 
Per os 
PT 
Preferred Term 
SC 
Subcutaneous 
SD 
Standard Deviation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SOC 
System Organ Class 
TEAE(s) 
Treatment Emergent Adverse Event(s) 
TLFs 
Tables, Listings, and Figures 
Tmax 
Time to reach maximum plasma concentration 
T½ 
Elimination half-life 
Vdss 
Volume of distribution at steady state for intravenous dosing 
Vz/F 
Apparent volume of distribution 
WHO 
World Health Organization 
 
 


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1 
Introduction 
Cumberland Pharmaceuticals Inc. (CPI) is developing atorvastatin injection for use in 
patients where an injectable route of atorvastatin administration is preferred.  
Oral (PO) atorvastatin is currently approved for a number of indications, including the 
treatment of hyperlipidemia and the reduction of risk of myocardial infarction, stroke, 
revascularization procedures and angina.  Atorvastatin injection is initially under study for 
treatment of hypercholesterolemia in patients where the intravenous (IV) or subcutaneous 
(SC) route is preferable to the oral route. 
Statins, i.e., 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, 
are a class of drugs to treat patients with hypercholesterolemia and for secondary 
prevention of coronary artery disease and stroke.  Statins are among the most potent 
cholesterol lowering drugs available, yet only commercially available in oral formulations. 
An injectable formulation of atorvastatin would allow for continuation of atorvastatin 
therapy in patients whenever enteral administration is not possible.  There is evidence that 
abrupt discontinuation of statin therapy in patients with acute vascular disease results in 
adverse outcomes like cardiac events and higher mortality. Patients that may potentially 
benefit from injectable statin administration include: (1) individuals on an established statin 
regimen who are hospitalized and listed as nil per os such as those who are intubated, 
sedated, unconscious, or perioperative; (2) classes of acutely vulnerable patients such as 
those experiencing stroke, acute coronary syndrome, and certain types of myocardial 
infarction who may obtain protective effects from immediate statin administration; and (3) 
patients at high-risk of vascular events prior to and immediately following surgery.  
Atorvastatin injection is being developed by CPI. The current formulation of atorvastatin 
injection is a 10 mg/mL (40 mg/4mL) liquid for injection, available in a glass vial. 
Several Cumberland-sponsored nonclinical studies of atorvastatin injection have been 
conducted.  No adverse trends were seen in a repeat-dose canine toxicity study, a rabbit-
ear venous irritation study, or hemolysis and flocculation studies with human 
plasma/serum.  The highest doses of atorvastatin injection caused elevated liver enzymes, 
a result consistent with high dose oral atorvastatin. The dog toxicity study determined a no 
observed adverse effect level of 20 mg/kg/day atorvastatin injection.  
In a Phase 1 clinical trial in healthy volunteers, a preliminary pharmacokinetic (PK) profile 
for the parent compound and the two active metabolites was established for the IV delivery 
route.  No major safety concerns were identified.   
The current study is intended to further define the pharmacodynamic properties of 
atorvastatin and metabolites when delivered intravenously or subcutaneously, and to 
propose a dosing regimen to meet efficacy and safety objectives in changing from an oral 
to an injectable route.  A single dose of atorvastatin will also be given by the subcutaneous 


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(SC) route in a sub-study and initial pharmacokinetic data will be collected for subjects 
enrolling under Amendments 1 or 2 of the study protocol.  In Protocol Amendment 3, dated 
03Sep2019, subjects taking oral atorvastatin change to a subcutaneous route for the 
treatment phase rather than an intravenous route. 
This statistical analysis plan (SAP) covers the detailed procedures for performing statistical 
analyses and for producing Tables, Figures, and Listings (TLFs) for this study. 


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2 
Study Objectives 
The objectives of this study apply to hypercholesterolemic subjects currently being 
maintained on a stable dose of oral atorvastatin: 
• To propose IV doses of atorvastatin injection that adequately replace each dose 
level of oral atorvastatin 
• To describe the PK profile of atorvastatin injection administered by the IV route   
• To explore the PK profile of atorvastatin administered by the SC route 
• To assess the safety of the study drug administered by either the IV or SC route. 


