Clinical trial NCT02633956
Conditions: Nonalcoholic Steatohepatitis
Keywords: Non-alcoholic Fatty Liver Disease NAFLD Fatty Liver Disease NASH
Sponsor: Intercept Pharmaceuticals
Start date: 2015-12-04; Completion date: 2018-03-12
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 2, double-blind, randomized, placebo-controlled, multicenter study, with an open-label long-term safety extension (LTSE), will evaluate the effect of Obeticholic Acid, and the subsequent addition of statin therapy, on lipoprotein metabolism in subjects with nonalcoholic steatohepatitis (NASH) with fibrosis stage 1 to 4, but no evidence of hepatic decompensation.

Detailed description:

Arms: arm 1: 5 mg Obeticholic Acid daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg. arm 2: 10 mg Obeticholic Acid daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg. arm 3: 25 mg Obeticholic Acid daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg. arm 4: One tablet daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg.
Interventions: intervention 1: Obeticholic Acid intervention 2: Atorvastatin intervention 3: Placebo
Intervention descriptions: intervention 1: Once a day (QD) by mouth (PO) intervention 2: Initiate treatment with Atorvastatin at Week 4 visit with a dose of 10 mg once daily (QD) by mouth (PO).

Increase Atorvastatin to 20 mg once daily (QD) by mouth (PO) at Week 8 visit if 10 mg daily is tolerated.

Atorvastatin may be titrated up or down at Week 12 visit as clinically indicated. intervention 3: Once a day (QD) by mouth (PO)

Protocol documents:
Prot_000.pdf: 
1. 
ITLE PAGE 
 
Clinical Study Protocol 747-209 
OBETICHOLIC ACID 
 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Study 
Investigating the Effects of Obeticholic Acid and Atorvastatin Treatment on 
Lipoprotein Metabolism in Subjects with Nonalcoholic Steatohepatitis 
 
The CONTROL Study 
Combination OCA aNd STatins for MonitoRing Of Lipids  
 
 
Version 4: 19 December 2016 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA 92121 
USA 
 
TEL:  +1 858 652 6800 
FAX:  +1 858 558 5961 
 
 
CONFIDENTIAL 
The information contained herein is the property of Intercept Pharmaceuticals, Inc. and may not 
be reproduced, published, or disclosed to others without written authorization of Intercept 
Pharmaceuticals, Inc. 
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Protocol 747-209  
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Confidential and Proprietary 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the current version of the Investigator’s Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-209.  Having fully considered all the information available, 
I agree that it is ethically justifiable to give OCA to selected subjects according to this protocol. 
I understand that all information concerning OCA supplied to me by the Sponsor, Intercept 
Pharmaceuticals, Inc., and/or its agents in connection with this study and not previously 
published is confidential information.  This includes the IB, clinical study protocol, electronic 
case report forms (eCRFs), and any other preclinical and clinical data provided by the Sponsor. 
I understand that no data are to be made public or published without prior knowledge and written 
approval by the Sponsor. 
By my signature below, I hereby attest that I have read, understood and agreed to abide by all the 
conditions, instructions and restrictions contained in Protocol 747-209 and in accordance with 
Good Clinical Practice (CPMP/ICH/135/95), the Declaration of Helsinki and all regulatory 
requirements for protection of human subjects in clinical studies and privacy requirements for 
the protection of individual and company data. 
I acknowledge that the Sponsor of the study has the right to discontinue the study at any time. 
 
 
 
 
 
 
Investigator’s Name (Printed) 
 
 
 
 
 
 
Investigator’s Signature 
 
Date 
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Protocol 747-209  
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Confidential and Proprietary 
STUDY PERSONNEL CONTACT INFORMATION 
Medical Monitor 
Investigators are encouraged to call the PRA Medical Support Center phone number for the 
United States and Canada at +1 866 326 5053 or send an email to the NASH medical monitor at 
CONTROL@prahs.com with safety questions as these lines of contact are monitored 24 hours a 
day.   
Primary Medical Monitor 
Contact: 
 
Phone: 
Email 
Emad Basta, MD 
(Lead) Medical Monitor/Medical Expert 
PRA Health Sciences 
+1 866 326 5053 
CONTROL@prahs.com 
Secondary Contact: 
Tolga Baykal, MD, PhD 
Medical Director, Clinical Development 
Intercept Pharmaceuticals, Inc. (Intercept) 
Mobile Phone: 
Email 
+1 619 643 8886 (Pacific time zone) 
tolga.baykal@interceptpharma.com 
Secondary Contact: 
Barbara Scholz, MD,  
Medical Director, Drug Safety  
Intercept  
Mobile Phone: 
Email: 
+1 858 353 1350 (Pacific time zone)  
barbara.scholz@interceptpharma.com 
 
Clinical Operations and Project Management 
Contact: 
Shawn Sheeron 
Executive Director, Clinical Operations  
Intercept 
Telephone: 
Mobile: 
Fax: 
Email: 
+ 1 858 964 1572 (Pacific time zone) 
+ 1 215 796 3286 
+ 1 858 558 5961 
ssheeron@interceptpharma.com 
 
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Protocol 747-209  
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Confidential and Proprietary 
2. 
SYNOPSIS 
Name of Sponsor/Company:   
Intercept Pharmaceuticals, Inc. 
Name of Investigational Product:   
Obeticholic Acid 
Name of Active Ingredient: 
Obeticholic Acid (OCA); 6α-ethyl-chenodeoxycholic acid (6-ECDCA); INT-747; DSP-1747 
Title of Study:   
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Study Investigating the Effects of 
Obeticholic Acid and Atorvastatin Treatment on Lipoprotein Metabolism in Subjects with Nonalcoholic 
Steatohepatitis 
Study Center(s): 
Approximately 30 investigational sites in the United States 
Study Period: 
Duration of individual subject participation:  up to 5 weeks in Screening (depending 
on current statin use) and 16 weeks during the double-blind treatment phase, 
followed by an optional open-label long-term safety extension (LTSE) expected to 
last approximately 2 years.  
Phase of Development: 
Phase 2  
 