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3 
Study Endpoints 
• To support a dose of atorvastatin injection that adequately replaces oral atorvastatin, 
the following primary endpoint will be evaluated for three of the four labelled oral 
doses of atorvastatin (10, 20, and 40 mg daily); endpoints are assessed using the 
subjects’ levels of low-density lipoprotein cholesterol (LDL-C) and high-density 
lipoprotein cholesterol (HDL-C):  
o Eleven or more subjects in a dosing cohort of thirteen with a Day 15       
LDL-C not more than 125% of their baseline LDL-C. 
Secondary endpoints that contribute to the same objective are as follows:  
o Eleven or more subjects in a dosing cohort of thirteen with a Day 15      
HDL-C not less than 75% of their baseline HDL-C. 
o The mean change in LDL-C at Day 15 for each treatment cohort (N=13) 
• To compare the PK profile of atorvastatin administered by the IV route to that of 
oral administration, the following parameters of atorvastatin, 2-hydroxy 
atorvastatin and 4-hydroxy atorvastatin will be calculated for each of the four final 
multiple dosing injectables (IV and SC) treatment cohorts:  
o Maximum serum concentration (Cmax) 
o Area under the curve to infinity (AUCinf) 
o Area under the curve to 24 hours (AUC0-24) 
o Elimination half-life (T1/2) 
o Volume of distribution at steady state (Vdss) 
o Elimination rate constant (Kel) 
o Clearance (CL) 
• To explore the PK profile of a single dose of atorvastatin administered by the SC 
route, the following parameters of atorvastatin, 2-hydroxy atorvastatin and                 
4-hydroxy atorvastatin will be calculated for each of the three final treatment 
cohorts:  
o Cmax  
o AUCinf   
o AUC0-24 
o T1/2 
o Vdss 


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o Kel 
o Apparent clearance (CL/F) 
• 
To assess the safety of the study drug, the following will be evaluated:  
o Adverse events 
o Mean change (baseline to Day 15) for creatine phosphokinase (CPK), 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in 
each dosing cohort. 
4 
Study Design and Methods 
This is a Phase II, open-label, single-center dose-ranging study. 
Three treatment cohorts of 13 subjects each are planned for intravenous route of 
administration. The different cohorts are composed of subjects taking three of the four 
commercially-prescribed levels of daily oral dosing:  10, 20, and 40 mg. The 4th Cohort for 
80 mg oral dosing did not proceed with enrollment (per Amendment 3).  Instead a 4th 
Cohort of 10 subjects (Amendment 03 of the protocol (Sections 9.3.6.2.3 and 12.2)) 
following the daily oral dosing of 20 mg will receive 15 days of subcutaneous treatment 
with atorvastatin. Subjects are treated with daily doses of injectable atorvastatin intended 
to be non-inferior to the efficacy of their stable oral dose at baseline.   
Enrollment of subjects into any one of the cohorts that does not prove to meet the primary 
endpoint is terminated as soon as this determination is made, and a new cohort intended 
for 13 subjects is opened at an adjusted dose with intentions to meet the primary endpoint 
(See Table 1).     
Table 1: Treatment Assignment – Main Study 
Cohort 
Lead-in Daily 
Dose of Oral 
Atorvastatin 
Initial Targeted, 
Daily IV or SC 
Atorvastatin Dose  
Maximum Daily 
IV or SC 
Atorvastatin 
Dose, after 
Escalations 
Subjects  
1 
10 mg 
2 mg IV 
5 mg IV 
13 
2 
20 mg 
4 mg IV 
10 mg IV 
13 
3 
40 mg 
8 mg*IV 
20 mg IV 
13 
4 
20 mg 
5 mg SC** 
  
10 
*Targeted starting doses for the cohort are shown; however actual starting doses may be adjusted pending 
findings from earlier cohorts **4th Cohort received 5 mg (0.5mL Atorvastatin) SC q 24 for 15 days. 
Subjects remain on the replacement treatment with atorvastatin for injection for 15 days, 
followed by a one-week follow-up period. 
Assessments include the following:  


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o 
Pharmacokinetic profile evaluation of both the oral and IV dosing 
o 
Cholesterol levels to assess efficacy 
o 
Safety assessment, including markers of rhabdomyolysis 
Sub-study:  For those subjects that are participating in the sub-study (only Cohorts 1, 2 
and 3) will resume their Lead-in visit oral dose of atorvastatin on Day 16. On Day 22, 
subjects that individually meet the study objective (Day 15 LDL-C < 125% of baseline 
level) may replace a daily oral dose of atorvastatin by a SC dose of the same quantity as 
the IV dose to which they were assigned (see Table 2).  Plasma levels of atorvastatin and 
the two metabolites are measured for a 24-hour period to assess the PK parameters of the 
SC route. 
 Table 2: Treatment Assignment – Sub-study 
Cohort 
Baseline Daily Dose 
of Oral Atorvastatin 
Daily SC Atorvastatin Dose 
Subjects* 
1 
10 mg 
Same as daily final dose of IV Atorvastatin 
≤13 
2 
20 mg 
Same as daily final dose of IV Atorvastatin 
≤13 
3 
40 mg 
Same as daily final dose of IV Atorvastatin 
≤13 
 
 
 
 
* Subjects are from those meeting the study objective (Day 15 LDL-C < 125% of baseline level) in the 
main study. 
Per protocol amendment, version 02, subjects eligible for enrollment in the main study will 
include: 
• Subjects taking oral atorvastatin prior to the study 
• Subjects taking statins other than atorvastatin prior to the study 
• Subjects not taking any statins prior to the study. 
 
Based on the subject’s prior use of atorvastatin, another statin, or no prior use of a statin, 
their progression through the screening and lead-in periods will follow the pathway as 
described in the following Study Procedures and description in the protocol (Section 9.1). 
For those subjects with prior oral atorvastatin use refer to Table 3A for the procedures.  For 
subjects on a different statin or whom do not have prior use of a statin refer to Table 3B for 
the procedures. 
During the Lead-in Period, daily dosing of oral atorvastatin allows the determination of 
baseline LDL-C levels and also provides PK data from steady-state oral administration that 
will be compared to that from the intravenous administration.      
The treatment period consists of an open-label treatment of 15 daily intravenous doses of 
atorvastatin injection.  A 7-day follow up period follows and concludes with a phone call 


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from the Investigator or designee to the subject to collect information on any possible 
adverse events or changes in concomitant treatments.   
The schedule of study procedures is presented in Table 3 below. For a detailed description 
of study procedures, please refer to protocol Section 9 “STUDY PROCEDURES”.


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Table 3A: Schedule of Study Procedures for Subject’s with Prior Oral Atorvastatin Use 
Study Phase 
Screen 
-ing 
Lead-in  
Treatment 
Follow-up 
call 
Optional 
SUB-STUDY 
Study Day 
Day -3 to 
0 from LI 
Day 0 
LI End Visit 
(Screening visit 
+ 7 to 10 days) 
AND 
(0 to -2 days 
before Day 1) 
Day 
1 
Day 
2 
Day 
3 
Days 
4–7 
Day 
8 
Days 
9-14 
Day 
15/ 
WD** 
Day 22 
Day 22  
+ 2 days 
 
Day 29  
+ 3 days 
(Phone call) 
LDL-C, Point of care 
X* 
X† 
 
 
 
 
 
 
 
 
 
 
LDL-C, Local laboratory 
 
 
 
 
 
 
X 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test, if needed 
X 
X 
 
 
 
 
 
 
X 
 
 
 
Drug, Alcohol, Viral screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC, CMP, lipid profile 
X   
X‡ 
 
 
 
 
 
 
X 
 
 
 
Basic Metabolic Panel 
 
 
 
 
X 
 
X 
 
 
 
 
 
Vital Signs 
X 
 
X‖ 
 
 
 
 
 
 
 
 
 
Review of Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
PK Blood Draws    
 
X§ 
 
 
 
 
 
 
X⁋ 
 
XΔ 
 
Daily oral atorvastatin 
dosing (standard of care). 
X 
 
 
 
 
 
 
 
Resume on 
Day 16, if in  
sub-study 
 
Daily IV or SC IMP 
 
 
X 
 
 
 
Single injection SC 
 
 
 
 
 
 
 
 
 
 
X 
 
Con Med monitoring 
X 
               X 
Adverse Event monitoring 
 
X 
X 


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* Point of care LDL-C is the first procedure done after the subject gives consent.  If the value does not meet eligibility, the subject screen fails and receives no other 
assessments.  Otherwise, the subject continues into the full screening phase.    
† On LI End Visit, the Point of Care LDL-C is performed first and, if the subject does not qualify for treatment, they are a screen fail and no other assessments are 
done.   
‡ The CMP, including liver enzymes and CK results must be reviewed by an Investigator before the subject is deemed eligible for treatment. The LDL result from this 
panel will not weigh in on the eligibility determination.  Only the point of care result from LI End Visit determines eligibility.   
§ PK sampling (oral PK) is performed at the Lead-in End visit.  Samples are taken per protocol Section 9.3.4.1. The pre-dose sample serves as the Hour 24 level.   
‖ On Day 1, vitals are measured twice: 1) between 30 and 0 minutes before the start of IMP, and 2) 15 (+ 5) minutes after the start of IMP  
⁋ PK sampling (multi-dose PK) is performed on subjects that complete a Day 15 visit.  Samples are taken per protocol Section 9.3.4.2. The pre-dose sample serves as 
the Hour 24 level. 
Δ PK sampling (SC PK) is performed On Day 22 for those subjects participating in the sub-study.  A subcutaneous injection of IMP is administered on a day that 
oral atorvastatin is withheld, then samples are taken per protocol Section 9.3.4.3. 
** If a subject withdraws (WD) from the treatment period before Day 15, the following assessments should be completed:  Physical exam, CBC, CMP, lipid profile, 
vital signs.  Withdrawn subjects do not have PK blood draws and are not eligible for the SC sub-study.     
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 3B: Schedule of Study Procedures for Subject’s without Prior Oral Atorvastatin Use at Study Entry 
Study Phase 
Screen 
-ing 
Lead-in 
Treatment 
Follow-
up call 
Optional 
SUB-STUDY 
Study Day 
Day -3 
to 0 
from LI 
Day 0 
LI 
Day 
0 
 