Objectives:  
Primary Objective 
• To evaluate the effect of OCA on low-density lipoprotein (LDL) metabolism in subjects with 
biopsy-confirmed nonalcoholic steatohepatitis (NASH) and to assess the ability of atorvastatin to 
modulate this effect 
Secondary Objectives 
• To evaluate the safety and tolerability of OCA alone and in combination with atorvastatin therapy in 
subjects with biopsy-confirmed NASH 
• To evaluate the effect of OCA, with and without atorvastatin therapy, on  
− High-density lipoprotein (HDL), very low-density lipoprotein (VLDL), triglycerides (TGs), total 
cholesterol, and apolipoprotein concentrations 
− Components of the reverse cholesterol transport pathway 
Exploratory Objectives  
• To evaluate the effect of OCA on  
− Liver biochemistry, inflammation, and apoptosis 
− Markers of glucose metabolism including C-peptide, insulin, fasting plasma glucose, hemoglobin-
specific A1c fraction (HbA1c), homeostatic model assessment–beta-cell function (HOMA-β) and 
homeostatic model assessment – insulin resistance (HOMA-IR) 
− Anthropometric measures including height (measured at Screening Visit 1 only), weight, and waist 
and hip circumference measurements; and body mass index (BMI), and waist-to-hip ratio calculations 
− Cardiovascular risk scores (eg, Framingham Risk Score [FRS] and Reynolds score) 
• To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of OCA and its conjugates 
• To evaluate the bioanalytical concentrations of atorvastatin and its metabolites 
• To evaluate improvement in noninvasive-radiological assessment of fibrosis via transient 
elastography (TE; at sites where available) 
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Protocol 747-209  
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Confidential and Proprietary 
Methodology:  
This Phase 2, double-blind, randomized, placebo-controlled, multicenter study, with an open-label LTSE, will 
evaluate the effect of OCA, and the subsequent addition of statin therapy, on lipoprotein metabolism in subjects 
with NASH with fibrosis stage 1 to 4, but no evidence of hepatic decompensation.  Approximately 80 subjects 
with histological evidence of definite or probable NASH, who meet all inclusion and none of the exclusion 
criteria will be enrolled.  The histological evidence of definite or probable NASH will be based on the central 
reading of a liver biopsy obtained no more than 1 year prior to randomization and a nonalcoholic fatty liver 
disease activity score (NAS) of 4 or greater.  Subjects not using statin therapy (ie, statin-free) and statin-treated 
subjects may be enrolled in the study.  Statin-treated subjects will be required to stop statin treatment (after 
signing informed consent) for up to 5 weeks, including a 4-week washout period, prior to Randomization/Day 1.   
Screening Period: 
Subjects will have a screening period of up to 5 weeks prior to Randomization/Day 1.   
Subjects using statins within 30 days of the initial Screening visit (Screening Visit 1) are required to stop statin 
therapy immediately following this initial visit and must undergo a 4-week statin washout period prior to 
Screening Visit 2.  At Screening Visit 2, these subjects will have a pre-randomization visit for assessment of 
their fasting LDL cholesterol levels.  Subjects with fasting LDL cholesterol values >200 mg/dL at Screening 
Visit 2 will be excluded from the study and their dyslipidemia should be managed according to standard of care.  
Subjects who are not using statin therapy at Screening Visit 1 are required to provide a fasting blood sample at 
Screening Visit 2, which can occur at any time prior to randomization but after signing of the ICF.  Statin-free 
subjects with fasting LDL cholesterol values >200 mg/dL at either Screening Visit will be excluded from the 
study and should be managed according to standard of care. 
Double-Blind Phase: 
At the Randomization (Day 1) Visit, subjects will be randomized in a 1:1:1:1 ratio to receive OCA 5 mg, 
OCA 10 mg, OCA 25 mg or placebo, orally once daily, for 16 weeks.  Randomization will be stratified by LDL 
concentration (fasting serum LDL cholesterol at Screening Visit 2; ≤125 mg/dL or >125 mg/dL) and baseline 
fibrosis stage (stage 1, 2 or stage 3, 4). 
At the Week 4 Visit, all subjects will initiate treatment with atorvastatin at a dose of 10 mg once daily.  At the 
Week 8 Visit, atorvastatin will be increased to 20 mg once daily (if 10 mg daily is tolerated), and continued for 
an additional 4 weeks.  After 4 weeks of treatment at 20 mg, the atorvastatin dose may be titrated (up or down) 
as clinically indicated.  The final visit during the double-blind phase will occur at Week 16, after which subjects 
may continue into the open-label LTSE phase.  
Subjects who discontinue investigational product or atorvastatin during the double-blind phase are still expected 
to attend scheduled study visits and are to be followed through the Week 16 Visit. 
Subjects who discontinue atorvastatin during the double-blind phase are eligible to continue OCA during the 
double-blind phase and enroll into the LTSE at the discretion of the Investigator, provided they continue to meet 
the LDLc cutoff of exclusion criteria #4 (ie, LDLc <200 mg/dL).   
LTSE Phase: 
During the LTSE phase, all subjects will be treated with open-label OCA 10 mg or OCA 25 mg.  Subjects 
randomized to placebo or OCA 5 mg during the double-blind phase will be randomized in a 1:1 ratio to receive 
OCA 10 mg or OCA 25 mg upon entry into and throughout the LTSE phase.  Subjects randomized to OCA 
10 mg or OCA 25 mg during the double-blind phase will continue on the same dose throughout the LTSE.  
During the LTSE, subjects may continue with atorvastatin therapy as clinically indicated.  
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Confidential and Proprietary 
• 
Barrier method, ie, condom (male or female) with spermicide or diaphragm with spermicide 
• 
Intrauterine device 
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection) 
• 
Abstinence (defined as refraining from heterosexual intercourse) 
7. Must provide written informed consent and agree to comply with the study protocol including 
adherence to protocol-described statin withdrawal and statin therapy. 
Exclusion Criteria 
Subjects who satisfy any of the following exclusion criteria will be ineligible for enrollment:  
1. Current or history of significant alcohol consumption for a period of more than 3 consecutive months 
within 1 year prior to Screening Visit 1 (significant alcohol consumption is defined as more than 
2 units/day in females and more than 4 units/day in males, on average). 
2. Prior intolerance to treatment with atorvastatin or other 3-hydroxy-3-methyl-glutaryl (HMG) 
Coenzyme A reductase inhibitors (including but not limited to rhabdomyolysis).  
3. LDL cholesterol ≥190 mg/dL and already on statin therapy at Screening Visit 1. 
4. LDL cholesterol >200 mg/dL at any Screening visit in subjects who are not on statin therapy, or at 
Screening Visit 2 in statin washout subjects.  
5. Planned change in diet or exercise habits during participation in the double-blind period, or a 
significant weight change of >5% in the prior 6 months. 
6. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal 
resection or plan to undergo either of these procedures.    
7. History of biliary diversion. 
8. Uncontrolled diabetes defined as HbA1c ≥9.5% within 60 days prior to randomization (Day 1).  
9. Administration of any of the following medications as specified below: 
• 
Prohibited 30 days prior to Day 1:   
− 
bile acid sequestrants including cholestyramine and it’s derivatives, colesevelam, colestipol, 
or 
− 
omega-3 fatty acid-containing dietary supplements 
• 
Prohibited 3 months prior to Day 1:   
− 
nicotinic acid and derivatives, ezetimibe, or  
− 
any prescription or over-the-counter medication or herbal remedy with putative NASH 
efficacy (except Vitamin E or TZDs), or 
− 
ursodeoxycholic acid, or 
− 
fenofibrate or other fibrates, or 
− 
Any over-the-counter or health foods used to treat lipids including plant sterols and berberine 
• 
Prohibited 6 months prior to Day 1:  
− 
azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate, mofetil, pentoxifylline; 
budesonide and other systemic corticosteroids, or  
− 
potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or 
nitrofurantoin) 
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Confidential and Proprietary 
• 
Prohibited 12 months prior to Day 1:  
− 
antibodies or immunotherapy directed against interleukins, or  
− 
other cytokines or chemokines 
10. Evidence of other forms of known chronic liver disease including but not limited to:  
• 
Positive test result at Screening for hepatitis B surface antigen 
• 
Active hepatitis C virus (HCV) infection (positive for HCV ribonucleic acid [RNA] at Screening) 
or history of positive HCV RNA test result  
• 
Primary biliary cirrhosis (also known as primary biliary cholangitis), primary sclerosing 
cholangitis, autoimmune hepatitis or overlap syndrome 
• 
Alcoholic liver disease 
• 
Wilson’s disease or hemochromatosis or iron overload as defined by presence of 3+ or 
4+ stainable iron on liver biopsy 
• 
Alpha-1-antitrypsin (A1AT) deficiency as defined by diagnostic features in liver histology 
(confirmed by A1AT level less than normal; exclusion at the Investigator’s discretion) 
• 
Prior known drug-induced liver injury within 5 years before Day 1 
• 
Known or suspected hepatocellular carcinoma  
11. History of liver transplant, current placement on a liver transplant list, or current Model for End-Stage 
Liver Disease (MELD) score >12.  Subjects who are placed on a transplant list despite a relatively 
early disease stage (eg, per regional guidelines) may be eligible as long as they do not meet any of the 
other exclusion criteria. 
12. Presence of hepatic decompensation, including: 
− 
Gastroesophageal varices 
− 
Ascites 
− 
Hepatic encephalopathy 
− 
Spontaneous bacterial peritonitis 
− 
Hepatorenal or hepatopulmonary syndromes 
13. Total bilirubin ≥2x upper limit of normal (ULN) at any Screening visit (subjects with Gilbert’s 
syndrome may be enrolled despite a total bilirubin level >2x ULN if their conjugated bilirubin is 
<2x ULN). 
14. Creatine phosphokinase >5x ULN at Screening Visit 2. 
15. Serum creatinine ≥1.5 mg/dL at any Screening visit. 
16. Serum ALT >300 U/L at any Screening visit. 
17. Platelet count <75 000/mm3 at any Screening visit. 
18. Known positivity for human immunodeficiency virus (HIV) infection. 
19. Subjects with recent history (within 1 year of randomization) of cardiovascular disease or with history 
or planned cardiovascular interventions to treat atherosclerotic cardiovascular disease, including: 
a. 
Peripheral or Coronary revascularization (percutaneous coronary intervention or coronary artery 
bypass grafting) 
b. Coronary angioplasty, stenting, or carotid atherectomy 
c. 
Cardiac pacemaker or defibrillator (placement of cardiac pacemaker or defibrillator for reasons 
other than atherosclerotic cardiovascular disease [eg, for treatment of atrial fibrillation subsequent 
to nodal ablation] is not exclusionary) 
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Protocol 747-209  
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Confidential and Proprietary 
d. Prosthetic heart valves 
e. 
Myocardial infarct, unstable angina, or acute coronary syndrome 
f. 
Other clinically significant atherosclerotic cardiovascular disease 
g. Cerebrovascular accident (stroke), cerebrovascular ischemia, or transient ischemic attack 
h. Unstable hypertension 
i. 
Familial hypercholesterolemia or other genetic lipid abnormality 
20. Other concomitant disease, malignancy, or condition likely to significantly decrease life expectancy to 
<5 years, including known cancers (except carcinomas in situ or other stable, relatively benign 
conditions such as chronic lymphocytic leukemia) and moderate to severe congestive heart failure. 
21. Known substance abuse, including inhaled or injected drugs in the year before Screening. 
22. For female subjects:  pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use 
effective birth control during the study, or breastfeeding.  
23. Participation in a clinical research study with any investigational product being evaluated for the 
treatment of diabetes or NASH in the 6 months before Day 1.  
24. Receipt of any investigational product not being evaluated for the treatment of diabetes or NASH from 
Screening Visit 1 to Day 1, within 30 days prior to Day 1, or within 5 half-lives of the compound 
before Day 1 (whichever was longer). 
25. Previous exposure to OCA. 
26. History of known or suspected clinically significant hypersensitivity to OCA or any of its components. 
27. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
28. Any other condition which, in the opinion of the Investigator, would impede compliance or hinder 
completion of the study.  
29. Acute cholecystitis or acute biliary obstruction 
Investigational Product, Dosage and Mode of Administration:   
OCA:  5 mg, 10 mg, or 25 mg or placebo tablets, once daily, oral administration   
Study Medication, Dosage and Mode of Administration: 
Atorvastatin:  10 mg, 20 mg, 40 mg, 80 mg once daily, oral administration 
Duration of Subject Participation: 
• 
Screening period for statin-using subjects:  Up to 5 weeks (including a 4-week statin washout period) 
• 
Screening period for non-statin-using subjects:  Up to 5 weeks 
• 
Double-Blind period:  16 weeks 
• 
LTSE:  2 years 
Duration of Treatment:  
Double-Blind period: 
• 
OCA/placebo:  16 weeks (Day 1 to Week 16) 
• 
Atorvastatin:  12 weeks (Week 4 to Week 16), administered open-label 
LTSE: 
• 
OCA:  2 years 
• 
Atorvastatin:  As clinically indicated 
Reference Therapy, Dosage and Mode of Administration:  
Not applicable 
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Criteria for Evaluation: 
Statistical Methods: 
The assessments supporting the primary, secondary, and exploratory objectives of the study are as follows: 
Primary Endpoints  
Assessment 
LDL metabolism 
LDL cholesterol concentration, particle size, and particle concentration 
Secondary Endpoints 
Lipoprotein metabolism 
HDL cholesterol concentration, particle size and particle concentration; 
VLDL cholesterol concentration, particle size and particle 
concentration; TG and total cholesterol concentrations; apolipoprotein 
(Apo)A1, ApoB, ApoE, ApoCII, ApoCIII and Lp(a) concentrations; 
PCSK9 concentration 
Reverse cholesterol transport 
Pre-β1 HDL concentration, macrophage cholesterol efflux; LCAT 
activity; CETP activity  
Safety and tolerability 
TEAEs (including cardiovascular events), physical exams, ECGs, vital 
signs, clinical laboratory assessments (including lipid profile changes)  
Exploratory Endpoints 
Liver biochemistry and markers of 
liver function 
Albumin, ALP (isoenzymes), ALT, AST, , direct bilirubin, GGT, INR,  
total bilirubin  
Markers of liver inflammation 
IL-6, hs-CRP, and TNF-α 
Marker for hepatic apoptosis and 
fibrosis 
CK-18-M30 and CK-18-M65 
Glycemic Control 
Glucose, insulin, C-peptide, HbA1c, HOMA-β, and HOMA-IR 
OCA pharmacokinetics  
OCA, tauro-OCA, glyco-OCA, total OCA, potentially other conjugates 
or metabolites not yet identified  
Atorvastatin bioanalytical 
concentrations 
Atorvastatin and its metabolites     
Anthropometric measures 
Height (at Screening Visit 1 only), weight, and waist and hip 
circumference measurements; and body mass index (BMI), and waist-
to-hip ratio calculations 
Pharmacodynamics 
C4 (7α-hydroxy-4-cholesten-3-one), and FGF-19; possible analysis of 
conjugated and unconjugated endogenous bile acids 
Noninvasive radiological liver 
fibrosis measurements 
By TE (where available) 
Cardiovascular risk scores 
FRS and Reynolds scores 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; ApoA1 = apolipoprotein A1; ApoB = apolipoprotein B; 
ApoCII = apolipoprotein CII; ApoCIII = apolipoprotein CIII; ApoE = apolipoprotein E; AST = aspartate aminotransferase; 
BMI = body mass index; C4 = 7α-hydroxy-4-cholesten-3-one; CK-18-M30 = cytokeratin-18 neoepitope M30; 
CK-18-M65 = cytokeratin-18 neoepitope M65; CTEP = cholesterol ester transfer protein; FGF-19 = fibroblast growth 
factor-19; FRS = Framingham Risk Score; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin-specific A1c fraction; 
HDL = high-density lipoprotein; HOMA-β:  homeostatic model assessment –beta-cell function; HOMA-IR = homeostatic 
model assessment – insulin resistance; hs-CRP = high sensitivity C-reactive protein; IL-6 = interleukin-6; 
INR = international normalized ratio; LCAT = lecithin cholesterol acyltransferase; LDL = low-density lipoprotein; 
Lp(a) = lipoprotein(a); PCSK9 = proprotein convertase subtilisin/kexin type 9; PD = pharmacodynamics; TE = transient 
elastography; TEAE = treatment emergent adverse event; TG = triglyceride; TNF-α = tumor necrosis factor-α; 
VLDL = very low-density lipoprotein  
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Protocol 747-209  
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Confidential and Proprietary 
Analysis Populations: 
The following analysis populations will be used: 
Intent-to-Treat (ITT) Population 
All randomized subjects who receive any amount of investigational product will be included in the ITT 
Population.  Treatment assignment will be based on the randomized treatment allocation.   
Safety Population 
The Safety Population will include all subjects who receive any amount of investigational product.  Treatment 
assignment will be based on the treatment actually received.  The Safety Population will be used for the analysis 
of all safety data. 
Efficacy Evaluable Population 
All subjects who complete the double-blind phase according to the indicated doses of investigational product 
and atorvastatin without any significant protocol deviations.  The Efficacy Evaluable Population will be the 
primary population used for efficacy analyses. 
Pharmacokinetic Populations 
The OCA PK Population will include all OCA subjects who consent to participate in the PK assessments and 
have at least one confirmed fasted analyzable sample. Subjects must have been fasting for approximately 
8 hours before the visit and must not have any major protocol deviations that potentially affect exposure levels.  
The Atorvastatin PK Population will include all subjects who consent to participate in the PK assessments and 
have at least one confirmed fasted analyzable sample.   
LTSE Population 
All subjects who receive any amount of investigational product as part of the LTSE will be included in the 
LTSE Population. 
Efficacy Analyses: 
The primary efficacy analyses will be based on the Efficacy Evaluable Population. 
The primary efficacy parameter, changes in LDL cholesterol, particle size and particle concentration at Week 16 
(end of the double-blind phase) compared to Baseline will be summarized by treatment group. 
Analyses of observed LDL values will be carried out using an analysis of covariance (ANCOVA) model at each 
visit with change from baseline as the dependent variable, including treatment group and randomization 
stratification factor as fixed effects and baseline as a covariate.  The same analysis will be carried out using 
percentage change from baseline as the dependent variable. 
Descriptive statistics of the values will be summarized by treatment group and visit.  The results, change from 
baseline, and percentage change from baseline values as well as estimates of least-square (LS) means, standard 
errors, and 95% confidence intervals (CIs) will be presented by treatment group.   
The comparison of LDL change from baseline and percentage change from baseline values between each active 
treatment group and placebo group will be performed as exploratory analysis.  Estimates of the LS mean 
difference between each active treatment group and placebo group, the standard error of the difference, and 
95% CI of the difference will be presented. 
The secondary parameters will be analyzed in the same manner as the primary efficacy variables.  Descriptive 
statistics will be generated and will include change from baseline, percentage change from baseline, and 
estimates of LS means, standard errors, and 95% CIs presented by treatment group. 
The secondary parameters related to lipoprotein metabolism include HDL cholesterol concentration, particle 
size and particle concentration; VLDL cholesterol concentration, particle size and particle concentration; TG 
and total cholesterol concentrations; and apolipoprotein (Apo)A1, ApoB, ApoE, ApoCII, ApoCIII and Lp(a) 
concentrations. 
The secondary parameters related to reverse cholesterol metabolism include pre-β1 HDL concentration, 
macrophage cholesterol efflux; lecithin cholesterol acyltransferase (LCAT) activity; and cholesterol ester 
transfer protein (CETP) activity. 
The baseline value for efficacy analyses is defined as the last value prior to administration of investigational 
product on Day 1 (predose).   
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The following exploratory parameters will be analyzed in the same manner as the secondary efficacy variable:  
markers of liver biochemistry, liver function, liver inflammation, apoptosis, liver fibrosis, glycemic control, and 
bile acids.  Additionally, descriptive statistics will be generated and will include change from baseline, 
percentage change from baseline, and estimates of LS means, standard errors, and 95% CIs presented by 
treatment group.  Changes from baseline will be summarized for anthropometric measures.  PK analysis will be 
done using non-compartmental methods.  The values will be summarized by active treatment group using 
descriptive statistics.  Only samples that have a confirmed fasting of approximately 8 hours or more before their 
visit will be included in the PK analysis.  Further details regarding specific parameters and methods will be 
described in the Statistical Analysis Plan. 
Safety Analyses: 
All safety analyses will be based on the Safety Population.  The incidence of treatment-emergent adverse events 
(TEAEs) and serious AEs (SAEs) will be tabulated by system organ class and preferred term for each treatment 
group, and similarly by severity and relationship to treatment.  The incidence of pre-treatment AEs and 
pre-treatment SAEs occurring after informed consent form signoff and before the first dosing of investigational 
product (OCA or placebo) will be tabulated in the same manner as above for all subjects participating in the 
washout period.  
Laboratory parameters, physical examinations including vital signs, and ECGs will be summarized by treatment 
group using descriptive statistics at Baseline and at each scheduled post-Baseline visit.  The absolute change 
from baseline will also be summarized. 
LTSE Analyses: 
Similar analyses to that which are described above will be conducted for the LTSE using the double-blind 
baseline value.  Analyses based on the double-blind baseline will be performed using randomized treatment 
groups (placebo, OCA 5 mg, OCA 10 mg, or OCA 25 mg).  Sensitivity analyses may be conducted using the 
last value prior to first dose in the LTSE for all subjects.  
Sample Size Justification: 
It is the intent of this study to characterize the components of LDL metabolism (cholesterol concentration, 
particle size, particle concentration) in subjects with NASH before and after treatment with OCA and to assess 
the changes induced by HMG Coenzyme A reductase inhibitor (atorvastatin) therapy.  Assuming a 22 mg/dL 
increase from baseline with a standard deviation of 24 in LDL in the OCA 25 mg group without atorvastatin 
therapy after 16 weeks of treatment based on data from FLINT, a sample size of 20 subjects per group will 
provide greater than 97.3% power to demonstrate the statistically significant difference of LDL increase from 
baseline with a 2-sided type I error of 0.05.   
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................22 
5. 
INTRODUCTION ......................................................................................................26 
5.1. 
Overview of Nonalcoholic Steatohepatitis and Obeticholic Acid ..............................26 
5.2. 
NASH, Lipoprotein Metabolism, and Statins .............................................................27 
5.3. 
Mechanism of Action of Obeticholic Acid .................................................................28 
5.4. 
Nonclinical Experience with Obeticholic Acid ..........................................................29 
5.5. 
Clinical Experience with Obeticholic Acid ................................................................30 
5.6. 
Rationale for Study Design, Doses of Investigational Product and Use of 
Atorvastatin .................................................................................................................32 
5.6.1. 
Rational for Study Design ..........................................................................................32 
5.6.2. 
Rationale for Placebo Control Group .........................................................................33 
5.6.3. 
Rationale for OCA Doses ...........................................................................................33 
5.6.4. 
Rationale for the Use of Atorvastatin .........................................................................34 
5.6.4.1. 
Rationale for Statin Withdrawal .................................................................................34 
5.6.5. 
Rationale for Duration of Treatment ..........................................................................35 
5.6.6. 
Rationale for Timing of Unblinding Process and Implications in LTSE ...................36 
5.7. 
Summary of Known Potential Risks with Investigational Product ............................36 
5.8. 
Summary of Known Potential Risks with Atorvastatin ..............................................36 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................38 
6.1. 
Primary Objective .......................................................................................................38 
6.2. 
Secondary Objectives .................................................................................................38 
6.3. 
Exploratory Objectives ...............................................................................................38 
7. 
INVESTIGATIONAL PLAN .....................................................................................39 
7.1. 
Overall Study Design ..................................................................................................39 
7.1.1. 
Study Design ...............................................................................................................40 
7.1.2. 
Schedule of Study Procedures ....................................................................................41 
7.1.3. 
Study Duration ............................................................................................................46 
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7.2. 
Number of Subjects ....................................................................................................46 
7.3. 
Treatment Assignment ................................................................................................46 
7.4. 
Dose Adjustment Criteria ...........................................................................................46 
7.4.1. 
Investigational Product Dose Adjustments .................................................................46 
7.4.2. 
Atorvastatin Dose Adjustments ..................................................................................46 
7.4.3. 
Safety Criteria for Adjustment or Stopping of Doses of Investigational 
Product ........................................................................................................................47 
7.5. 
Criteria for Study Termination ...................................................................................48 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................48 
8.1. 
Subject Population ......................................................................................................48 
8.2. 
Subject Inclusion Criteria ...........................................................................................48 
8.3. 
Subject Exclusion Criteria ..........................................................................................49 
8.4. 
Subject Withdrawal Criteria .......................................................................................52 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product or 
Atorvastatin .................................................................................................................52 
8.4.1.1. 
Adverse Events ≥Grade 3 in Severity and Possibly, Probably, or Definitely 
Related to Investigational Product ..............................................................................52 
8.4.1.2. 
Pregnancy ...................................................................................................................52 
8.4.1.3. 
Severe Drug-Induced Liver Injury ..............................................................................52 
8.4.1.4. 
Myonecrosis ................................................................................................................53 
8.4.2. 
Reasons for Mandatory Interruption of Investigational Product ................................53 
8.4.2.1. 
Adverse Events ≥Grade 4 in Severity and Not or Unlikely Related to 
Investigational Product ...............................................................................................53 
8.4.2.2. 
Suspected Mild or Moderate Drug-Induced Liver Injury ...........................................53 
8.4.3. 
Other Reasons for Study or Treatment Discontinuation of Subjects ..........................54 
8.4.4. 
Subject Discontinuation Notification .........................................................................54 
9. 
TREATMENT OF SUBJECTS ..................................................................................54 
9.1. 
Investigational Product and Atorvastatin Treatment Regimen ...................................54 
9.1.1. 
Double-Blind Period ...................................................................................................55 
9.1.2. 
LTSE ...........................................................................................................................55 
9.2. 
Concomitant Medications ...........................................................................................55 
9.2.1. 
Medications with Potential NASH-Modifying Properties ..........................................55 
9.2.2. 
Diabetes-Specific Therapy ..........................................................................................56 
9.2.3. 
Management of Changes in Cholesterol .....................................................................56 
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9.2.4. 
Prohibited Medications ...............................................................................................56 
9.2.5. 
Standard of Care and Other Concomitant Medications ..............................................60 
9.3. 
Treatment Compliance ................................................................................................60 
9.4. 
Randomization and Blinding ......................................................................................60 
9.4.1. 
Stratification ...............................................................................................................61 
9.4.2. 
Emergency Unblinding Procedures ............................................................................61 
9.5. 
Assignment of Site and Subject Numbers ..................................................................62 
9.5.1. 
Site Numbers ..............................................................................................................62 
9.5.2. 
Subject Numbers .........................................................................................................62 
9.6. 
Restrictions .................................................................................................................62 
9.6.1. 
Fasting Requirement at Study Visits ..........................................................................62 
9.6.2. 
Grapefruit and Grapefruit Juice ..................................................................................62 
9.6.3. 
Diet and Exercise ........................................................................................................62 
9.7. 
Visit Procedures ..........................................................................................................62 
9.7.1. 
Visit Windows ............................................................................................................62 
9.7.2. 
Informed Consent Procedures.....................................................................................63 
9.7.3. 
Screening Visit 1 Procedures ......................................................................................64 
9.7.4. 
Screening Visit 2 Visit Procedures .............................................................................65 
9.7.5. 
Randomization/Day 1 Visit Procedures ......................................................................65 
9.7.6. 
Week 2 Visit Procedures ............................................................................................67 
9.7.7. 
Week 4 Visit Procedures ............................................................................................68 
9.7.8. 
Week 6 Safety Contact ...............................................................................................69 
9.7.9. 
Week 8 Visit Procedures ............................................................................................69 
9.7.10. 
Week 10 Safety Contact .............................................................................................70 
9.7.11. 
Week 12 Visit Procedures ..........................................................................................71 
9.7.12. 
Week 14 Safety Contact .............................................................................................72 
9.7.13. 
Week 16 Visit Procedures ..........................................................................................72 
9.7.13.1. 
Additional Week 16 Procedures for PK Subjects .......................................................73 
9.7.14. 
Additional Procedures at Week 16/LTSE Day 1 Visit for Subjects 
Continuing into the LTSE ...........................................................................................73 
9.7.15. 
Early Termination/End of Study Procedures:  Double-Blind Period .........................74 
9.7.16. 
LTSE Visits ................................................................................................................75 
9.7.17. 
LTSE Month 1 Visit Procedures .................................................................................75 
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9.7.18. 
LTSE Month 3, Month 6, Month 9, Month 15, Month 18, and Month 21 
Visit Procedures ..........................................................................................................77 
9.7.19. 
LTSE Month 12 Visit Procedures ...............................................................................78 
9.7.20. 
LTSE End of Study/Early Termination Procedures ...................................................79 
9.7.21. 
Unscheduled Safety Visits ..........................................................................................81 
10. 
INVESTIGATIONAL PRODUCT AND STUDY MEDICATION ..........................81 
10.1. 
Investigational Product (OCA or Placebo) .................................................................81 
10.2. 
Investigational Product Packaging and Labeling .......................................................81 
10.3. 
Investigational Product Storage ..................................................................................82 
10.4. 
Investigational Product Administration ......................................................................82 
10.4.1. 
Investigational Product Dispensation .........................................................................82 
10.4.2. 
Missed Doses ..............................................................................................................82 
10.5. 
Atorvastatin Tablets ....................................................................................................82 
10.5.1. 
Atorvastatin Packaging and Labeling .........................................................................83 
10.5.1.1. 
Atorvastatin Storage ...................................................................................................83 
10.5.2. 
Atorvastatin Administration .......................................................................................83 
10.5.3. 
Atorvastatin Dispensation ...........................................................................................83 
10.5.4. 
Missed Doses of Atorvastatin .....................................................................................83 
10.5.5. 
Atorvastatin Overdose ................................................................................................83 
10.6. 
Investigational Product and Atorvastatin Accountability and Disposal .....................84 
11. 
ASSESSMENT OF EFFICACY AND PHARMACOKINETICS .............................84 
11.1. 
Efficacy Assessments .................................................................................................84 
11.1.1. 
Efficacy Laboratory Assessments ...............................................................................86 
11.1.2. 
Liver Biopsy ...............................................................................................................86 
11.1.2.1. 
Central Reading of Liver Histology ...........................................................................86 
11.1.3. 
Noninvasive Radiological Liver Fibrosis Measurements ...........................................87 
11.1.4. 
Blood Samples for Future Analysis ............................................................................87 
11.2. 
Pharmacokinetic and Pharmacodynamic Assessments ..............................................87 
11.2.1. 
Pharmacodynamic Assessments .................................................................................87 
11.2.2. 
Pharmacokinetic Assessments ....................................................................................88 
11.3. 
Anthropometric Assessments .....................................................................................88 
11.3.1. 
BMI .............................................................................................................................88 
11.3.2. 
Body Weight ...............................................................................................................88 
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11.3.3. 
Waist and Hip Circumference: ...................................................................................88 
12. 
ASSESSMENT OF SAFETY .....................................................................................89 
12.1. 
Adverse Events and Serious Adverse Events .............................................................89 
12.1.1. 
Definitions ..................................................................................................................89 
12.1.1.1. 
Adverse Event .............................................................................................................89 
12.1.1.2. 
Treatment-Emergent Adverse Event ..........................................................................89 
12.1.1.3. 
Serious Adverse Event ................................................................................................89 
12.1.2. 
Relationship to Investigational Product or Study Medication ....................................90 
12.1.3. 
Relationship to Liver Biopsy ......................................................................................91 
12.1.4. 
Recording Adverse Event Severity .............................................................................91 
12.1.4.1. 
Severity of Pruritus (as an AE) ...................................................................................92 
12.1.5. 
Reporting of Adverse Events and Serious Adverse Events ........................................93 
12.1.5.1. 
Reporting of Adverse Events ......................................................................................93 
12.1.5.2. 
Reporting of Serious Adverse Events .........................................................................93 
12.1.6. 
Additional Investigator Responsibilities for SAEs .....................................................94 
12.1.7. 
Notification of Post-Study SAEs ................................................................................94 
12.1.8. 
Follow-Up of Adverse Events and Serious Adverse Events ......................................95 
12.1.8.1. 
Pregnancy and Follow-Up ..........................................................................................95 
12.2. 
Other Safety Parameters .............................................................................................96 
12.2.1. 
Medical History/Demographics ..................................................................................96 
12.2.2. 
Physical Examination .................................................................................................96 
12.2.3. 
Vital Signs ..................................................................................................................96 
12.2.4. 
Electrocardiogram .......................................................................................................96 
12.2.5. 
Alcohol Consumption .................................................................................................97 
12.2.6. 
Laboratory Assessments .............................................................................................97 
13. 
STATISTICS ..............................................................................................................99 
13.1. 
Analysis Sets ...............................................................................................................99 
13.2. 
Determination of Sample Size ..................................................................................100 
13.3. 
General Statistical Considerations ............................................................................100 
13.4. 
Handling of Dropout and Missing Data ....................................................................100 
13.5. 
Subject Population and Demographic Characteristics ..............................................100 
13.6. 
Efficacy Analysis ......................................................................................................100 
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13.6.1. 
Primary Efficacy Analysis ........................................................................................101 
13.6.2. 
Secondary Efficacy Analysis ....................................................................................101 
13.6.3. 
Additional Exploratory Efficacy Analyses ...............................................................101 
13.6.3.1. 
Liver Biochemistry, Hepatobiliary Damage, and Liver Function ............................101 
13.6.3.2. 
Markers of Inflammation, Fibrosis, and/or Apoptosis..............................................102 
13.6.3.3. 
Glycemic Control Measures .....................................................................................102 
13.6.3.4. 
Anthropometric Measures and Blood Pressure ........................................................102 
13.6.3.5. 
Noninvasive Radiological Liver Fibrosis Measurements .........................................103 
13.6.3.6. 
Pharmacodynamic Analysis......................................................................................103 
13.6.3.7. 
Pharmacokinetic Analysis ........................................................................................103 
13.6.3.8. 
Cardiovascular Risk Scores ......................................................................................103 
13.6.4. 
LTSE Analyses .........................................................................................................104 
13.7. 
Safety Analysis .........................................................................................................104 
13.7.1. 
Adverse Events .........................................................................................................104 
13.7.2. 
Clinical Laboratory Evaluations ...............................................................................104 
13.7.3. 
Lipoprotein Evaluations ............................................................................................104 
13.7.4. 
Additional Safety Analysis .......................................................................................105 
13.7.4.1. 
Vital Signs ................................................................................................................105 
13.7.4.2. 
Electrocardiograms ...................................................................................................105 
13.7.5. 
Adjudicated Cardiovascular Events ..........................................................................105 
13.8. 
Data Monitoring Committee .....................................................................................105 
13.9. 
Adjudication Committees .........................................................................................106 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.......................................107 
14.1. 
Study Monitoring ......................................................................................................107 
14.2. 
Audits and Inspections ..............................................................................................107 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................107 
16. 
ETHICS ....................................................................................................................108 
16.1. 
Ethics Review ...........................................................................................................108 
16.2. 
Ethical Conduct of the Study ....................................................................................108 
16.3. 
Written Informed Consent ........................................................................................108 
16.4. 
Subject Confidentiality and Data Protection ............................................................109 
17. 
INVESTIGATOR OBLIGATIONS .........................................................................109 
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17.1. 
AE Reporting ............................................................................................................109 
17.2. 
Protocol Deviations ..................................................................................................110 
17.3. 
Regulatory Documentation .......................................................................................110 
17.4. 
Ethics Review ...........................................................................................................110 
17.5. 
Archiving and Record Retention ..............................................................................110 
18. 
PUBLICATION POLICY ........................................................................................111 
19. 
LIST OF REFERENCES ..........................................................................................113 
APPENDIX A. AMERICAN COLLEGE OF CARDIOLOGY/AMERICAN HEART 
ASSOCIATION GUIDANCE FOR THE USE OF STATINS .......................118 
APPENDIX B. GUIDANCE FOR ELEVATED LIVER BIOCHEMISTRY VALUES .........165 
APPENDIX C. COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS .........167 
APPENDIX D. STANDARDIZED DEFINITIONS FOR CARDIOVASCULAR 
ENDPOINT EVENTS .....................................................................................248 
APPENDIX E. ATORVASTATIN PRESCRIBING INFORMATION ...................................277 
APPENDIX F. 747-209 PROTOCOL VERSION 2 SUMMARY OF CHANGES .................310 
APPENDIX G. 747-209 PROTOCOL VERSION 3 SUMMARY OF CHANGES .................335 
APPENDIX H. 747-209 PROTOCOL VERSION 4 SUMMARY OF CHANGES .................359 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures:  Double-Blind Period ................................................41 
Table 2: 
Schedule of Study Procedures:  LTSE ........................................................................44 
Table 3: 
Medications Prohibited Prior to Randomization and/or During Study 
Participation ................................................................................................................58 
Table 4: 
List of Planned Assessments ......................................................................................85 
Table 5: 
NASH CRN Scoring System for Determining Eligibility and Primary 
Histological Endpoint Assessment .............................................................................87 
Table 6: 
Relationship of Adverse Events to Investigational Product or Study 
Medication ..................................................................................................................91 
Table 7: 
Relationship of Adverse Events to Liver Biopsy .......................................................91 
Table 8: 
Severity of Adverse Events ........................................................................................92 
Table 9: 
Severity of Pruritus .....................................................................................................92 
Table 10: List of Laboratory Analytes to be Tested ...................................................................98 
 