LI Interim 
Visit   
(LI Day 28 
+/-2 days) 
LI End Visit 
(Interim visit + 
7 to 10 days 
AND 
0 to -2 days 
before Day 1) 
Day 
1 
Day 
2 
Day 
3 
Days 
4–7 
Day 
8 
Days 
9-14 
Day 
15 
Day 22 
Day 22 
+ 2 days 
Day 29 
+ 3 days 
(Phone call)
LDL-C, Point of care 
X* 
 
X 
X† 
 
 
 
 
 
 
 
 
 
LDL-C, Local 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test, if 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
Drug, Alcohol, Viral 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC, CMP, lipid profile 
X   
 
 
X‡ 
 
 
 
 
 
 
X 
 
 
Basic Metabolic Panel 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Vital Signs 
X 
 
 
 
X‖ 
 
 
 
 
 
 
 
 
Review of Eligibility 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
PK Blood Draws    
 
 
 
X§ 
 
 
 
 
 
 
X⁋ 
 
XΔ 
 
Dispense oral 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Daily oral atorvastatin 
dosing 
 
X 
 
 
 
 
 
 
 
Resume 
on Day 
16, if in  
sub-study 
 
Drug accountability 
 
 
X 
X 
 
 
 
 
 
Daily IV or SC IMP 
 
 
 
 
X 
 
 


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* Point of care LDL-C is the first procedure done after the subject gives consent.  If the value does not meet eligibility, the subject screen fails and receives no other 
assessments.  Otherwise, the subject continues into the full screening phase.     
† On LI End Visit, the Point of Care LDL-C is performed first and, if the subject does not qualify for treatment, they are a screen fail and no other assessments are done.   
‡ The CMP, including liver enzymes and CK results must be reviewed by an Investigator before the subject is deemed eligible for treatment. The LDL result from this panel 
will not weigh in on the eligibility determination.  Only the point of care result from LI End Visit determines eligibility.   
§ PK sampling (oral PK) is performed at the Lead-in End visit.  Samples are taken per protocol Section 9.3.4.1. The pre-dose sample serves as the Hour 24 level.   
‖ On Day 1, vitals are measured twice: 1) between 30 and 0 minutes before the start of IMP, and 2) 15 (+ 5) minutes after the start of IMP  
⁋ PK sampling (multi-dose PK) is performed on subjects that complete a Day 15 visit.  Samples are taken per protocol Section 9.3.4.2. The pre-dose sample serves as the 
Hour 24 level. 
Δ PK sampling (SC PK) is performed On Day 22 for those subjects participating in the sub-study.  A subcutaneous injection of IMP is administered on a day that oral 
atorvastatin is withheld, then samples are taken per protocol Section 9.3.4.3. 
** If a subject withdraws (WD) from the treatment period before Day 15, the following assessments should be completed:  Physical exam, CBC, CMP, lipid profile, vital signs.  
Withdrawn subjects do not have PK blood draws and are not eligible for the SC sub-study.    
 
Single injection SC 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Con Med monitoring 
X 
               X 
Adverse Event 
 
X 
X 


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4.1 
Study Measurements 
4.1.1 Efficacy Measurements 
The main efficacy measurements are the assessments of the LDL-C and HDL-C levels and 
the mean change in LDL-C in the injectable atorvastatin administration for each dosing 
cohort. 
To assess the main efficacy objectives of the study, the lipid profile (including LDL-C and 
HDL-C) will be measured at the Screening Visit and Day 15, and the LDL-C level will be 
measured at Day 8. 
4.1.2 Pharmacokinetic Measurements 
The PK measurements in each dosing cohort are the assessments of plasma concentrations 
of atorvastatin and its metabolites (2-hydroxy atorvastatin and 4-hydroxy atorvastatin) in 
the oral administration and the administrations by the injectable route. 
At the oral PK visit (Screening Period), serial PK blood samples to measure plasma 
concentrations of atorvastatin and its metabolites will be collected within 60 minutes prior 
to taking the oral dose of atorvastatin, at 30 minutes (± 5 minutes), 1, 2, 4, 6, and 8 h (± 10 
minutes) after taking the oral dose.  
Levels of atorvastatin and metabolites measured from the pre-dose (oral) timepoint are 
imputed as 24-hour levels since the subject is on daily, constant dosing. 
In the last dose of injectable atorvastatin at Day 15 visit, serial PK blood samples to 
measure plasma concentrations of atorvastatin and its metabolites will be collected within 
60 minutes prior to the start of the dose, immediately after completion of IV dose (within 
3 to 7 minutes), at 30 minutes (± 5 minutes), 1, 2, 4, 6, and 8 h (± 10 minutes) after 
completing the injected dose.  
Levels of atorvastatin and metabolites measured from the pre-dose (IV) timepoint are 
imputed as 24-hour levels since the subject is on daily, constant dosing. 
In the sub-study for the single SC atorvastatin dose, serial PK blood samples to measure 
plasma concentrations of atorvastatin and its metabolites will be collected at 30 minutes (± 
5 minutes), 1, 2, 4, 6, 8 (± 10 minutes) and 24 h (± 60 minutes) after the SC dose.  
4.1.3 Safety Measurements 
The safety and tolerability of study drug in each dosing cohort will be evaluated through: 
• 
Incidence of treatment-emergent adverse events (TEAEs)  
• 
Study discontinuation information 
• 
Changes in clinical laboratory tests (CPK, ALT and AST) 
• 
Vital signs (clinically significant changes in a subject will be recorded as AEs)  


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Adverse events (AEs) will be collected from the signing of informed consent form (ICF) 
to last subject contact/visit/end of post-treatment follow-up period. 
Clinical laboratory tests including complete blood count (CBC), comprehensive metabolic 
panel (CMP), and lipid profile will be conducted at the Screening and, End Lead-in Visits, 
and at Day 15 or withdrawal.   
Vital signs, including seated systolic blood pressure (SBP) and diastolic blood pressure 
(DBP), heart rate, respiration rate and body temperature, will be measured at the Screening 
Visit, between 30 and 0 minutes before the start of investigational medicinal product (IMP) 
and at 15 (+ 5) minutes after the start of IMP on Day 1. 
4.2 
Randomization  
There is no randomization planned in the study. 
4.3 
Blinding 
This is an unblinded study.  All subjects will be openly assigned atorvastatin injection 
and their daily dose will be known by the Investigator and the subject. 
4.4 
Sample Size Justification 
The clinical goal of replacing stable oral dosing of atorvastatin with temporary injectable 
dosing is to maintain constant LDL-C levels during and following the replacement 
therapy window.   Therefore, the target mean change in LDL-C is zero.  Utilizing the 
standard biological variabilities of LDL-C and an associated, estimated standard 
deviation of 0.15, a sample size of 13 would provide 80% power to show that the mean 
change in LDL-C after switching to injectable dosing is less than 10% of baseline levels 
if the true mean change for the group is zero.  A mean change in LDL-C of up to 10% is 
not considered to be clinically significant over a short, two-week period. 
4.5 
Data Handling 
All subject data used for analysis will be displayed in listings. 
Summaries for continuous variables will include the descriptive statistics for number of 
subjects (n), mean (arithmetic and geometric), standard deviation (SD), minimum (min), 
median, and maximum (max). Summaries for categorical (discrete) variables will include 
the number and/or percentage of subjects in a particular category. 
Conventions for presentation of numerical data: 
Minimum and maximum values will be presented to the same number of decimal places 
as the electronic Case Report Form (eCRF) data. Means and medians will be presented to 
one more decimal place than the eCRF data. Standard deviations will be presented to two 
more decimal places than the eCRF data. 


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Plasma concentration and PK parameters in tables and listings will be displayed with 3 
significant figures as follows: 
(1) Values > = 0.0001 and < 1 will be reported with 3 significant figures (e.g., 0.0123). 
(2) Values >= 1 and < 10 will be reported with 3 significant figures (e.g., 1.02). 
(3) Values > = 10 and < 100 will be reported with 3 significant figures (e.g., 10.2). 
(4) Values >= 100 and < 1000 will be reported with 3 significant figures (e.g., 102). 
(5) Values >= 1000 will be reported with 3 significant figures (e.g., 1020). 
(6) Values = 0 will be reported as 0. 
Values for Tmax will be reported to 2 significant figures.  
In the evaluation of both oral and injectable, multiple-dose PK, levels of atorvastatin and 
its metabolites measured from the pre-dose timepoint are imputed as the Hour 24 levels 
since the subject will have been on at least a two-week period of daily, constant dosing, 
and the pre-dose value will essentially be the Hour 24 level from the previously 
administered dose.  This will relieve subjects from making an extra clinic visit. 
Baseline is defined as the last value measured prior to the first dose of study drug. 
Change from Baseline is defined as [Post-baseline Value – Baseline Value]. 
 