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LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................40 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this protocol. 
Abbreviation or Specialist Term 
Explanation 
6-ECDCA 
6α-ethyl-chenodeoxycholic acid 
A1AT 
alpha-1-antitrypsin 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ApoA1 
apolipoprotein A1 
ApoB 
apolipoprotein B 
ApoCII 
apolipoprotein CII 
ApoCIII 
apolipoprotein CIII 
ApoE 
apolipoprotein E 
AST 
aspartate aminotransferase 
β-hCG 
beta human chorionic gonadotropin 
BAS 
bile acid sequestrants 
BMI 
body mass index 
BNP 
B-type natriuretic peptide 
BUN 
blood urea nitrogen 
C4 
7α-hydroxy-4-cholesten-3-one 
CAC 
Cardiovascular Adjudication Committee 
CDCA 
chenodeoxycholic acid 
CETP 
cholesterol ester transfer protein 
CI 
confidence interval 
CK-18-M30 
cytokeratin-18 neoepitope M30 
CK-18-M65 
cytokeratin-18 neoepitope M65 
COX-2 
cyclooxygenase-2 
CPK 
creatine phosphokinase 
CRA 
Clinical Research Associate 
CRF 
case report form(s) 
CRN 
clinical research network 
CTCAE 
Common Terminology Criteria for Adverse Events 
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Abbreviation or Specialist Term 
Explanation 
DMC 
Data Monitoring Committee 
eCRF 
electronic case report form(s) 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOS 
End of Study 
ET 
Early Termination 
FGF-19 
fibroblast growth factor-19 
FLINT 
Farnesoid X Receptor Ligand Obeticholic Acid in NASH 
Treatment 
FRS 
Framingham Risk Score 
FXR 
farnesoid X receptor 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
glyco-OCA 
glycine conjugate of OCA 
GMP 
Good Manufacturing Practice 
HbA1c 
hemoglobin-specific A1c fraction 
HCC 
hepatocellular carcinoma 
HDL 
high-density lipoprotein  
HDLc 
high-density lipoprotein cholesterol 
HDPE 
High-density polyethylene 
HIV 
human immunodeficiency virus 
HMG 
3-hydroxy-3-methyl-glutaryl 
HOMA-β 
homeostatic model assessment–beta-cell function 
HOMA-IR 
homeostatic model assessment – insulin resistance 
hs-CRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 
iNOS 
inducible nitric oxide synthase 
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Abbreviation or Specialist Term 
Explanation 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISF 
Investigator site file 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
LCAT 
lecithin cholesterol acyltransferase 
LDL 
low-density lipoprotein 
LDLc 
low-density lipoprotein cholesterol 
Lp(a) 
lipoprotein(a) 
LS 
least-square 
LTSE 
long-term safety extension 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-Stage Liver Disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
nonalcoholic fatty liver disease activity score 
NASH 
nonalcoholic steatohepatitis 
NMR 
nuclear magnetic resonance 
OCA 
obeticholic acid 
PAI-1 
plasminogen activator inhibitor-1 
PBC 
primary biliary cirrhosis (also known as primary biliary 
cholangitis 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PD 
pharmacodynamics(s) 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PSC 
primary sclerosing cholangitis 
QTcF 
QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
suspected adverse reaction 
SREBP1c 
sterol regulatory element binding protein  
SUSAR 
suspected unexpected serious adverse reaction 
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Abbreviation or Specialist Term 
Explanation 
T3 
triiodothyronine 
T4 
thyroxine 
tauro-OCA 
taurine conjugate of OCA 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
TG 
triglyceride 
TNF-α 
tumor necrosis factor-α 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
VLDL 
very low-density lipoprotein 
 
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5. 
INTRODUCTION 
5.1. 
Overview of Nonalcoholic Steatohepatitis and Obeticholic Acid 
Nonalcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of 
metabolic syndrome, a cluster of closely related clinical features linked to visceral obesity and 
characterized by insulin resistance, dyslipidemia, and hypertension (Chalasani 2012, 
Angulo 2011).  NAFLD is the most common cause of chronic liver disease in the western 
hemisphere, and as the prevalence of obesity and metabolic syndrome rises, a parallel rise of 
NAFLD across the world is generally expected.  NAFLD is thought to be represented by a 
spectrum of histological disease, which progresses from pure fatty liver (simple steatosis) to 
nonalcoholic steatohepatitis (NASH).  While NAFLD itself is considered a relatively benign and 
reversible condition, up to one-third of patients in the spectrum of NAFLD develop NASH, a 
chronic, serious, life-threatening, inflammatory liver disease characterized by hepatocellular 
injury, inflammation, and progressive fibrosis.  As opposed to simple steatosis, NASH is 
associated with significant morbidity and progression that, if left untreated, can progress to 
advanced fibrosis, cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), and 
liver-related death (Vernon 2011). 
Of all the histologic features of NASH, fibrosis is considered the strongest predictor of adverse 
clinical outcomes, including liver-related death (Younossi 2011, Ekstedt 2014).  Patients with 
NASH develop progressive fibrosis over a period of 4 to 6 years (Pagadala 2012) and 21% to 
26% of these patients develop cirrhosis in 8.2 years (Loomba 2013).  In patients with NASH who 
have progressed to cirrhosis, it is estimated 38% to 45% have liver failure after 7 years to 
10 years, and 2% to 5% of this population will develop HCC per year (Organisation 2012).  
Accumulating evidence suggests that patients with NASH can progress to HCC, even in the 
absence of apparent cirrhosis (Williams 2013, Ertle 2011).  
There are currently no approved therapies for the treatment of NASH nor an accepted standard of 
care.  The therapeutic options for NASH are largely limited to lifestyle modifications and 
treatment of concurrent conditions such as diabetes (Chalasani 2012, Neuschwander-Tetri 2003, 
Sanyal 2010, Belfort 2006), although practice guidelines from the American Association for the 
Study of Liver Diseases recommend the use of vitamin E as first line therapy for patients with 
NASH without diabetes. 
In view of the serious nature of the disease, the increasing prevalence, the complications that 
arise from the disease, and the clear unmet medical need, evaluation of therapies for NASH is 
warranted. 
Obeticholic acid (OCA) is a modified bile acid and farnesoid X receptor (FXR) agonist that is 
derived from the primary bile acid chenodeoxycholic acid (CDCA).  CDCA is the natural ligand 
for FXR, which is a nuclear receptor expressed at high levels in the liver, intestine, kidney, and 
adrenal glands.  In the liver, FXR is expressed in hepatocytes, Kupffer cells, and endothelial 
cells, and at a low level in hepatic stellate cells.  Nuclear receptors constitute a family of 
ligand-activated transcription factors that can either activate or repress a variety of target genes. 
OCA is 100-fold more potent than the endogenous FXR agonist CDCA, which makes OCA an 
attractive novel therapeutic agent for NAFLD and NASH due to its multiple FXR-mediated 
effects, including an increase in insulin sensitivity, glucose and lipid metabolism; hepatocyte 
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protection against bile acid-induced cytotoxicity; anti-inflammatory effects in liver and 
vasculature; and prevention and reversal of liver fibrosis (Mudaliar 2013, Adorini 2012).  Thus, 
there is strong rationale to advance OCA for the treatment of NASH based on its FXR-mediated 
hepatoprotective properties, and results that indicate OCA improves glycemia by increasing 
peripheral glucose uptake, enhances glucose-stimulated insulin secretion, and inhibits hepatic 
lipid synthesis and content while inducing lipid uptake by adipocytes. 
5.2. 
NASH, Lipoprotein Metabolism, and Statins 
NAFLD is the most common cause of incidental abnormal serum liver enzymes and is associated 
with dyslipidemia and high-risk of cardiovascular events.  Statins have been shown to reduce the 
risk of major coronary and vascular events in NAFLD (Pastori 2015).  There has been some 
concern that patients with underlying liver disease are at an increased risk of hepatotoxicity 
because the statins are hepatically cleared and can cause elevations in liver enzymes.  However, 
there have also been studies that have shown that elevated serum transaminases secondary to 
comorbid conditions like NAFLD or NASH may be improved by statin treatment (Athyros 2010, 
Pastori 2015).  Atherogenic hyperlipidemia, which is defined by increased triglycerides (TGs), 
decreased high-density lipoprotein (HDL), and the presence of small, dense low-density 
lipoprotein (LDL), is frequently associated with NAFLD, thus the treatment of dyslipidemia 
plays a critical role in the overall management of NAFLD and NASH. 
In the Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) Trial 
conducted by the NASH Clinical Research Network (CRN) at the National Institute of Diabetes 
and Digestive and Kidney Diseases, subjects with non-cirrhotic NASH were randomized to 
either placebo or 25-mg OCA for 72 weeks (Neuschwander-Tetri 2014).  Subjects in this study 
were representative of the NASH population with baseline total cholesterol and LDL cholesterol 
(LDLc) levels at the high end of normal, HDLc levels within the normal range, and TG levels 
borderline high.  Approximately 50% of subjects were receiving antilipidemic agents at Baseline.  
Increases in total cholesterol, LDLc, and TG were observed in both treatment groups with 
OCA-treatment being associated with a somewhat greater percentage of subjects exhibiting 
increased concentrations of total cholesterol and LDLc.  Similarly, decreases in HDL cholesterol 
(HDLc) were observed in both treatment groups with a higher percentage of OCA-treated 
subjects compared with placebo.   While the OCA-related changes in lipids was modest and 
initial increases in total cholesterol and LDLc trended back towards baseline values with 
continued treatment, it is important to characterize the mechanism of OCA treatment on lipids in 
patients with NASH and the functionality of concomitant lipid therapies. 
Using nuclear magnetic resonance (NMR) lipid profiling, it will be possible to characterize the 
effect of OCA on the actual concentration and sizes of the particles within each lipoprotein class.  
While a standard lipid panel measures the cholesterol or TG content of lipoproteins, it does not 
measure the actual particle concentration.  The cholesterol and TG content of LDL, HDL, and 
very low-density lipoprotein (VLDL) particles is not constant, but varies widely among 
individuals and over time.  Even within a given lipoprotein class, the sizes of the particles are not 
uniform as the relative amounts of cholesterol and TG carried in the core of a lipoprotein particle 
varies across individuals.  Compositional differences also relate to plasma TG levels with LDL 
and HDL particles becoming more cholesterol-depleted and TG-rich as plasma TG levels 
increase.  Thus, presentation of the same measured concentration of LDL in 2 patients may 
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represent significantly different numbers of LDL particles and, therefore, a different risk for 
cardiovascular disease (Jeyarajah 2006, Otvos 2006).  The patient with the higher number of 
small, atherogenic LDL particles would be considered to be at higher cardiovascular risk.  Thus, 
NMR lipid profiling, which allows differentiation of particle size and number, will provide a 
better understanding of the mechanistic impact of OCA treatment on lipids. 
Recent evidence also suggests that HDL-mediated atheroprotection is largely governed through 
regulation of reverse cholesterol transport from macrophages within atherosclerotic plaques to 
HDL acceptor particles for ultimate return to the liver and biliary excretion (Rohatgi 2014).  
Thus, this study will also assess macrophage efflux and candidate components of this pathway to 
further elucidate the mechanism of OCA and atorvastatin treatment on lipids in the presence of 
NASH. 
5.3. 
Mechanism of Action of Obeticholic Acid 
CDCA is the principal natural ligand of FXR in humans.  When cellular levels are high, the 
negative feedback pathway inhibits the further synthesis of bile.  OCA is structurally related to 
CDCA and differs by the addition of a single ethyl group (the chemical name of OCA is 
3α 7α-dihydroxy-6α-ethyl-5βcholan-24-oic acid.  It is also referred to as 
6α-ethyl-chenodeoxycholic acid, or (6-ECDCA) and as an agonist it is approximately 100-fold 
more potent than CDCA in vitro (Pellicciari 2002).  OCA is also highly selective for FXR and 
does not bind other nuclear receptors, and with the exception of weakly activating the dedicated 
bile acid receptor TGR5, it does not activate any G-protein coupled receptors (CEREP 2008).  
OCA is an attractive novel therapeutic agent for NAFLD and NASH due to its multiple 
FXR-mediated effects including an increase in insulin sensitivity, hepatocyte protection against 
bile acid-induced cytotoxicity, anti-inflammatory effects in liver and vasculature, and prevention 
and reversal of liver fibrosis (Adorini 2012, Mudaliar 2013).  Specifically: 
• FXR and other identified bile acid receptors, such as TGR5, play a role in regulating 
key aspects of carbohydrate and lipid metabolism; thus, serving as important 
mediators of energy expenditure and metabolic homeostasis. 
• FXR agonists have been shown to suppress hepatic fatty acid and TG synthesis 
through down-regulation of sterol regulatory element binding protein (SREBP1c) and 
increase hepatic fatty acid oxidation through up-regulation of pyruvate 
dehydrogenase kinase 4 (Lefebvre 2009). 
• FXR activation has insulin-sensitizing effects.  In mice fed a high-fat diet, treatment 
with recombinant fibroblast growth factor-19 (FGF-19) improves indices of 
dyslipidemia, hepatic steatosis, hyperinsulinemia, hyperleptinemia, and insulin 
sensitivity, while reducing body weight and adiposity (Fu 2004).  Studies in FXR 
knockout mice show that FXR is involved in the regulation of insulin signaling 
pathways and the receptor appears to have a beneficial role in decreasing insulin 
resistance (both hepatic and in skeletal muscle) and gluconeogenesis, as well as in 
regulating TG, free fatty acid, and lipid levels. 
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• Treatment of OCA at doses of 25 mg and 50 mg for 6 weeks resulted in increased 
insulin sensitivity and reduced markers of liver inflammation and fibrosis in subjects 
with NAFLD and type 2 diabetes mellitus (Mudaliar 2013). 
• Treatment with OCA at a dose of 25 mg for 72 weeks was superior to placebo in 
improving not only the key histologic features important in the underlying 
pathophysiology of the disease (inflammation, ballooning, steatosis), but notably that 
OCA was superior to placebo in improving fibrosis, a strong predictor of liver-related 
death (Neuschwander-Tetri 2014). 
The FXR-SHP cascade is postulated to mediate the links between lipid and glucose metabolism 
(Zhang 2008, Cariou 2006, Rizzo 2006, Ma 2006, Shulman 2005). 
OCA induces lipid uptake by mouse adipocyte cell line (3T3-L1) and primary human adipocytes, 
which correlate with reduced hepatic and circulating lipid levels, together with increased insulin 
sensitivity (Rizzo 2009, Rizzo 2006).  Moreover, OCA significantly enhances adiponectin and 
leptin secretion by mouse and human adipocytes, which can enhance insulin sensitivity in 
peripheral tissues.  Pancreatic beta cells express FXR messenger ribonucleic acid (mRNA) and 
protein, and OCA significantly enhances insulin secretion by mouse β-TC6 cells and human 
pancreatic islets (Rizzo 2009).  
Collectively, these results indicate that OCA improves glycemia by increasing peripheral glucose 
uptake, enhancing glucose-stimulated insulin secretion, and inhibiting hepatic lipid synthesis and 
content while inducing lipid uptake by adipocytes (Adorini 2012, Mudaliar 2013). 
5.4. 
Nonclinical Experience with Obeticholic Acid 
Nonclinical studies have shown several potentially beneficial properties of FXR agonism in 
NASH, including 
Effects of OCA on glycemic, metabolic, and cardiovascular properties 
• FXR plays a role in bile acid homeostasis, metabolism, and clearance (Zhang 2008, 
Ma 2006, Cariou 2006). 
• FXR controls glucose metabolism through regulation of gluconeogenesis and 
glycogenolysis in the liver, as well as regulation of peripheral insulin sensitivity in 
striated muscle and adipose tissue (Mudaliar 2013, Zhang 2006). 
• In nonclinical models, FXR agonism is associated with beneficial effects on body 
weight and composition (Xu 2009, Fu 2004). 
• The absence of endogenous intact FXR signaling results in dyslipidemia and a hepatic 
phenotype similar to NASH patients (Zhang 2008).  Conversely, FXR agonists lower 
plasma TGs by repressing hepatic sterol regulatory element binding protein 1-c 
(Watanabe 2004) and increased hepatic fatty acid oxidation (Savkur 2005). 
• In addition, OCA and other FXR agonists are anti-atherogenic and cardioprotective in 
animal models (Hartman 2009, Miyazaki-Anzai 2010). 
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Anti-inflammatory and anti-fibrotic effects of OCA 
• OCA exerts direct effects on serum-starved LX2 cells (an immortalized hepatic 
stellate cell line) to reduce the expression of key fibrotic genes (collagen I, alpha 
smooth muscle actin, transforming growth factor β-1 and matrix metalloproteinases; 
(Albanis 2005).  
• In primary and cultured hepatocytes treated with pro-inflammatory mediators, OCA 
exerted direct effects to inhibit pro-inflammatory gene expression (eg, tumor necrosis 
factor-α [TNF-α], cyclooxygenase-2 [COX-2], and inducible nitric oxide synthase 
[iNOS]; (Wang 2008, Li 2007).  
• FXR activation (with WAY-362450) reduced inflammatory cell infiltration and 
hepatic fibrosis in a mouse model of NASH (Zhang 2009). 
• OCA improved portal hypertension in cirrhosis models (Mookerjee 2014). 
• OCA inhibited gastrointestinal inflammation and preserves intestinal barrier function 
in models of inflammatory bowel diseases (Gadaleta 2011).   
Effects of OCA on diabetic nephropathy 
• OCA ameliorates TG accumulation by modulating fatty acid synthesis and oxidation 
in a murine model of diet-induced obesity (Wang 2009) 
• In the same murine model of diet-induced obesity, OCA improves proteinuria, 
prevents podocyte loss, mesangial expansion, accumulation of extracellular matrix 
proteins, and increased expression of pro-fibrotic growth factors and fibrosis markers, 
and reduces inflammation and oxidative stress (Wang 2009) 
• In a murine model of diabetes, OCA improves renal injury by decreasing proteinuria, 
glomerulosclerosis, and tubulointerstitial fibrosis, and modulating renal lipid 
metabolism, macrophage infiltration, renal expression of SREBPs, pro-fibrotic growth 
factors, and oxidative stress enzymes (Wang 2010) 
In summary, there is strong rationale to advance OCA for the treatment of NASH based on its 
FXR-mediated hepatoprotective properties and results indicating that OCA improves glycemia 
by increasing peripheral glucose uptake, enhances glucose-stimulated insulin secretion, and 
inhibits hepatic lipid synthesis and content while inducing lipid uptake by adipocytes. 
5.5. 
Clinical Experience with Obeticholic Acid 
OCA is under investigation for the treatment of multiple chronic liver diseases, including the 
treatment of NASH, primary biliary cirrhosis (PBC, also known as primary biliary cholangitis 
[Beuers 2015a, Beuers 2015b, Beuers 2015c]), primary sclerosing cholangitis (PSC), and biliary 
atresia.  The clinical development program for OCA includes the following 3 studies conducted 
using subjects with NAFLD or NASH: 
• Study 747-203:  A proof-of-concept, Phase 2 study in subjects with type 2 diabetes and 
NAFLD to evaluate the effects of OCA on insulin sensitivity (Mudaliar 2013) 
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• FXR Ligand OCA in NASH Treatment (FLINT):  A Phase 2 study conducted by the 
National Institute of Diabetes and Digestive and Kidney Diseases and the NASH CRN to 
evaluate the efficacy and safety of OCA in the treatment of NASH 
(Neuschwander-Tetri 2014) 
• Study D8602001:  A Phase 2 study conducted by Intercept’s Asian development partner 
(Sumitomo Dainippon Pharma Co., Ltd) to evaluate the efficacy and safety of 3 doses of 
OCA versus placebo in NASH 
Study 747-203 showed improved insulin sensitivity in subjects with type 2 diabetes and NAFLD, 
demonstrating the clinical relevance of the FXR agonist pathway and supporting the potential of 
OCA to treat NAFLD and/or NASH.  With the exception of weight loss, OCA 25 mg appeared 
to be at least as effective as OCA 50 mg for the majority of endpoints evaluated.   
The FLINT study demonstrated that OCA was superior to placebo in improving not only the key 
histologic features important in the underlying pathophysiology of the disease (inflammation, 
ballooning, steatosis), but notably that OCA was superior to placebo in improving fibrosis, a 
strong predictor of liver-related death.  OCA treatment was also associated with improvement in 
markers of hepatocellular injury and some cardiometabolic features including weight and 
systolic blood pressure.  Salutary effects on weight and blood pressure are important 
considerations since patients with NASH present with higher cardiovascular risk given the 
comorbidities of obesity and diabetes.  
On average, LDL cholesterol demonstrated a significant increase in subjects treated with OCA 
compared to placebo; however, this increase was reversed and LDL cholesterol returned to 
below baseline levels in subjects who initiated statin therapy.   The change in lipid profile, which 
was attenuated with continued treatment and reversed post-treatment, needs to be further 
investigated mechanistically and with respect to clinical management with standard of care statin 
therapy.  With the exception of pruritus, which occurred more frequently in the OCA-treated 
subjects (23% OCA versus 6% placebo) and led to 1 discontinuation, the general adverse event 
(AE) profile was similar across both groups.  There were 2 deaths in the FLINT study, both in 
OCA treatment groups (one from sepsis and congestive heart failure, and the other from cardiac 
ischemia or infarction (Neuschwander-Tetri 2014).  The event of cardiac ischemia or infarction 
was assessed by the Investigator as possibly related to OCA while the event of sepsis was 
assessed as unrelated to OCA by the Investigator (Data on File). 
Study D8602001 demonstrated a dose-dependent increase in the percentage of OCA-treated 
subjects compared to placebo subjects who achieved the primary endpoint (p = 0.053, not 
significant).  The 40 mg OCA dose group achieved statistical significance for the primary 
endpoint compared to placebo (p = 0.0496).  Dose-dependent trends not reaching statistical 
significance were also observed for several other pre-specified histologic endpoints, including 
the proportion of subjects with steatosis and inflammation improvement, ballooning resolution, 
and NASH resolution.  In the completer analysis, similar dose-dependent effects were observed, 
with 51% of patients in the 40 mg dose group compared to 22% in the placebo group meeting the 
primary endpoint (p = 0.0061).  With the exception of dose-dependent pruritus, OCA appeared to 
be generally safe and well tolerated.  The number of pruritus-associated discontinuations were 0, 
0, 2, and 5 subjects in the placebo, 10 mg, 20 mg, and 40 mg OCA groups, respectively.  
Changes in lipid parameters were directionally similar to those observed in the FLINT study.  
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No other meaningful differences in the rate of AEs between the OCA and placebo groups were 
noted.  
Overall, the safety and efficacy profiles of OCA support a favorable benefit-risk ratio and 
demonstrate that OCA is a potentially important therapeutic option for patients with NASH, 
PBC, and other liver and gastrointestinal conditions.  Pruritus is the most common dose-related 
AE associated with OCA treatment, especially in subjects with cholestasis.  Other potential risks 
include liver toxicity and lipid profile abnormalities.   
5.6. 
Rationale for Study Design, Doses of Investigational Product and Use 
of Atorvastatin 
5.6.1. 
Rational for Study Design 
As described in Section 5.1, the incidence of NASH is increasing and is likely to be the leading 
cause of liver transplant by 2020, highlighting the need for development of effective therapies 
that may improve steatohepatitis and resulting fibrosis, potentially delaying liver transplant or 
death.  Given the atherosclerotic risk associated with elevations in LDL cholesterol, which are 
common in NASH, and also an observed effect of treatment with OCA, it is important to 
characterize the changes observed in circulating cholesterol associated with OCA treatment and 
the potential for management of those changes.  
FXR has been shown to play an important role in lipid homeostasis and atherosclerosis with the 
potential to modulate circulating levels of both LDL and HDL cholesterol, which are 
components of cardiovascular prognosis in rodents (Gautier 2013, Zhang 2010, Nissen 2007).  
Similarly, the FLINT study demonstrated OCA-related changes in LDL and HDL cholesterol 
(Neuschwander-Tetri 2014).  While the observed changes in LDL cholesterol in both rodents and 
humans run counter to changes that have been typically associated with improved cardiovascular 
health, animal data have consistently shown FXR agonism to be associated with reductions in 
atherosclerotic plaque formation.  Rodent studies have shown that this anti-atherogenic effect 
with FXR agonism is possibly due to an increase in the hepatic clearance of excess cholesterol 
(Mencarelli 2009, Hartman 2009, Zhang 2010).  It should be noted that the relevance of these 
findings to humans needs further evaluation due to differences in human and rodent lipid 
physiology.   
In addition to cholesterol concentration, lipoprotein particle concentration and sizes have 
emerged as important factors in the evaluation of cardiovascular risk (Jeyarajah 2006).  A recent 
Veterans Affairs study assessing LDL and HDL cholesterol concentrations, as well as particle 
size and numbers, in subjects treated with gemfibrozil demonstrated that these factors were 
stronger predictors of cardiovascular risk or benefit, respectively, than cholesterol concentrations 
(Otvos 2006).  Consistently, examination of LDL and HDL cholesterol concentrations and 
particle concentration from the Framingham Offspring cohort (n = 3066), showed that LDL 
particle concentration was more predictive of cardiovascular risk (Cromwell 2007). 
Given the complex role of FXR in lipid homeostasis, the observations of OCA on HDL and LDL 
concentrations in NAFLD and NASH, and the importance of evaluating the underlying function 
and composition of apolipoproteins, it is essential to evaluate the effect of OCA on these 
lipid-driven mechanisms of cardiovascular risk/benefit when considering OCA as a potential 
treatment for NASH. As such, this study, 747-209, will evaluate the effect of OCA on lipid 
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metabolism and the subsequent management of lipid changes with atorvastatin therapy.  
Evaluated parameters will include changes in cholesterol concentrations, lipoprotein particle size 
and number, apolipoprotein concentrations and the effects on reverse cholesterol transport in 
subjects with NASH. 
5.6.2. 
Rationale for Placebo Control Group 
The use of a randomized placebo control will provide the best scientific evidence of safety and 
efficacy of OCA in NASH subjects.  As there is no approved or proven pharmacologic therapy 
for NASH, the use of a placebo arm for comparative analysis is desired for robust analysis of 
efficacy and safety data.  As the intent of the present study is to assess the effects of multiple 
doses of OCA and the subsequent addition of atorvastatin on cholesterol metabolism as well as 
the safety and tolerability of OCA in subjects with NASH, it is important to include a placebo 
control group to understand the relationship to OCA of any changes observed.  In addition, the 
combination of OCA and atorvastatin (or any other statin) has not been previously evaluated in 
clinical studies; thus, the placebo control group, which will be treated with atorvastatin, will 
provide comparative information regarding the safety and tolerability of the OCA and 
atorvastatin combination compared to atorvastatin alone.  
5.6.3. 
Rationale for OCA Doses 
The selection of OCA doses for the present study (5 mg, 10 mg, and 25 mg) was guided by the 
available safety and tolerability data from randomized, double-blind, placebo-controlled Phase 2 
and Phase 3 studies in subjects with NAFLD, NASH, and PBC as described in Section 5.5 
above. 
In Study 747-203, subjects with type 2 diabetes and NAFLD were treated with placebo, OCA 
25 mg, or OCA 50 mg for 6 weeks.  Although both doses were similarly efficacious, there were 
clinically significant increases in the LDLc levels in both OCA dose groups, with a significant 
reduction in HDL observed in the OCA 50 mg treatment group.  Similarly, OCA was efficacious 
and well-tolerated in the subsequent, Phase 2, randomized, double-blind FLINT study, which 
evaluated OCA 25 mg and placebo in subjects with NASH over a period of72 weeks.  In this 
study, small but statistically significant changes in the levels of total cholesterol and LDLc levels 
(increase from Baseline), and HDL levels (decrease from Baseline) were observed with OCA 
treatment.  Due to the similarity in efficacy and the observed lipoprotein changes in the two 
Phase 2 studies in subjects with NASH, OCA 25 mg will be the maximum dose in this study. 
There was an increased incidence of mostly mild or moderate pruritus in OCA-treated subjects 
compared to placebo-treated subjects in the FLINT study.  Pruritus was also the most common 
AE associated with OCA in PBC studies, and has been shown to be dose-related, warranting 
evaluation of lower doses as a potential strategy to improve tolerability.  Phase 2 and Phase 3 
studies evaluating OCA for the treatment of PBC have shown that the incidence and severity of 
pruritus with OCA treatment can be mitigated with lower OCA doses of 5 mg to 10 mg.  
Therefore, based on the therapeutic effect of 10 mg in PBC and to evaluate potential attenuation 
of the effect of OCA on pruritus and serum lipid levels, both 5 mg and 10 mg daily will be 
evaluated in the proposed NASH study in addition to the 25-mg dose. 
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5.6.4. 
Rationale for the Use of Atorvastatin 
Subsequent to diet and lifestyle modification, statin therapy is recommended for the management 
of cholesterol to reduce cardiovascular risk globally (Perk 2012, NICE 2014, Stone 2014).  
Atorvastatin is one of the most commonly used statins worldwide (Jackevicius 2012).  
Historically, statin therapy has been contraindicated in subjects with elevations in liver 
aminotransferases.  However, several studies have evaluated statin use in chronic liver diseases 
where cardiovascular risk is a significant concern and the consensus findings have not shown an 
increased risk of hepatotoxicity in subjects with elevated liver aminotransferases.  Calderon et al 
reported that statin treatment is safe and can improve both liver aminotransferase levels and 
reduce cardiovascular morbidity (Calderon 2010, Tikkanen 2013, Athyros 2010). 
The increase in LDL cholesterol levels in the OCA-treated NASH population observed in 
clinical studies may predispose these subjects to increased cardiovascular risk.  Atorvastatin is 
one of the most widely prescribed statins for dyslipidemia in North America (Jackevicius 2012, 
Jackevicius 2013).  The atorvastatin prescribing information suggests a starting dose of 10 mg, 
with dose adjustments every 2 to 4 weeks.  In line with this recommendation, all subjects will be 
started at an atorvastatin dose of 10 mg at Week 4, titrating to 20 mg atorvastatin at Week 8 (if 
10 mg daily is tolerated), and allowing for further dose adjustments at Week 12 based on clinical 
need and Investigator discretion. 
In addition to mitigating the potential risk of statin use in this population by initiating treatment 
at the lowest indicated dose (10 mg once daily), subjects with excessive (>300 U/L) elevations in 
alanine aminotransferase (ALT), pre-existing cardiovascular disease, and those with elevated 
cardiovascular risk (eg, unstable hypertension) will be excluded.  Finally, liver function, 
cholesterol levels, and vital signs will be monitored at all visits in this study, and investigational 
product will be withdrawn or its dosing interrupted in subjects who develop elevated levels of 
liver enzymes per protocol discontinuation criteria (see Section 8.4.1).  
5.6.4.1. 
Rationale for Statin Withdrawal  
The intent of this study is to assess the increase in LDL cholesterol with OCA and then to 
determine the extent to which this can be mitigated with appropriate use of statin therapy.  
Therefore, participating subjects need to either be statin-free or have washed off of their current 
statin therapy.  Given the clear role of statins in reducing cardiovascular risk, it is imperative to 
minimize the potential risk associated with withdrawing statin therapy.  These steps include 
minimizing the duration of statin withdrawal and exclusion of subjects for whom removal of 
statin therapy is of significant concern.  
Duration of statin withdrawal 
A statin withdrawal period of 5 weeks was selected and is similar to other recent studies in 
statin-using patients where a 4-week washout period was employed (Teramoto 2012, 
Teramoto 2014).  The extra week in the present study allows for the assessment of LDL levels 
after 4 weeks of washout, and based on prior studies, assumes levels of LDL to be stable after 
4 weeks, and enables the stratification of subjects at randomization on Day 1 by this value.   
Following randomization, subjects will be treated with OCA or placebo for 4 weeks prior to the 
introduction of atorvastatin.  Based on data in healthy subjects, PBC, and NAFLD, 4 weeks is 
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sufficient to observe peak changes in LDL and HDL cholesterol due to OCA alone in most 
subjects.   
Overall, statin therapy will be withheld from subjects for a maximum of 9 weeks:  5 weeks prior 
to randomization on Day 1 and 4 weeks following randomization.  This duration of statin 
withdrawal is less than the combined withdrawal period used in the Teramoto et al study, which 
included a group of subjects who had statin therapy withheld for a total of 16 weeks (4 week 
washout period followed by 12 weeks of placebo treatment) (Teramoto 2014).  There was no 
appreciable difference in the safety profile of these patients compared to those who had statin 
therapy reintroduced after the washout period.  Further support for the minimal impact of 
short-term discontinuation of statins is seen in follow-up analyses of the Treating to New Target 
study which showed that even in patients with stable coronary artery disease, that a 6-week 
interruption of statin therapy did not acutely impact cardiac events (McGowan 2004). 
Exclusion of subjects at elevated risk 
Subjects where the removal of a statin would be considered to be clinically concerning are 
excluded from participation in this study.  At risk subjects include subjects with existing 
cardiovascular disease (including but not limited to stable or unstable angina, previous 
myocardial infarction or stroke or a previous peripheral or coronary revascularization procedure), 
significant dyslipidemia (as defined by LDLc ≥190 mg/dL) despite the use of statin therapy, 
unstable hypertension, and familial hypercholesterolemia. 
Safety monitoring during the off-statin period 
All subjects will have frequent safety assessments prior to and following the reintroduction of 
statin therapy.  Following Screening Visit 1, subjects will have 4 visits to the study site over the 
9-week period prior to initiation of atorvastatin:  Screening Visit 2/Week -1, 
Randomization/Day 1, Week 2 and Week 4.  During these visits AEs, vital signs, and safety labs 
will be assessed and monitored by the site staff.   
5.6.5. 
Rationale for Duration of Treatment 
In the clinical studies where healthy subjects and subjects with PBC were treated with OCA, 
changes in cholesterol were evident by 2 weeks of treatment.  Accordingly, the effect of OCA on 
lipoprotein metabolism, prior to the introduction of atorvastatin, will be assessed at 2 and 
4 weeks of treatment to evaluate the change in these parameters and the effect of sustained 
treatment with OCA; all subjects will then initiate atorvastatin therapy, in addition to their 
blinded treatment, and the effect on lipoprotein metabolism will be evaluated over an additional 
12 weeks.  The total duration of the double-blind phase of the study is 16 weeks, which is 
sufficient to evaluate the effect of atorvastatin on the OCA treatment-induced alterations in the 
lipoprotein profile of statin-naïve and statin-washed out NASH subjects. 
Following the double-blind phase, subjects may volunteer to continue in a 2-year open-label 
long-term safety extension (LTSE) during which all subjects will receive OCA.  During the 
LTSE, LDL cholesterol will be managed as clinically indicated.  The LTSE will evaluate the 
long-term safety of OCA and atorvastatin treatment and the effect of OCA and atorvastatin on 
histological markers of NASH.  
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5.6.6. 
Rationale for Timing of Unblinding Process and Implications in LTSE 
As Study 747-209 is a randomized, double-blind study, the double-blind data will not be 
unblinded until all double-blind data are final and the database is locked.  Accordingly, all 
subjects continuing in the LTSE, Investigators, and the Sponsor will remain blinded to subjects’ 
double-blind treatment regimen.  Subjects who were receiving placebo or 5 mg OCA in the 
double-blind phase will be randomized to receive either OCA 10 mg or OCA 25 mg in the 
LTSE.  Subjects who were receiving OCA 10 mg or OCA 25 mg in the double-blind phase will 
continue on the same dose throughout the LTSE.  Using this approach, blinding of the trial will 
be maintained. 
5.7. 
Summary of Known Potential Risks with Investigational Product 
The primary AE shown to be related to OCA is pruritus.  Pruritus has also been observed in 
clinical studies with OCA in other indications, as well as in healthy subjects, with the highest 
frequency observed in subjects with PBC. 
An increase in liver enzymes and hepatic AEs, including jaundice, were observed in subjects 
with liver disease at OCA doses between 10 mg and 50 mg.  Elevated liver enzymes were 
observed in healthy subjects who were treated at doses ≥100 mg in Phase 1, multiple-dose 
studies; however, these elevations were only considered to be of clinical concern at the 
maximum dose of 250 mg daily. 
Changes in lipid profiles have also been observed with OCA dosing, including a decrease in 
HDL cholesterol and an increase in LDL cholesterol.  The clinical significance of these lipid 
findings remains unclear and is being studied further.  HDL levels have generally remained 
within normal limits in subjects treated with OCA.  While LDLc levels increased with OCA 
treatment, the changes were modest, and trended toward baseline values with continued 
treatment through to 72 weeks. 
Refer to the Investigator’s Brochure (IB) for additional information regarding the known 
potential risks with the investigational product. 
5.8. 
Summary of Known Potential Risks with Atorvastatin 
Muscle complaints are the most frequent adverse reports among patients treated with statins with 
the most severe side effects including myopathy and rhabdomyolysis.  The Statin Muscle Safety 
Task Force (Rosenson 2014) has provided a classification of the spectrum of statin-associated 
muscle AEs that may be seen in clinical practice and can be used in characterizing reports of 
muscle-related events.  
a. Myalgia – unexplained muscle discomfort often described as “flu-like” symptoms 
− Muscle aches 
− Muscle soreness 
− Muscle stiffness 
− Muscle tenderness 
− Muscle cramps with or shortly after exercise (not nocturnal cramping) 
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b. Myopathy – muscle weakness (not attributed to pain and not necessarily associated 
with elevated CPK) 
c. Myositis – muscle inflammation 
d. Myonecrosis – muscle enzyme elevations or hyperCPKemia 
− Mild >3x baseline or ULN 
− Moderate ≥10x baseline or ULN 
− Severe ≥50x baseline or ULN 
e. Clinical Rhabdomyolysis - Myonecrosis with myoglobinuria or acute renal failure 
(increase in serum creatinine ≥0.5 mg/dL  
There is no evidence that these muscle-related AEs are a continuum beginning with myalgia and 
progressing to more severe manifestations of myopathy; rather events occur independent of each 
other.  Myalgia events, with frequencies ranging from 1% to 5% in clinical trials to 11% to 29% 
in observational cohorts, typically occur within 1 month of statin initiation and resolve within 
2 weeks of statin cessation (Rosenson 2014).  Retrospective analyses have suggested that 
patients who discontinue statins due to intolerance are able to tolerate statins long-term following 
re-challenge (Zhang 2013, Mampuya 2013).   
Historically, statins have been associated with biochemical abnormalities of liver function, but 
available data suggest that increases in liver transaminases associated with statins are 
asymptomatic and generally reversible (Desai 2014).  In the absence of liver disease, US 
guidelines (Stone 2013) recommend that baseline transaminase levels should be checked before 
initiating statin therapy and subsequent testing should only be done in the presence of symptoms 
suggestive of hepatic disease.  As this study is being conducted in subjects with confirmed 
NASH, liver enzymes will be frequently monitored and Section 8.4.1.3, Section 8.4.2.2, and 
Appendix B provide detailed guidance for handling elevated liver biochemistry values.  
Statins modestly increase the risk of type 2 diabetes mellitus in individuals with risk factors for 
diabetes.  Individuals receiving statin therapy should be evaluated for new-onset diabetes 
according to the current diabetes screening guidelines (American Diabetes Association 2013). 
Confusion and memory loss have been reported with statins, but medical evidence supporting a 
causal effect is weak or nonexistent (Simic 2015).  However, any reports of cognitive events 
should be appropriately evaluated, particularly in individuals whose symptoms persist despite 
statin discontinuation. 
In this study, any AEs (including signs and symptoms described above) regardless of relationship 
to investigational product or study medication, must be documented appropriately 
(see Section 12). 
If treatment with statins is initiated, women of childbearing potential must be informed that statin 
use is contraindicated during pregnancy.  Methods of contraception should be reviewed and 
modified, if necessary, to ensure highly effective methods with failure rates <1% per year, such 
as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual 
abstinence, or history of vasectomy of partner are used. 
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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of the study is: 
• To evaluate the effect of OCA on LDL metabolism in subjects with biopsy-confirmed 
NASH and to assess the ability of atorvastatin to modulate this effect 
6.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the safety and tolerability of OCA alone and in combination with 
atorvastatin therapy in subjects with biopsy-confirmed NASH 
• To evaluate the effect of OCA with and without atorvastatin therapy, on  
− HDL, VLDL, TGs, total cholesterol, and apolipoprotein concentrations 
− Components of the reverse cholesterol transport pathway 
6.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To evaluate the effect of OCA on  
− Liver biochemistry, inflammation, and apoptosis 
− Markers of glucose metabolism including C-peptide, insulin, fasting plasma 
glucose, hemoglobin-specific A1c fraction (HbA1c), homeostatic model 
assessment–beta-cell function (HOMA‑β), and homeostatic model assessment – 
insulin resistance (HOMA-IR) 
− Anthropometric measures including height (measured at Screening Visit 1 only), 
weight, and waist and hip circumference measurements; and body mass index 
(BMI), and waist-to-hip ratio calculations 
− Cardiovascular risk scores (eg, Framingham Risk Score [FRS] and Reynolds 
score) 
• To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of OCA and its 
conjugates 
• To evaluate the bioanalytical concentrations of atorvastatin and its metabolites 
• To evaluate improvement in noninvasive-radiological assessment of fibrosis via 
transient elastography (TE; at sites where available) 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This Phase 2, double-blind, randomized, placebo-controlled, multicenter study, with an 
open-label LTSE, will evaluate the effect of OCA, and the subsequent addition of statin therapy, 
on lipoprotein metabolism in subjects with NASH with fibrosis stage 1 to 4, but no evidence of 
hepatic decompensation.  Approximately 80 subjects with histological evidence of definite or 
probable NASH, who meet all inclusion and none of the exclusion criteria will be enrolled in 
the study.  The histological evidence of definite or probable NASH will be based on the central 
read of a liver biopsy obtained no more than 1 year prior to randomization and a nonalcoholic 
fatty liver disease activity score (NAS) of 4 or greater.  Subjects not using statin therapy 
(ie, statin-free) and statin-treated subjects may be enrolled.  Statin-treated subjects will be 
required to stop statin treatment (after signing informed consent) for up to 5 weeks, including 
a 4-week statin washout period, prior to Randomization/Day 1. 
Screening Period: 
Subjects will have a screening period of up to 5 weeks prior to Randomization/Day 1.     
Subjects using statins within 30 days of the initial Screening Visit (Screening Visit 1) are 
required to stop statin therapy immediately following this initial visit and must undergo a 4-week 
statin washout period prior to Screening Visit 2.  At Screening Visit 2 these subjects will have a 
pre-randomization visit for assessment of their fasting LDL cholesterol levels.  Subjects with 
fasting LDL cholesterol values >200 mg/dL at Screening Visit 2 will be excluded from the study 
and their dyslipidemia should be managed according to standard of care.  
Subjects who are not using statin therapy at Screening Visit 1 are required to provide a fasting 
blood sample at Screening Visit 2, which can occur at any time prior to randomization but after 
signing of the ICF.  Statin free subjects with fasting LDL cholesterol values >200 mg/dL at 
either Screening Visit will be excluded from the study and should be managed according to 
standard of care. 
Double-Blind Phase: 
At the Randomization (Day 1) Visit, subjects will be randomized in a 1:1:1:1 ratio to receive 
OCA 5 mg, OCA 10 mg, OCA 25 mg, or placebo, orally, once daily, for 16 weeks.  
Randomization will be stratified by the pre-randomization fasted serum LDL cholesterol 
concentration (≤125 mg/dL or >125 mg/dL) and baseline fibrosis stage (stage 1, 2 or stage 3, 4). 
At the Week 4 Visit, all subjects will initiate treatment with atorvastatin at a dose of 10 mg once 
daily.  At the Week 8 Visit, atorvastatin will be increased to 20 mg once daily (if 10 mg daily is 
tolerated), and continued for an additional 4 weeks.  After 4 weeks of treatment at 20 mg, the 
atorvastatin dose may be titrated (up or down) as clinically indicated.  The final visit during the 
double-blind phase will occur at Week 16, after which subjects may continue into the open-label 
LTSE.  
Subjects who discontinue investigational product or atorvastatin during the double-blind phase 
are still expected to attend scheduled study visits and are to be followed through the Week 16 
Visit. 
Page 39 of 364