 


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5 
Data Analysis 
5.1 
Analysis Populations 
The following analysis populations will be used to summarize the results from this study. 
• Enrolled Population: All subjects who were eligible, signed informed consent and 
were assigned IMP. 
• Safety Population: All subjects who received at least a partial dose of IMP. No 
treated subjects will be excluded from the safety population. 
• Efficacy Population: A completed group of subjects that 1) finished the two-week 
treatment period, 2) provided a Day 15 LDL-C level, and 3) took the final targeted 
dose for that cohort comprise the four efficacy populations.  
• Pharmacokinetic Population: All subjects in the Efficacy Population who have 
no major protocol deviations and who have sufficient plasma atorvastatin 
concentration data for reliable estimates of the key PK variables for each of the four 
baseline cohorts.  
• Bioavailability Population: All subjects in the PK Population who have complete 
PK profiles for either the IV or the SC multiple-dose treatment. This population 
will be used for the bioavailability analysis of PO/IV and PO/SC, respectively. 
The frequency and percentage of subjects in each population will be summarized by cohort. 
Subjects who are excluded from the analysis populations will be listed by cohort, subject 
and treatment. 
5.2 
Study Subjects 
Subject Disposition 
Subject disposition will be summarized by cohort, using the number and percent of subjects 
who complete the study, the number and percent of subjects who discontinue the study, 
and the reasons for discontinuation. 
Subject disposition and completion status will be listed for all enrolled subjects. 
Protocol Deviations 
Protocol deviations will be identified prior to database lock and may include but are not 
limited to: significant violations of inclusion/exclusion criteria, noncompliance of the trial 
treatment taken, conditions such as vomiting and diarrhea or use of prohibited medications, 
and not following clinical trial protocol procedures that may affect evaluation of the PK 
profile. 
Protocol deviations will be listed by subject, cohort, and treatment for all enrolled subjects. 


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Subject Eligibility 
Following protocol amendment, version 01 the eligibility for enrollment included subjects 
taking oral atorvastatin prior to the study, subjects taking statins other than atorvastatin 
prior to the study, and subjects not taking any statins prior to the study.  A summary of these 
groups and cohort, final intravenous treatment, and final subcutaneous treatment will be 
produced.  A listing by subject and cohort will be produced. 
5.3 
Subject Demographics 
Demographics will be summarized by cohort and by IV or SC treatment in the safety 
population. The demographic consist of age, gender, race, and ethnicity. Individual 
demographics for the safety population will be listed by cohort, subject and treatment.  
The age is a calculated parameter. Age will be calculated using the subject’s date of birth 
and the subject’s informed consent date.  
Continuous variables (age) will be summarized by n, mean, SD, min, median, and max. 
Number of subjects and percentages will be used to describe categorical (discrete) variables 
(gender, race and ethnicity).  
5.4 
General Medical/Surgical History and Procedures/Non-Drug Therapies 
The presence/absence of any current medical condition and/or other significant 
medical/surgical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) Version 22.0. Any procedures/non-drug therapies that are incurred during the 
course of the study will also be coded using MedDRA or World Health Organization 
(WHO) Drug Enhanced Dictionary (version Global B3 March 2019), as appropriate.  
Medical/surgical history and procedures/non-drug therapies will be listed by cohort, 
subject and treatment, respectively. 
5.5 
Prior and Concomitant Medications  
All prescription medications and over-the-counter (OTC) products, including herbal 
products, taken from 30 days prior to Screening until the end of treatment will be 
documented in the subject’s source documentation and the eCRF. 
Prior and concomitant medications will be recorded and coded using the current version of 
WHO Drug Enhanced Dictionary (version Global B3 March 2019). Prior medications will 
be those that start and end prior to first dose of study drug. Concomitant medications will 
be those that have a known end date after the first dose of study drug or have a missing end 
date. Medications will be listed by cohort, subject, treatment, preferred term (PT) and 
Anatomical Therapeutic Chemical (ATC) classification, including the start and end dates 
and times, dose, unit and indication.  


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5.6 
Efficacy Analysis 
Efficacy will be determined by evaluating the final cohorts for each dosing level and the 
ability to meet the targets of 
• 11 of 13 subjects with a Day 15 LDL-C not more than 125% of their baseline 
LDL-C 
• 11 of 13 subjects with a Day 15 HDL-C not less than 75% of their baseline HDL-C 
• The mean change at Day 15 in LDL-C for each treatment cohort 
The dose required to meet the targets for each cohort will be listed by subject and 
summarized. A dosing cohort will be considered successful if eleven or more subjects have 
a Day 15 LDL-C not more than 125% of their baseline LDL-C. The responders for LDL-
C and HDL-C and LDL-C change from baseline in each dosing cohort will be summarized 
for final IV daily dose as well as each IV daily dose.  
5.7 
Pharmacokinetic Analysis 
The PK analysis will be conducted using WinNonlin Version 8.1 or higher (Certara, 
Princeton, NJ). In the PK analyses and summary statistics, all plasma concentrations below 
the lower limit of quantification (BQL) for the assay will be treated as “0” if they occur 
before the first measurable or after the last measurable concentration, and will be set as 
missing for data points in between two measurable concentrations.  
5.7.1 Plasma Concentrations 
Plasma concentrations of atorvastatin and its metabolites will be listed at each time point 
by cohort, subject and treatment, and summarized by route and final treatment cohort at 
each time point using descriptive statistics (n, arithmetic mean, SD and coefficient of 
variation (CV), geometric mean, geometric CV%, min, median and max).  
Plots of individual concentrations of atorvastatin and its metabolites versus time, and mean 
plasma concentrations of atorvastatin and its metabolites versus the planned sampling time, 
will be presented on linear and semi-logarithmic scales. 
5.7.2 Pharmacokinetic Parameters 
Pharmacokinetic parameters will be derived for atorvastatin and its metabolites for subjects 
in the PK population.  
Pharmacokinetic parameters are defined in Table 4. 