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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures:  Double-Blind Period 
Study Visits 
Screening 
Visit 1a 
Screening 
Visit 2b 
Randomi-
zation/ Day 1 
Wk 2 
Wk 4 
Wk 6 
(Contact) 
Wk8 
Wk 10 
(Contact) 
Wk 12 
Wk 14 
(Contact) 
Wk 16/ 
LTSE Day 1 
ET/ 
EOSc 
Week 
-5 to -1 
-1 to 1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
 
Visit Window (Days) 
-35 to -7 
-7 to -1 
 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±7c 
STUDY PROCEDURES 
Fast ≥8 h Prior to Visit 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Vital Signsd  
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Anthropometric Measurese 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
12- Lead 
Electrocardiogram 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
AUDIT Alcohol Intake 
Questionnaire  
X 
 
X 
 
 
 
 
 
 
 
X 
X 
Liver Biopsyf  
X 
 
 
 
 
 
 
 
Transient Elastographyg 
X 
X 
X 
 
 
 
 
X 
X 
AEsh 
Xh 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization/Treatment 
Assignedi 
 
 
Xi 
 
 
 
 
 
 
 
Xi 
 
Dispense/Administer 
Investigational Productk 
 
 
X 
X 
X 
 
X 
 
X 
 
Xj 
 
Dispense/Administer 
Open-Label Atorvastatink 
 
 
 
 
X 
 
X 
 
X 
 
Xj 
 
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Table 1: 
Schedule of Study Procedures:  Double-Blind Period (Continued) 
Study Visits 
Screening 
Visit 1a 
Screening 
Visit 2/ 
Wk -1b 
Randomi-
zation/ 
Day 1 
Wk 2 
Wk 4 
Wk 6 
(Contact) 
Wk8 
Wk 10 
(Contact) 
Wk 
12 
Wk 14 
(Contact) 
Wk 16/ 
LTSE 
Day 1 
ET/ 
EOSc 
Collect 
Bottles/Investigational 
Product 
Accountability/Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect Bottles/Atorvastatin  
Accountability/Compliance 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
CLINICAL LABORATORY EVALUATIONSk 
Hepatitis B Virus and 
Hepatitis C Virus Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistryl, m 
/Hematology/ Coagulation 
Parameters 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Lipoprotein Analysesn 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Reverse Cholesterol 
Transport Analyteso 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
PD Assessments 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Markers of Inflammation, 
Fibrosis, and Apoptosis 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vitamin D 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Markers of Glucose 
Metabolism Including 
C-peptide, Insulin, Fasting 
Plasma Glucose, and 
HbA1cp 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Thyroid Function Tests:  
T3, T4, and TSH 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Urinalysis  
X 
 