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Table 4: Pharmacokinetic Parameters 
Parameter 
Description 
Cmax 
Maximum plasma concentration 
AUC0-24 
Area under the plasma concentration-time curve from time zero to 24 
hours 
AUCinf 
Area under the plasma concentration-time curve from time zero to 
infinity 
Tmax 
Time to reach maximum plasma concentration 
T½ 
Elimination half-life 
Kel 
Elimination rate constant 
Cl(/F) 
(Apparent) clearance of drug from plasma for extravascular dosing 
VDss 
Volume of distribution at steady state for intravenous dosing 
Vz/F 
Apparent volume of distribution for extravascular dosing 
 
Pharmacokinetic parameters will be calculated using noncompartmental methods and 
actual blood sampling times. In case of missing actual time, planned (or nominal) time 
will be used.  
Concentration listed as below the limit of quantitation will be set to zero for the 
calculations. If a sample is missing or the value is not reportable and is between two 
measurable concentrations, the value at that time point will be left blank for the analysis 
and reported as either Not Reportable (NR) or No Sample (NS).  
The PK timepoint at 24-hour post oral dosing is the pre-dose concentration due to reaching 
steady state. The first timepoint immediately following IV bolus dosing is set as 0.0055 
hour (assume 20 seconds bolus dosing). The 24-hour post-dose concentration is set as pre-
dose concentration before IV and multiple-dose SC  dosing. For the single dose SC (sub-
study) the pre-dose concentration is the 24-hour post-oral dose concentration. 
No value of Kel, AUCinf or t½ will be reported for cases that do not exhibit a terminal log-
linear phase in the concentration versus time profile. If the adjusted R-squared value 
(Rsq_adjusted) is < 0.8, the analyst may evaluate if other time points are more appropriate 
and use those for the calculation of Kel, or no value of Kel, AUCinf or t½ will be reported.  
For determination of AUCinf, if calculated AUC from last to infinity is greater than 20% of 
the calculated AUC from 0 to infinity, then AUCinf will not be reported. 
Summary statistics for PK parameters except for Tmax will be described by n, arithmetic 
mean (mean), arithmetic mean SD, arithmetic CV%, geometric mean, geometric CV%, 
min, median, inter-quartile range (Q1:Q3) and max. For Tmax, summary statistics will be 
described by n, median, Q1:Q3, min and max. All PK parameters will be listed by cohort, 
subject and treatment.  


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5.7.3 Relative Bioavailability Analysis 
To compare the PK profile of atorvastatin and metabolites administered by the IV or SC 
route to that of oral administration, the relative bioavailability analysis will be performed 
for each cohort using key PK parameters (Cmax, AUC0-24 and AUCinf) of atorvastatin and, 
if data allow, its metabolites. Dose-normalized key PK parameters of the oral and IV (or 
SC) routes of administration will be log-transformed and analyzed using an analysis of 
variance (ANOVA) model including terms for treatment route as a fixed effect and subject as 
a random effect. The least squares geometric means ratio of atorvastatin oral vs IV (or SC) 
will be calculated. A 90% CI on the ratio of untransformed PK parameters will be derived 
through reverse transformation of the 90% CI for the difference in the log scale to the 90% 
CI for the ratio in the original scale. 
When appropriate, the same analysis may be performed to compare the PK profile of the 
atorvastatin SC vs oral (Cohort 4). 
The least-squares geometric means, ratio of the geometric means and 90% CIs on the ratio 
will be displayed.  
5.7.4 Exploratory Dose Response 
An exploratory dose response analysis may be conducted if the efficacy data vs the dose 
indicates a trend.  Summary of the baseline, Day 8 and Day 15 for LDL-C and HDL-C by 
IV dose will be produced. A dose-response plot (mean change from baseline in LDL-C 
and HDL-C for Day 8 and Day 15 vs. IV dose) may be produced.  If the efficacy over 
time vs IV dose indicates a trend then a plot of percent change from baseline for LDL-C 
and HDL-C at Days 8 and 15 vs IV dose may be produced. 
5.8 
Safety Analysis 
The safety and tolerability of IV and SC atorvastatin will be assessed by the evaluation of 
TEAEs, study discontinuation information, laboratory test results, and vital signs.  
Safety variables will be tabulated and presented for all subjects in the Safety Population. 
Data will be summarized by cohort and by route. Adverse events will be summarized by 
MedDRA system organ class (SOC), preferred term (PT) and treatment. Mean change 
(baseline to Day 15) for CPK, ALT and AST in each dosing cohort, changes from 
baseline in other clinical laboratory parameters and vital signs parameters will be 
summarized. 
5.8.1 Study Product Exposure 
Exposure to study drug will be listed by cohort, subject and treatment received, indicating 
dose date and time. Any deviations will be documented.  
5.8.2 Adverse Events 