X 
 
 
 
 
X 
X 
Pregnancy Testq 
Xq 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Blood Sample for Future 
Exploratory Analysisr 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
PK Assessmentss 
 
 
Xs 
 
 
 
 
 
 
 
Xs 
 
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AE = adverse event; AUDIT = Alcohol Use Disorders Identification Test; β-hCG = beta human chorionic gonadotropin; BMI = body mass index;  
CPK = creatine phosphokinase; EOS = End of Study; ET = Early Termination; HbA1c = hemoglobin-specific A1c fraction; hs-CRP = high-sensitivity C-reactive 
protein; PD = pharmacodynamics; PK = pharmacokinetics; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; Wk = Week 
Note:  No study-related procedures, including Screening procedures, will be performed prior to obtaining informed consent from the subject.  Historical 
procedures (eg, liver biopsy samples collected, FibroScan) completed as part of standard of care, may be used for screening analysis if collected within the 
allowed windows specified in the protocol. 
a  Subjects using statins within 30 days of Screening are required to stop administering statin therapy after Screening Visit 1, and must complete a 4-week statin 
washout prior to performing assessments at Screening Visit 2. 
b  Screening Visit 2 is required for all subjects.  All subjects must have been fasting for at least 8 hours prior to the visit.  The Randomization/Day 1 Visit may occur 
as soon as screening labs are available and eligibility is confirmed for all subjects.  For subjects undergoing a 4-week washout period, Screening Visit 2 may 
occur on day 28 (±1) day of the washout period.  For subjects not taking statins at Screening Visit 1, Screening Visit 2 can occur at any time within 28 days after 
Screening Visit 1.  All Screening assessments must be completed ≤35 days prior to the Randomization/Day 1 Visit. 
c  The ET Visit will occur as soon as possible upon study discontinuation and as near as possible to last dose taken.  The EOS Visit will occur ±1 week (7 days) 
relative to the EOS date announced by the Sponsor. 
d  Sitting heart rate, blood pressure, body temperature, and respiratory rate. 
e  Weight, waist and hip circumference (and height at Screening Visit 1).  BMI and waist-to-hip ratio will be calculated via electronic data capture (EDC). 
f  Liver biopsy will be performed to histologically confirm NASH only if slides from historic biopsy (within 1 year of Day 1) are not available.  A central reader 
designated by the Sponsor will perform all biopsy scoring; the results of which must be available prior to randomization on Day 1. 
g  Transient elastography (TE) will be conducted at selected trial sites where the FibroScan® TE device is available.  TE is scheduled for Screening Visit 1; however, 
it may be performed any time after Screening Visit 1 and prior to randomization.  In addition, if TE has been done within 3 months of Day 1 and a report/adequate 
data are available, a pretreatment TE at Day 1 is not required. 
h  AEs occurring after the signing of the informed consent form (ICF) must be entered on the AE eCRF. 
i   Only those subjects who were statin naive at Screening or who have successfully completed the washout period and meet all other inclusion criteria, and none 
of the exclusion criteria, may be randomized.  Subjects randomized to placebo or OCA 5 mg during the double-blind period will be randomized to OCA 10 or 
25 mg during the LTSE. 
j  Only applies to subjects continuing in LTSE. 
k  Blood samples for all analyses will be collected predose (before administering investigational product or atorvastatin) on indicated visit days. 
l  CPK will be assessed in all subjects at Screening Visit 2 and as clinically indicated, including anytime myopathy is suspected. 
m  Serum chemistry will include a basic lipid panel and also liver biochemistry panel (see Table 10). 
n  Serum and plasma samples will be collected for lipoprotein analysis, which will include cholesterol concentration in LDL, HDL, and VLDL, their particle 
concentration and sizes; concentrations of apolipoprotein (Apo)A1, ApoB, ApoE, ApoCII, ApoCIII and Lp(a); and proprotein convertase subtilisin/kexin type 
9 (PCSK9).  
o  Reverse cholesterol transport analysis will include following analytes:  Pre-β1 HDL concentration, macrophage cholesterol efflux, lecithin cholesterol 
acyltransferase activity, and cholesterol ester transfer protein activity. 
p  The homeostatic model assessment–beta-cell function (HOMA-β) and homeostatic model assessment – insulin resistance (HOMA-IR) indexes will be 
calculated using fasting plasma glucose and serum insulin values. 
q  Serum pregnancy test will be administered if urine-based β-hCG pregnancy test is positive.  Screening pregnancy tests will be serum-based tests. 
r  Includes markers of cardiovascular risk (adiponectin, plasminogen activator inhibitor-[(PAI-1], and B-type natriuretic peptide [BNP]). 
s  At selected investigational sites, subjects will have the option to provide blood samples for measurement of PK for OCA (Day 1 and Week 16), and for 
atorvastatin (Week 16).  PK samples will be collected within 30 minutes prior to dosing and again at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose.  
Subjects should not drink additional water for 1 hour after taking the dose of investigational product and will remain fasted until the 1 hour sample is collected. 
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Table 2: 
Schedule of Study Procedures:  LTSE 
 
 
Annual Schedule (Year 1 through Study Termination)b 
Study Visits 
Month 1a 
Month 3, 
Month 15 
Month 6,  
Month 18 
Month 9,  
Month 21 
Month 12 
EOS/ETc 
Visit Windows (weeks) 
±1 
±1 
±1 
±1 
±1 
±1/ N/Ac 
STUDY PROCEDURES 
Fast ≥8 h Prior to Visit 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
X 
X 
12-Lead Electrocardiogram 
 
X 
X 
X 
X 
X 
Vital Signsd 
X 
X 
X 
X 
X 
X 
Anthropometric Measurese 
 
X 
X 
X 
X 
X 
AUDIT Alcohol Intake Questionnaire 
 
 
X 
 
X 
X 
AEs 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
Transient Elastographyf 
 
X 
X 
Dispense/Administer Investigational Productg 
 
X 
X 
X 
X 
 
Dispense/Administer Atorvastating,h,i 
 
X 
X 
X 
X 
 
Collect Bottles/Investigational Product 
Accountability/Compliance 
X 
X 
X 
X 
X 
X 
Collect Bottles/Atorvastatin  
Accountability/Compliance 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSg 
Serum Chemistryj,k/Hematology/ Coagulation Parameters 
X 
X 
X 
X 
X 
X 
Lipoprotein Analysesl 
 
X 
X 
X 
X 
X 
Reverse Cholesterol Transport Analysism 
 
 
X 
 
X 
X 
PD Assessments 
 
X 
X 
X 
X 
X 
Markers of Inflammation, Fibrosis, and Apoptosis 
 
X 
X 
X 
X 
X 
Vitamin D 
 
X 
X 
X 
X 
X 
Markers of Glucose Metabolism Including C-peptide, 
Insulin, Fasting Plasma Glucose, HbA1cn 
X 
X 
X 
X 
X 
X 
Thyroid Function Tests:  T3, T4, and TSH 
 
 
 
 
X 
X 
Urinalysis  
 
 
 
 
X 
X 
Urine Based β-hCG Pregnancy Testo 
X 
X 
X 
X 
X 
X 
Blood Sample for Future Exploratory Analysisp 
 
 
 
 
X 
X 
 
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AE = adverse event; AUDIT = Alcohol Use Disorders Identification Test; β-hCG = beta human chorionic gonadotropin; BMI = body mass index;  
CPK = creatine phosphokinase; EOS = End of Study; ET = Early Termination; HbA1c = hemoglobin-specific A1c fraction; PD = pharmacodynamics;  
T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone 
a  The first visit after start of LTSE (Month 1 Visit) is relative to Week 16 Visit of the double-blind phase (LTSE Day 1 Visit).   
b  After the Month 12 Visit, the procedures will be performed as listed for Month 3, Month 6, and Month 9 visits (at 15 months, 18 months, and 21 months, 
respectively, into the LTSE). 
c  The ET Visit will occur as soon as possible upon study discontinuation and as near as possible to last dose taken.  The EOS Visit will occur ±1 week (7 days) 
relative to the EOS date announced by the Sponsor. 
d  Sitting heart rate, blood pressure, body temperature, and respiratory rate. 
e  Weight, waist and hip circumference.  BMI and waist-to-hip ratio will be calculated via electronic data capture (EDC). 
f  Transient elastography (TE) will be conducted during the LTSE at selected trial sites where the FibroScan® TE device is available. 
g  Blood samples for all analyses will be collected predose (before administering investigational product) on indicated visit days. 
h  Atorvastatin may be continued or subjects may change or discontinue statins as clinically indicated. 
i  NOTE:  Any time atorvastatin is up-titrated or re-initiated, a telephone safety contact must be conducted to assess AEs, concomitant medications, and 
atorvastatin compliance. 
j CPK will be assessed in all subjects only as clinically indicated, including anytime myopathy is suspected, in subjects taking statins. 
k  Serum chemistry will include a basic lipid panel and liver biochemistry panel (see Table 10).   
l  Serum samples will be collected for lipoprotein analyses, which will include cholesterol concentration in LDL, HDL, and VLDL, their particle concentration 
and sizes; concentrations of apolipoprotein (Apo)A1, ApoB, ApoE, ApoCII, ApoCIII and Lp(a); and proprotein convertase subtilisin/kexin type 9 (PCSK9). 
m Reverse cholesterol transport analysis will include following analytes:  Pre-β1 HDL concentration, macrophage cholesterol efflux, lecithin cholesterol 
acyltransferase activity, and cholesterol ester transfer protein activity. 
n The homeostatic model assessment–beta-cell function (HOMA-β) and homeostasis model assessment – insulin resistance (HOMA-IR) indexes will be 
calculated using fasting plasma glucose and serum insulin values. 
o  Serum pregnancy test will be administered if urine-based β-hCG pregnancy test is positive. 
p  Blood sample for future exploratory analysis, including markers of cardiovascular risk (adiponectin, plasminogen activator inhibitor-[(PAI-1], and B-type 
natriuretic peptide [BNP]). 
 
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7.1.3. 
Study Duration 
The overall study duration is up to 125 weeks including a Screening period of up to 5 weeks 
(depending on current statin use), a 16-week double-blind treatment phase, and a 2-year, 
open-label LTSE.  The LTSE may be terminated earlier by the Sponsor if OCA becomes 
commercially available, or for other reasons as described in Section 8.4.3. 
7.2. 
Number of Subjects 
Approximately 80 subjects who meet the eligibility criteria, including biopsy-confirmed NASH 
and evidence of liver fibrosis, but no hepatic decompensation, will be included in this study.  A 
maximum of 30% of subjects will have stage 4 fibrosis. 
7.3. 
Treatment Assignment 
Eligible subjects will be randomized into 4 groups in a 1:1:1:1 ratio to receive OCA 5 mg, 
OCA 10 mg, OCA 25 mg, or placebo during the double-blind phase of the study.  
Randomization will be stratified by LDL concentration (fasting serum LDL cholesterol at 
Screening Visit 2; ≤125 mg/dL or >125 mg/dL) and baseline fibrosis stage (stage 1, 2 or stage 3, 
4).  All subjects will also receive atorvastatin starting at Week 4 at 10 mg daily, escalating to 
20 mg at Week 8 (if 10 mg daily is tolerated), with further dose adjustments to be performed as 
clinically indicated at Week 12, and throughout the LTSE phase.  Subjects will receive 
open-label OCA 10 mg or OCA 25 mg during the LTSE depending on their double-blind 
randomized dose (see Section 7.1 ).  The study design schematic is shown in Figure 1.  
7.4. 
Dose Adjustment Criteria 
7.4.1. 
Investigational Product Dose Adjustments 
Dose adjustments of investigational product are not permitted during the double-blind phase.  
Please refer to Section 8.4.4 for instructions regarding subject withdrawal if investigational 
product is discontinued. 
During the LTSE phase, all subjects will be treated with open-label OCA 10 mg or 25 mg.  
Subjects randomized to placebo or OCA 5 mg during the double-blind phase will be 
re-randomized in a 1:1 ratio through IWRS to OCA 10 mg or OCA 25 mg upon entry into and 
throughout the LTSE phase.  Subjects randomized to OCA 10 mg will continue to receive OCA 
10 mg throughout the LTSE.  Subjects randomized to OCA 25 mg will continue to receive OCA 
25 mg throughout the LTSE.  Subjects may continue with atorvastatin therapy as clinically 
indicated.  
7.4.2. 
Atorvastatin Dose Adjustments 
For all subjects, atorvastatin therapy will be initiated at a dose of 10 mg at Week 4.  At Week 8 
the dose will be increased to 20 mg (if 10 mg daily is tolerated), and following the Week 12 
Visit, the dose can be adjusted to manage cholesterol as clinically indicated (Section 9 and 
Appendix A).  During the LTSE, subjects may continue with atorvastatin therapy as clinically 
indicated. 
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If at any time during the double-blind or LTSE phases, serum chemistry results indicate 
LDLc<40 mg/dL, the subject should be brought back to the site within 1 to 2 weeks after the first 
result is obtained for an unscheduled (repeat) laboratory assessment.  If LDLc<40 mg/dL is 
obtained on 2 consecutive visits, the subject may discontinue or reduce the dose of atorvastatin. 
Subjects may also interrupt or discontinue atorvastatin due to tolerability issues including 
muscle-related symptoms (Section 5.8) and abnormal liver biochemistry.  Any muscle-related 
complaints should be assessed per the ACC/AHA Guidelines (Appendix A) and statin dose 
adjusted accordingly:   
• To avoid unnecessary discontinuation of statins, obtain a history of prior or current 
muscle symptoms to establish a baseline prior to initiation of statin therapy. 
• If mild to moderate muscle symptoms develop during statin therapy: 
− Discontinue the statin until symptoms can be evaluated. 
− Evaluate the patient for other conditions that might increase the risk for muscle 
symptoms. 
− If muscle symptoms resolve, and if no contraindication exists, re-challenge the 
subject with the same or a reduced dose of atorvastatin to establish a causal 
relationship between the muscle symptoms and statin therapy. 
− Once a low dose statin is tolerated, the dose may be gradually increased as 
tolerated and clinically indicated. 
− If after 2 months without statin treatment, muscle symptoms or elevated CPK 
levels do not completely resolve, consider other causes of muscle symptoms. 
− If persistent muscle symptoms are determined to arise from a condition unrelated 
to statin therapy, or if the predisposing condition has been treated, resume statin 
therapy at the original dose. 
• If unexplained severe muscle symptoms or fatigue develop during statin therapy, 
discontinue the statin and address the possibility of rhabdomyolysis by evaluating CPK 
and serum creatinine, and performing urinalysis for myoglobinuria. 
Elevations in liver biochemistry should be monitored per protocol subject withdrawal criteria 
(Section 8.4 and Appendix B). 
Subjects who discontinue atorvastatin may continue on investigational product through the 
double-blind and LTSE phases, as deemed appropriate by the Investigator and Medical Monitor, 
and provided they continue to meet exclusion criteria #4 (LDLc <200 mg/dL). 
7.4.3. 
Safety Criteria for Adjustment or Stopping of Doses of Investigational Product 
The Data Monitoring Committee (DMC) will review safety data from this study as well as other 
ongoing OCA studies on a periodic basis (Section 13.8).  Adjustments to or discontinuation of 
treatment may be considered based on DMC evaluation of OCA safety and tolerability.  The 
criteria for study termination are described in Section 7.5.  
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7.5. 
Criteria for Study Termination 
The Sponsor reserves the right to terminate the study at any time.  It is normal procedure to 
review the emerging clinical and safety data.  As a result of such a review or a recommendation 
by the DMC, it may be necessary to stop the study before all subjects have completed the study.  
In addition, the Sponsor may terminate the study at an investigational site, at any time (eg, Good 
Clinical Practice [GCP] noncompliance, poorly performing sites, as determined by the number of 
subjects enrolled or the quality of the study data). 
The Investigator and/or the Sponsor (or designee) must notify the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) of discontinuation of a site or the study and the 
reason(s) for doing so. 
Investigators will be informed by the Sponsor as to when the final study visit is to be completed, 
and should then schedule all subjects for the End of Study (EOS) or Early Termination (ET) 
Visit. 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Population 
Approximately 80 subjects with biopsy-confirmed NASH without evidence of hepatic 
decompensation who meet eligibility criteria will be enrolled at approximately 30 investigational 
sites in the US.  Prospective subjects will be identified primarily from the hospital and/or 
physician’s database of patients with NASH, or may be referred from other physicians.  Subjects 
may self-refer to an Investigator if they become aware of the study through local, national, or 
international NASH patient societies, forums, or networks.  Subjects will be selected according 
to the inclusion and exclusion criteria below. 
8.2. 
Subject Inclusion Criteria 
Subjects must satisfy all of the following criteria to be eligible for enrollment:  
1. Age ≥18 years of age 
2. Histologic evidence of NASH, as assessed by central reading of a liver biopsy obtained 
no more than 1 year prior to randomization, defined by the presence of all 3 key 
histological features of NASH with a score of at least 1 for each and a combined score of 
4 or greater out of a possible 8 points according to NASH CRN criteria.  
3. Histologic evidence of fibrosis stage 1 to stage 4 (as defined by NASH CRN scoring of 
fibrosis) without any evidence of hepatic decompensation. 
4. If subject has type 2 diabetes, is on stable dose of anti-diabetic medication (except 
thiazolidinediones [TZDs]) for ≥3 months prior to Day 1. 
5. Is either not taking or is on stable doses of TZDs and/or Vitamin E for ≥6 months prior to 
Day 1 
6. Contraception:  Female subjects of childbearing potential must use ≥1 effective method 
of contraception during the study and until 30 days following the last dose of 
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investigational product.  Effective methods of contraception are considered to be those 
listed below.  
• Barrier method, ie, condom (male or female) with spermicide or diaphragm with 
spermicide  
• Intrauterine device 
• Vasectomy (partner) 
• Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection) 
• Abstinence (defined as refraining from heterosexual intercourse).  
7. Must provide written informed consent and agree to comply with the study protocol, 
including adherence to protocol-described statin withdrawal and statin therapy. 
8.3. 
Subject Exclusion Criteria 
Subjects who satisfy any of the following exclusion criteria will be ineligible for enrollment:  
1. Current or history of significant alcohol consumption for a period of more than 
3 consecutive months within 1 year prior to Screening Visit 1 (significant alcohol 
consumption is defined as more than 2 units/day in females and more than 4 units/day in 
males, on average). 
2. Prior intolerance to treatment with atorvastatin or other 3-hydroxy-3-methyl-glutaryl 
(HMG) Coenzyme A reductase inhibitors (including but not limited to rhabdomyolysis). 
3. LDLc ≥190 mg/dL and already on statin therapy at Screening Visit 1.  
4. LDL cholesterol >200 mg/dL at any Screening Visit in subjects who are not on statin 
therapy, or at Screening Visit 2 in statin washout subjects. 
5. Planned change in diet or exercise habits during participation in the double-blind period, 
or a significant weight change of >5% in the prior 6 months. 
6. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) 
or ileal resection or plan to undergo either of these procedures.  
7. History of biliary diversion. 
8. Uncontrolled diabetes defined as HbA1c ≥9.5% within 60 days prior to randomization 
(Day 1). 
9. Administration of any of the following medications as specified below: 
• Prohibited 30 days prior to Day 1:   
− bile acid sequestrants (BAS) including cholestyramine and its derivatives, 
colesevelam, colestipol, or 
− omega-3 fatty acid containing dietary supplements 
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• Prohibited 3 months prior to Day 1:   
− nicotinic acid and derivatives, ezetimibe, or  
− any prescription or over-the-counter medication or herbal remedy with putative 
NASH efficacy (except Vitamin E or TZDs), or  
− ursodeoxycholic acid, or 
− fenofibrate or other fibrates, or 
− Any over-the-counter or health foods used to treat lipids including plant sterols 
and berberine 
• Prohibited 6 months prior to Day 1:   
− azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate, mofetil, 
pentoxifylline; budesonide and other systemic corticosteroids; or 
− potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, 
isoniazide, or nitrofurantoin) 
• Prohibited 12 months prior to Day 1:  
− antibodies or immunotherapy directed against interleukins, or  
− other cytokines or chemokines 
10. Evidence of other forms of known chronic liver disease including but not limited to:  
• Positive test result at Screening for hepatitis B surface antigen  
• Active hepatitis C virus (HCV) infection (positive for HCV ribonucleic acid [RNA] at 
Screening) or history of positive HCV RNA test result 
• PBC, PSC, autoimmune hepatitis or overlap syndrome 
• Alcoholic liver disease 
• Wilson’s disease or hemochromatosis or iron overload as defined by presence of 3+ 
or 4+ stainable iron on liver biopsy  
• Alpha-1-antitrypsin (A1AT) deficiency as defined by diagnostic features in liver 
histology (confirmed by A1AT level less than normal; exclusion at the Investigator’s 
discretion) 
• Prior known drug-induced liver injury within 5 years before Day 1 
• Known or suspected HCC  
11. History of liver transplant, current placement on a liver transplant list, or current Model 
for End-Stage Liver Disease (MELD) score >12.  Subjects who are placed on a transplant 
list despite a relatively early disease stage (eg, per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria. 
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12. Presence of hepatic decompensation including: 
− Gastroesophageal varices 
− Ascites 
− Hepatic encephalopathy 
− Spontaneous bacterial peritonitis 
− Hepatorenal or hepatopulmonary syndromes 
13. Total bilirubin ≥2x upper limit of normal (ULN) at any Screening Visit (subjects with 
Gilbert’s syndrome may be enrolled despite a total bilirubin level >2x ULN if their 
conjugated bilirubin is <2x ULN)  
14. Creatine phosphokinase (CPK) >5x ULN at Screening Visit 2 
15. Serum creatinine ≥1.5 mg/dL at any Screening Visit 
16. Serum ALT >300 U/L at any Screening Visit 
17. Platelet count <75 000 /mm3 at any Screening Visit 
18. Known positivity for human immunodeficiency virus (HIV) infection 
19. Subjects with recent history (within 1 year of randomization) of cardiovascular disease or 
with history or planned cardiovascular interventions to treat atherosclerotic 
cardiovascular disease, including: 
a) Peripheral or Coronary revascularization (percutaneous coronary intervention or 
coronary artery bypass grafting) 
b) Coronary angioplasty, stenting, or carotid atherectomy 
c) Cardiac pacemaker or defibrillator (placement of cardiac pacemaker or defibrillator 
for reasons other than atherosclerotic cardiovascular disease [eg, for treatment of 
atrial fibrillation subsequent to nodal ablation] is not exclusionary) 
d) Prosthetic heart valves 
e) Myocardial infarct, unstable angina, or acute coronary syndrome 
f) Other clinically significant atherosclerotic cardiovascular disease 
g) Cerebrovascular accident (stroke), cerebrovascular ischemia, or transient ischemic 
attack 
h) Unstable hypertension 
i) Familial hypercholesterolemia or other genetic lipid abnormality 
20. Other concomitant disease, malignancy, or condition likely to significantly decrease life 
expectancy to <5 years, including known cancers (except carcinomas in situ or other 
stable, relatively benign conditions such as chronic lymphocytic leukemia) and moderate 
to severe congestive heart failure. 
21. Known substance abuse, including inhaled or injected drugs in the year before Screening 
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22. For female subjects:  pregnancy, planned pregnancy, potential for pregnancy and 
unwillingness to use effective birth control during the study, or breastfeeding  
23. Participation in a clinical research study with any investigational product being evaluated 
for the treatment of diabetes or NASH in the 6 months before Day 1  
24. Receipt of any investigational product not being evaluated for the treatment of diabetes or 
NASH from Screening Visit 1 to Day 1, within 30 days prior to Day 1, or within 
5 half-lives of the compound before Day 1 (whichever was longer) 
25. Previous exposure to OCA 
26. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components 
27. Mental instability or incompetence, such that the validity of informed consent or ability 
to be compliant with the study is uncertain 
28. Any other condition which, in the opinion of the Investigator, would impede compliance 
or hinder completion of the study  
29. Acute cholecystitis or acute biliary obstruction 
8.4. 
Subject Withdrawal Criteria 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product or 
Atorvastatin 
8.4.1.1. 
Adverse Events ≥Grade 3 in Severity and Possibly, Probably, or Definitely 
Related to Investigational Product 
If a subject experiences an AE that is ≥Grade 3 in severity (Section 12.1.4) that is considered 
possibly, probably, or definitely related to investigational product, the investigational product 
must be discontinued. 
8.4.1.2. 
Pregnancy 
Whenever the site is notified of a possible pregnancy, the subject should be asked to come in for 
an unscheduled visit to perform a serum pregnancy test.  If a female subject becomes pregnant, 
she must discontinue treatment with investigational product and atorvastatin immediately, but 
should continue with the study visit schedule and must be followed by the Investigator through 
pregnancy outcome.  The mother (and infant) will be followed as considered appropriate by the 
Investigator and the Medical Monitor.  As described in Section 12.1.8.1, pregnancy is not 
considered an AE for reporting purposes. 
8.4.1.3. 
Severe Drug-Induced Liver Injury 
If a subject develops signs and symptoms of a severe drug-induced liver injury, regardless of 
causality, investigational product and atorvastatin should be interrupted until the event has 
resolved or returned to baseline, but the subject should continue with the study visit schedule.  
Subjects who develop significant drug-induced liver injury, which is considered to be causally 
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related to the investigational product or atorvastatin, should be discontinued from investigational 
product or atorvastatin, as appropriate and should not be rechallenged.  Significant injury as 
described in Appendix B, and includes evidence of functional hepatic impairment as indicated by 
rising bilirubin or INR.  Natural progression of the underlying condition and other causal factors 
such as a common bile duct stone or development of other concurrent liver disease should be 
considered before the investigational product is permanently discontinued.   
Severe drug induced-liver injury that is not considered related to investigational product or 
atorvastatin must be discussed with the Sponsor before investigational product or atorvastatin is 
reinitiated.  Follow-up procedures for subjects resuming treatment, including laboratory 
evaluations and physical examinations, must be performed after a maximum of 2 weeks of 
re-treatment and may be conducted at a local clinic if the subject is unable to return to this site.  
Results must be reported immediately to the site so the Investigator can determine if the subject 
is to be allowed to continue treatment.  Subjects who discontinue due to significant drug-induced 
liver injury must be followed until the AE has resolved, stabilized, or is not of clinical concern. 
8.4.1.4. 
Myonecrosis 
Moderate myonecrosis as defined by creatine kinase ≥10x the untreated baseline levels or ULN.  
Muscle-related symptoms that do not necessitate mandatory discontinuation of investigational 
product or atorvastatin are detailed in Section 5.8. 
8.4.2. 
Reasons for Mandatory Interruption of Investigational Product 
8.4.2.1. 
Adverse Events ≥Grade 4 in Severity and Not or Unlikely Related to 
Investigational Product 
If a subject experiences an AE categorized as ≥Grade 4 in severity and not or unlikely related to 
investigational product, at least a mandatory interruption of investigational product is required. 
8.4.2.2. 
Suspected Mild or Moderate Drug-Induced Liver Injury  
Because transient fluctuations of ALT or AST are common, and progression to severe drug-
induced liver injury or acute liver failure is uncommon, automatic discontinuation of 
investigational product with an elevation of ALT or AST that is >3x ULN/baseline/nadir or total 
bilirubin >2x ULN/baseline/nadir, as described in Appendix B, may be unnecessary.  If a subject 
develops signs of a mild or moderate event of drug-induced liver injury, regardless of causality, 
investigational product should be interrupted until the event has resolved or returned to baseline, 
but the subject should continue with the study visit schedule.  The subject may restart treatment 
after resolution of the event or return to baseline.  Follow-up procedures, including laboratory 
evaluations and physical examinations, must be performed after a maximum of 2 weeks of 
re-treatment and may be conducted at a local clinic if the subject is unable to return to the site.  
Results must be reported immediately to the site so the Investigator can determine if the subject 
will be allowed to continue treatment. 
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8.4.3. 
Other Reasons for Study or Treatment Discontinuation of Subjects 
A reasonable effort must be made to determine the reason(s) why a subject fails to return for 
his/her final visit or is discontinued from the study.  This information and date must be recorded 
on the appropriate electronic case report form (eCRF).  The following events are considered 
appropriate reasons for a subject to discontinue from the study: 
• The subject decides that it is in his/her best interest.  It is fully understood that all 
subjects volunteer for the study and that they may withdraw their consent to continue 
in the study at any time 
• The Investigator or Sponsor considers that it is advisable or in the best interest of the 
subject  
• There is a major violation of the clinical study protocol 
• Noncompliance of the subject 
• An inability to provide plasma or urine samples 
8.4.4. 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor as soon as possible if any subject prematurely 
discontinues from the study.  The date when the subject is withdrawn and the reason for 
discontinuation must be recorded in the eCRF; additional information may be requested by the 
Sponsor to complete a discontinuation narrative.  Subjects will be considered “lost to follow-up” 
only after reasonable, documented attempts to reach the subject prove unsuccessful.  In all cases, 
a reasonable effort must be made to determine the reason(s) that a subject fails to return for 
required study visits or discontinues from the study.  This information must be documented in 
the eCRF. 
If a subject is withdrawn from the study early (regardless of the cause), all of the ET evaluations, 
with the exception of PK procedures, should be performed at the time of withdrawal, to the 
extent possible. 
9. 
TREATMENT OF SUBJECTS 
9.1. 
Investigational Product and Atorvastatin Treatment Regimen 
While placebo, OCA, and atorvastatin are all study medications provided by the Sponsor, for the 
purposes of this protocol, investigational product refers to OCA or placebo, and study 
medication, where used, refers to atorvastatin. 
Four treatment groups will be evaluated:  placebo, OCA 5 mg, OCA 10 mg, and OCA 25 mg.  
Each dose will be made up of 1 tablet (ie, 1 placebo tablet, 1 OCA 5-mg tablet, 1 OCA 10-mg 
tablet, or 1 OCA 25-mg tablet).  The list of excipients included in the tablets are provided in the 
IB. 
Investigational product will be taken orally with water, once daily for the duration of the study.  
Subjects will be instructed to begin dosing on Day 1 and are to take investigational product at 
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approximately the same time each day.  Subjects must be instructed to swallow the tablets whole 
with water; they must not chew, divide, or crush the tablets. 
9.1.1. 
Double-Blind Period 
Subjects enrolled in the study will be randomized to receive one of the following treatments: 
OCA 5 mg, OCA 10 mg, OCA 25 mg, or placebo, starting on Day 1. 
At the Week 4 Visit, all subjects will also initiate treatment with atorvastatin at a dose of 10 mg 
once daily.  At the Week 8 Visit, atorvastatin will be increased to 20 mg once daily (if 10 mg 
daily is tolerated), and continued for an additional 4 weeks.  After 4 weeks of treatment at 20 mg, 
the atorvastatin dose may be titrated (up or down) at the Week 12 Visit as clinically indicated 
using the atorvastatin prescribing information and the guidance for lipid management (see 
Appendix A).  Blinded treatment with investigational product and open-label atorvastatin will 
continue through the Week 16 Visit.  Investigational product will be dispensed in bottles of 
30 tablets. 
9.1.2. 
LTSE 
Subjects who complete the Week 16 Visit of the double-blind phase will be able to participate in 
an open-label LTSE.  The Week 16 Visit of the double-blind phase will be Day 1 of the LTSE 
phase of the study. 
Following completion of Week 16 Visit procedures, all subjects will be treated with open-label 
OCA 10 mg or OCA 25 mg.  Subjects randomized to placebo or OCA 5 mg during the 
double-blind phase will be randomized in a 1:1 ratio to receive OCA 10 mg or OCA 25 mg upon 
entry into and throughout the LTSE phase.  Subjects randomized to OCA 10 mg or OCA 25 mg 
during the double-blind phase will continue on the same dose throughout the LTSE.    
Investigational product during the LTSE period will be dispensed in bottles of 30 or 100 tablets, 
and subjects will be instructed to take one or more tablets per day per his/her OCA dose 
assignment.  During the LTSE phase, the dose of atorvastatin may remain the same as during the 
double-blind phase or may be modified as clinically indicated per atorvastatin prescribing 
information and lipid management guidelines (Appendix A). 
9.2. 
Concomitant Medications 
Relevant information about all concomitant medications (including prescribed, over-the-counter, 
or herbal preparations) taken prior to (ie, within 12 months of Day 1) and during the study must 
be recorded in the source documents and eCRF, as well as any dose or dose regimen changes that 
occur during the study. 
9.2.1. 
Medications with Potential NASH-Modifying Properties 
Doses of TZDs and Vitamin E should be stable 6 months before Day 1 through Week 16.  
Ideally, subjects should generally remain on baseline TZDs and/or Vitamin E throughout both 
the double-blind and LTSE phases of the study unless the baseline therapy is no longer 
considered clinically appropriate by the Investigator. 
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9.2.2. 
Diabetes-Specific Therapy 
All diabetes-specific therapies except TZDs should be at a stable dose for ≥3 months prior to 
Day 1 through Week 16.  TZDs must be at a stable dose for ≥6 months prior to Day 1 through 
Week 16.  Ideally, subjects should remain on Baseline diabetes-specific therapies through the 
end of the LTSE, but will be allowed to make changes if the Baseline therapy is no longer 
considered clinically appropriate by the Investigator.  
9.2.3. 
Management of Changes in Cholesterol 
During the double-blind phase of the study, the dose of atorvastatin administration should be as 
described in this protocol through Week 12 unless tolerability issues develop as referenced in 
Section 7.4.2.  At the Week 12 Visit, Investigators may increase or decrease the dose of 
atorvastatin as clinically indicated. 
During the LTSE, Investigators may add or change the management of treatment as clinically 
appropriate.  Appendix A provides a general guidance for cholesterol management including 
monitoring, triggers for intervention, and treatment goals. 
9.2.4. 
Prohibited Medications 
The medications prohibited per the study enrollment exclusion criteria and or during the study 
are listed below and summarized in Table 3: 
• Prohibited 30 days prior to Day 1:   
− BAS including cholestyramine, colesevelam, colestipol, or 
− omega-3 fatty acid containing dietary supplements 
• Prohibited 3 months prior to Day 1 and throughout the double-blind period:   
− nicotinic acid and derivatives, ezetimibe, or  
− fenofibrate or other fibrates 
− any over-the-counter or health foods used to treat lipids including plant sterols 
and berberine 
• Prohibited 3 months prior to Day 1 and throughout the double-blind period and 
LTSE: 
− any prescription or over-the-counter medication or herbal remedy with putative 
NASH efficacy (except Vitamin E or TZDs)  
− ursodeoxycholic acid 
• Prohibited 6 months prior to Day 1 and throughout the double-blind period and 
LTSE: 
− azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate, mofetil, 
pentoxifylline; budesonide and other systemic corticosteroids;  
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− potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, 
isoniazide, or nitrofurantoin) 
• Prohibited 12 months prior to Day 1 and throughout the double-blind period:  
− antibodies or immunotherapy directed against interleukins or  
− other cytokines or chemokines 
• Prohibited throughout the double-blind phase of the study: 
− weight loss drugs including appetite suppressants (eg, orlistat, lorcaserin) 
− medications contraindicated in the atorvastatin label, including HIV and 
Hepatitis C protease inhibitors, clarithromycin, and itraconazole (refer to 
atorvastatin prescribing information in Appendix E for complete list).  These 
medications are also prohibited during the LTSE phase if the subject continues to 
receive atorvastatin during the LTSE. 
• Prohibited during the double-blind and LTSE phases of the study: 
− medications historically associated with NAFLD including:  amiodarone, 
tetracyclines, tamoxifen, estrogens (at doses greater than those used for hormone 
replacement), anabolic steroids 
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Table 3: 
Medications Prohibited Prior to Randomization and/or During Study Participation 
 
Use Prohibited Prior to Randomization 
Use Prohibited During Study 
Medications 
-12 Months 
-6 Months 
-3 Months 
-30 Days 
Double-Blind 
Phase 
LTSE 
Bile acid sequestrants including 
cholestyramine, colesevelam, 
colestipol 
 
 
 
X 
 
 
Omega-3 fatty acid containing dietary 
supplements 
 
 
 
X 
 
 
Nicotinic acid and derivatives 
 
 
X 
X 
X 
 
Ezetimibe 
 
 
X 
X 
X 
 
Fenofibrate or other fibrates 
 
 
X 
X 
X 
 
Any over-the-counter or health foods 
used to treat lipids including plant 
sterols and berberine 
 
 
X 
X 
X 
 
Any prescription or over-the-counter 
medication or herbal remedy with 
putative NASH efficacy (except 
Vitamin E or TZDs ) 
 
 
X 
X 
X 
X 
Ursodeoxycholic acid 
 
 
X 
X 
X 
X 
Azathioprine, colchicine, 
cyclosporine, methotrexate, 
mycophenolate, mofetil, 
pentoxifylline; budesonide and other 
systemic corticosteroids 
 
X 
X 
X 
X 
X 
Potentially hepatotoxic drugs 
(including α-methyl-dopa, sodium 
valproic acid, isoniazide, or 
nitrofurantoin) 
 
X 
X 
X 
X 
X 
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Table 3: 
Medications Prohibited Prior to Randomization and/or During Study Participation (Continued) 
 
Use Prohibited Prior to Randomization 
Use Prohibited During Study 
Medications 
-12 Months 
-6 Months 
-3 Months 
-30 Days 
Double-Blind 
Phase 
LTSE 
Antibodies or immunotherapy 
directed against interleukins 
X 
X 
X 
X 
X 
 
Other cytokines or chemokines 
X 
X 
X 
X 
X 
 
Weight loss drugs including appetite 
suppressants (eg, orlistat, lorcaserin) 
 
 
 
 
X 
 
HIV and Hepatitis C protease 
inhibitors, clarithromycin, 
itraconazole 
 
 
 
 
X 
X 
Medications historically associated 
with NAFLD including:  amiodarone,  
tetracyclines, tamoxifen, estrogens (at 
doses greater than those used for 
hormone replacement), anabolic 
steroids 
 
 
 
 
X 
X 
Note:  For clarity, only prior months and study periods with prohibited use are indicated with “X”; other periods with no restrictions are shaded grey. 
 