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Adverse events will be collected from the ICF signing to last subject contact/visit/end of 
post-treatment follow-up period. 
 All AEs will be coded and classified according to MedDRA (Version 22.0). The 
intensity of adverse events is judged by the Investigator as mild, moderate or severe, and 
a causal relationship to study drug is judged by the Investigator as related, probably 
related, unlikely related or not related. Adverse events occurring prior to the date and 
time of first dose of study drug are considered non-TEAEs. Events occurring on or after 
the date and time of the first dose of study drug through last contact/visit of follow-up are 
considered treatment emergent if they are not listed in the subject’s history. 
A summary table of AEs will be created containing: number of AEs, number of subjects 
experiencing AEs, number of TEAEs, number of subjects experiencing TEAEs, severe 
TEAE, serious AEs, serious TEAEs, AEs causing discontinuation and AEs causing death.  
All TEAEs will be summarized as the number and percentage of subjects by SOC, PT 
and treatment. Separate summaries will be created by intensity and by relationship to 
study drug. If the same AE (PT) is reported more than once for the same subject, it will 
only be counted once in the summary table. For summary tables by intensity and 
relationship to study drug, if the same AE (PT) is reported more than once for the same 
subject, the highest intensity grade (severe > moderate > mild) or the strongest 
relationship to treatment (related > probably related > unlikely related > not related) will 
be counted in the summary table. 
All AEs will be listed, and a flag will indicate if the AE is treatment emergent.  
All serious AEs (SAEs) will be listed, and a flag will indicate if the SAE is treatment 
emergent. 
All adverse events leading to study discontinuation will be listed by subject.  
All adverse events leading to death will be listed by subject. 
5.8.3 Clinical Laboratory Assessments 
Clinical laboratory tests (CBC, CMP, and/or lipid profile) will be performed at the 
Screening Visit and at Day 15 or withdrawal. Per the protocol amendment, version 02, 
basic metabolic panels will be performed at Day 3 and Day 8. 
Clinical laboratory test parameters, with associated reference ranges provided by the 
laboratory, will be listed by cohort, subject and treatment. Clinical laboratory test results 
will be indicated as normal or abnormal (high, low). Mean change (baseline to Day 15) 
for CPK, ALT and AST in each dosing cohort will be summarized by cohort and by final 
IV treatment. For other clinical laboratory test parameters, observed values change from 
baseline will be also summarized for cohorts and final IV treatments.  


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5.8.4 Vital Signs Assessments 
Vital signs (seated SBP, DBP, heart rate, respiration rate and body temperature) will be 
measured at the Screening Visit, between 30 and 0 minutes before the start of IMP and at 
15 (+ 5) minutes after the start of IMP on Day 1. 
Vital signs results will be listed by cohort, subject and treatment. Observed values and 
change from baseline to the one time point for vital signs will be summarized for cohort 
and final IV treatments.  
5.8.5 Physical Examinations 
A physical examination will be performed at the Screening Visit. 
Physical examination results will be listed by cohort, subject and treatment. 
5.9 
Interim Analysis 
No interim analysis is planned for this study. 
5.10 
Statistical Programming and Deliverables  
All statistical analyses, tables and listings will be generated in SAS (version 9.3 or later) 
with appropriate documentation and programming validation. The table of contents of all 
tables, figures, and listings will be presented in a TFLs shell supplemental document. 
5.11 
Changes from Pre-Specified Analyses 
5.12 
Changes to the Planned Analysis 
Any deviation(s) of consequence from the SAP during the data analysis will be 
documented and justified in an amended SAP and/or in the final report or addressed in a 
separate document, as appropriate.  
 
 


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6 
Revision History 
 
Version 
Date 
Comments 
2.0 
3/16/20 
Updated per Amendment 3 04 September 
2019.