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9.2.5. 
Standard of Care and Other Concomitant Medications 
With the exception of Vitamin E, TZDs and other diabetes-specific therapy, allowed concomitant 
medications should be at a stable dose 30 days before Day 1.  Concomitant medications will be 
used at the discretion of the usual care provider (or Investigator if also the usual care provider).  
Relevant information about all concomitant medications taken before (ie, within 12 months of 
Day 1; Table 3) and during the study must be recorded in the source documents and eCRF, as 
well as any dose or dose regimen changes that occur during the study. 
Subjects taking BAS (including cholestyramine and its derivatives, colestipol, colesevelam, or 
other sequestrants) or aluminum hydroxide- or smectite-containing antacids should be instructed 
to stagger their dosing of investigational product, ensuring at least 4 hours between doses of the 
BAS and/or antacids and the investigational product (ie, BAS should be administered 4 hours 
before or 4 hours after investigational product administration). 
Taken concomitantly, OCA and warfarin may decrease INR, thus INR should be monitored and 
the dosage of warfarin adjusted, as needed, to maintain the target INR range. 
The effect of OCA on drug metabolizing enzymes has been evaluated in both in vitro and clinical 
studies.  The PK profile of caffeine, a sensitive CYP1A2 substrate, showed weak effect of OCA 
on CYP1A2.  Based on these results, OCA may increase the exposure of narrow therapeutic 
index drugs that are substrates for CYP1A2, such as theophylline and tizanidine. 
9.3. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of investigational product 
and open-label atorvastatin on an ongoing basis throughout the study and confirm by conducting 
drug accountability (ie, count of returned tablets) during subjects’ onsite visits. 
Subjects should be instructed to retain all bottles of investigational product and atorvastatin, even 
if empty, and to return them to the Investigator at the subsequent visit (refer to Table 1 and 
Table 2).  The Investigator or designee should perform drug accountability and, if applicable, 
follow up with the subject to retrieve any investigational product and atorvastatin bottles that 
have not been returned.  
If the Investigator has concerns about a subject’s dosing compliance s/he should discuss this with 
the subject, assess the reasons for noncompliance and the likelihood that the subject will remain 
noncompliant, and notify the Sponsor accordingly.  Continued study eligibility should be 
assessed based on the subject’s compliance with investigational product and atorvastatin dosing 
and clinic visits. 
9.4. 
Randomization and Blinding 
The initial phase of the study will be conducted in a double-blind, placebo-controlled manner.  
Enrolled subjects will be randomized in a 1:1:1:1 ratio to 1 of 4 treatment groups (OCA 5 mg, 
OCA 10 mg, OCA 25 mg, or placebo) based on a predefined randomization code (generated by 
Sponsor or designee) using an IWRS.  The IWRS will serve as the investigational product 
inventory and management system and may be integrated with the study database.  
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The Investigator or designee will be required to register the subject in the IWRS and may be 
prompted to provide patient data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned and investigational product (OCA or 
placebo) dispensing information will be provided (eg, bottle numbers allocated) while 
maintaining the study blind.  The subjects, Investigator, and study site staff will be blinded to the 
subjects’ treatment allocation in the double-blind phase of the study until all subjects have 
completed the double-blind phase of the study and the database is locked. 
In the LTSE phase, all subjects will be treated with open-label OCA 10 mg or OCA 25 mg: 
subjects randomized to placebo or OCA 5 mg during the double-blind phase will be randomized 
in a 1:1 ratio to receive OCA 10 mg or OCA 25 mg upon entry into and throughout the LTSE 
phase, and subjects randomized to OCA 10 mg or OCA 25 mg during the double-blind phase 
will continue on the same dose throughout the LTSE.   
9.4.1. 
Stratification 
In order to ensure that factors with the potential to affect treatment response are randomized in 
equal proportions to the different treatment groups, subjects will be stratified by LDL cholesterol 
concentration (Screening Visit 2 LDL cholesterol value for statin washout subjects or Screening 
LDL cholesterol value for statin-free subjects).  Randomization will be stratified by the 
pre-randomization fasted serum LDL cholesterol concentration (≤125 mg/dl or >125 mg/dL) and 
baseline fibrosis stage (stage 1, 2 or stage 3, 4). 
9.4.2. 
Emergency Unblinding Procedures 
Randomization codes and corresponding treatment assignments will be made available to the 
Investigator and the Medical Monitor for emergency use only through the IWRS system.  When 
possible, the Medical Monitor should be consulted in the event that a medical emergency 
necessitates unblinding (ie, in situations where knowledge of the blinded treatment is necessary 
for further medical management of the subject).  If it is not reasonable to inform the Medical 
Monitor in advance of unblinding, the Investigator must promptly document the case in the 
subject’s source record.  Subsequently, the Investigator should contact the Medical Monitor to 
explain any premature unblinding of treatment assignment (eg, accidental unblinding or 
unblinding due to a serious AE [SAE]).  Procedures for unblinding a subject’s treatment will be 
provided separately to the Investigator.  The Medical Monitor will document within study 
correspondence the rationale, circumstances, and the person(s) being informed about the 
unblinding.   
The DMC (refer to Section 13.8) will have access to the IWRS and will be able to unblind 
individual subjects.  The DMC will review aggregate data during closed sessions.  The DMC 
will document details about any subject who was unblinded in the closed session DMC minutes, 
which will be made available to the Sponsor only after the double-blind database is locked and 
unblinded.  
Access to randomization codes and corresponding treatment assignments will also be made 
available through the IWRS system to the appropriate, named individual(s) responsible for 
reporting SAEs and suspected unexpected serious adverse reactions (SUSARs) to the regulatory 
authorities. 
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9.5. 
Assignment of Site and Subject Numbers 
9.5.1. 
Site Numbers 
Each study site selected to participate in this study will be assigned a Site Number by the 
Sponsor.  The Site Number will be used to categorize subject data and to identify the site and or 
Investigator within study documents.  This number will be recorded in the eCRF. 
9.5.2. 
Subject Numbers 
Subjects will be identified by a unique 6-digit number.  The first 3 digits will represent the site 
number and the last 3 digits, the Screening number, which will be assigned sequentially by the 
site. 
9.6. 
Restrictions 
9.6.1. 
Fasting Requirement at Study Visits 
All subjects must have been fasting for at least 8 hours prior to Screening Visit 2 (Week -1 Visit) 
and all subsequent study visits, as all analytes will be assayed in fasting blood, serum, or plasma 
samples (Table 1 and Table 2).  Water is permitted during the fasting period. 
If the subject reports having eaten within 8 hours, the information will be documented 
accordingly in the source and eCRF and the subject will be reminded that at least 8-hour fasting 
is required prior to all study visits, but water is permitted.  The blood sample will still be 
collected during the visit with the exception of Screening Visit 2, which will require 
rescheduling of the visit. 
9.6.2. 
Grapefruit and Grapefruit Juice 
Grapefruit and grapefruit juice consumption should be discouraged following initiation of 
atorvastatin due to possible increases in plasma concentration of atorvastatin (please refer to 
atorvastatin prescribing information [Appendix E]). 
9.6.3. 
Diet and Exercise 
Consistent with the exclusion criteria (Section 8.3), subjects should not make significant changes 
to their diet and exercise habits during the double-blind phase.  This is not intended to override 
physician advice for lifestyle modification, and inclusion in the study should preferably be after 
lifestyle modifications have been made and are stable. 
9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
All Screening assessments should occur ≤35 days prior to the Randomization/Day 1 Visit.  
Subjects who are taking statins at the time of screening or within 30 days of Screening Visit 1 are 
required to stop statin therapy for 4 weeks (28 (±1) days), and provide a fasting blood sample at 
Screening Visit 2 to confirm eligibility.  Subjects who have not taken statins within 30 days of 
Screening Visit 1 are not required to enter into the washout period and may proceed to Screening 
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Visit 2 to provide a fasting blood sample.  The Randomization/Day 1 Visit may occur as soon as 
all screening labs are available and eligibility is confirmed. 
All visits during the double-blind phase will be relative to Day 1 (eg, if the Week 2 Visit occurs 
4 days late, the Week 4 Visit should still be 4 weeks from Day 1), and should occur within 
±4 days of the visit day.  The timing of all study visits during the LTSE is relative to 
Week 16/LTSE Day 1.  LTSE Visits should occur within ±1 week of the visit day. 
The visit windows are summarized below: 
Visit or Procedure 
Visit Window and/or Interval 
Screening Visit 1 
Visit(s) are to occur ≤5 weeks (35 days) prior to Day 1.  
Screening Visit 2 (Week -1) 
±1 day  
Randomization (Day 1) 
This is the day of Randomization and the first day of dosing with 
investigational product.  On-treatment visit scheduling should be 
calculated from this point going forward unless stated otherwise.  
Week 2, Week 4, Week 8, and 
Week 12 
±4 days; the visits during double-blind phase will be relative to Day 1 
(ie, first dose of investigational product) 
Week 6, Week 10, and Week 14 
(Contact visits) 
±4 days 
Week 16 (LTSE Day 1) 
±4 days 
LTSE Visits:  Month 1, Month 3, 
Month 6, Month 9, Month 12, 
Month 15, Month 18, and Month 21 
±1 week (7 days); the LTSE visits are relative to LTSE Day 1 (ie, 
Week 16 of double-blind phase) 
EOS 
±1 week (7 days) relative to the EOS date announced by the Sponsor 
ET 
As soon as possible upon study discontinuation and as near as possible to 
last dose taken 
EOS = End of Study; ET = Early Termination 
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose possible risks and benefits of the 
study to the subject and will provide him/her with a copy of the written information and 
informed consent form (ICF).  The subject will be given sufficient time to consider the study 
before deciding whether or not to participate.  The subject will be informed that participation is 
voluntary and that his/her future medical treatment will not be compromised by participation in 
the study and that he or she can withdraw from the study at any time.  The subject must be 
willing and able to provide written informed consent before entering the study.  The Investigator 
or a medically qualified designee is responsible for administering and documenting the written 
informed consent of the subject.  The subject will be given a copy of the written information 
sheet and his/her signed and dated consent form).  At selected study sites, subjects will have the 
option to consent to participate in an additional PK assessment.  Subjects may also be required to 
sign a new consent form prior to entering the LTSE phase of the study.  Subjects will be 
requested to provide blood samples for exploratory future analysis of analytes such as 
adiponectin, plasminogen activator inhibitor-1(PAI-1), and B-type natriuretic peptide (BNP; 
Table 10).    
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9.7.3. 
Screening Visit 1 Procedures  
The Screening Visit assessments must be performed ≤5 weeks prior to Day 1 to determine 
whether the subject meets all the inclusion criteria and none of the exclusion criteria.  Subjects 
who do not fulfill all eligibility criteria will not be enrolled in the study.   
Subjects who are statin-free (ie, no statin use within 30 days of Screening) must return for fasted 
serum chemistry labs at Screening Visit 2, and may proceed to the Randomization/Day 1 Visit 
once screening labs are available and eligibility is confirmed; subjects who need to wash out 
statin therapy are required to return for Screening Visit 2 following the washout period.   
Screening Visit procedures for all subjects are as follows: 
• Review ICFs and obtain signatures before performing any study-related procedures, 
including Screening procedures. 
• Collect medical history. 
• Verify inclusion and exclusion criteria for eligibility. 
• Perform a physical examination. 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure).  
• Assess and record anthropometric measures:  body weight, waist and hip 
circumference, and height. 
• Determine alcohol consumption (using AUDIT questionnaire). 
• Assess availability of liver biopsy samples:  If >1 year since last biopsy, schedule 
pretreatment biopsy.  Liver biopsies conducted within 1 year of Day 1, for which 
unstained slides can be obtained and submitted for central review, are considered 
adequate for study entry.  All samples must be submitted for central read such that the 
report is available prior to Day 1.  
• For participating sites only:  TE is scheduled for Screening Visit 1; however, it may 
be performed any time between Screening Visit 1 and prior to Randomization 
(Day 1).  In addition, if TE has been done within 3 months of Day 1 and a 
report/adequate data is/are available, a pretreatment TE at Day 1 is not required.     
• Assess and record any pretreatment-emergent AEs (after the ICF has been signed). 
• Record prior (if within 12 months of Day 1) and current concomitant medications. 
• Obtain serum sample for hepatitis B surface antigen or hepatitis C antibody (and 
positive HCV ribonucleic acid [RNA]) testing to confirm study eligibility. 
• Schedule laboratory visit for fasted blood samples for  
− Serum chemistry (includes basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
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• Obtain urine sample for urinalysis. 
• Perform serum pregnancy test in females of childbearing potential. 
• Instruct the subject to fast overnight (at least 8 hours) before the next visit (water is 
permitted). 
Additional Screening Visit 1 procedure for subjects currently taking statins: 
• Subjects who are currently taking statins, defined as statin use within 30 days of 
Screening, will be instructed to discontinue statin therapy following Screening 
Visit 1.  After 4 weeks of statin washout, subjects will return for Screening Visit 2 to 
provide blood samples for fasted serum chemistry. 
9.7.4. 
Screening Visit 2 Visit Procedures 
All subjects will return for Screening Visit 2 to confirm eligibility criteria and provide blood 
samples for fasted serum chemistry. 
For subjects who were receiving statin therapy at the time of screening: 
• Verify that subjects have completed a 4-week washout period. 
For all subjects: 
• Review inclusion and exclusion criteria for eligibility. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and eCRF. 
− If the subject reports having eaten within 8 hours, the visit should be rescheduled. 
• Obtain blood samples for  
− Serum chemistry (will include basic lipid and liver biochemistry panel), 
hematology, and coagulation 
− CPK 
• Assess and record pretreatment-emergent AEs. 
• Assess and record new concomitant medications. 
• For participating sites only:  Perform TE if not done during Screening Visit 1 or a 
report/adequate data from a scan done within 3 months and Day 1 is/are not available. 
9.7.5. 
Randomization/Day 1 Visit Procedures  
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and eCRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that at least 8-hour fasting is required 
prior to all study visits, but water is permitted. 
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• Review inclusion and exclusion criteria for eligibility. 
• Perform a standard 12-lead ECG. 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record anthropometric measures:  body weight, and waist and hip 
circumference. 
• Determine alcohol consumption (using AUDIT questionnaire). 
• Assess and record any pretreatment-emergent AEs. 
• Record prior (since Screening Visit 1) and current concomitant medications. 
• For participating sites only:  Perform TE if not done during Screening Visit 1 or 
Screening Visit 2, or if a report/adequate data from a scan done within 3 months and 
Day 1 is/are not available. 
• Obtain blood samples for: 
− Serum chemistry (includes basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
− Lipoprotein analyses and reverse cholesterol transport analytes 
− CPK, if myopathy suspected 
− PD assessments; markers of inflammation, fibrosis and apoptosis; and markers of 
glucose metabolism (see Table 4 and Table 10) 
− Vitamin D 
− Blood sample for future exploratory analysis of biomarkers adiponectin, PAI-1, 
and BNP 
− Thyroid Function Tests:  TSH, T4, and T3 
− Possible analysis of conjugated and unconjugated bile acids 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in female subjects of childbearing 
potential.  Perform serum pregnancy test in females of childbearing potential if urine 
β-hCG pregnancy test is positive. 
• Randomize the subject only if s/he meets all inclusion criteria and no exclusion 
criteria:  Record the visit in IWRS along with the subject’s Screening Visit 2 
(Week -1) fasting LDL cholesterol value, randomize the subject to study treatment 
group, and dispense investigational product according to IWRS instructions. 
• Administer the first dose of investigational product at the study site.  Instruct the 
subject to swallow the tablet whole with water; s/he must not chew, divide, or crush 
the tablet. 
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• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product on the morning of the next visit 
− To bring the investigational product bottle(s); s/he will dose at the clinic 
− To fast overnight (at least 8 hours) before the next visit, but water is permitted 
Additional Day 1 Procedures for PK Subjects 
At participating investigational sites, subjects will have the option to consent to participate in an 
additional PK assessment.  This is optional and subjects may decline to participate without 
affecting their involvement in the rest of the study.   
Following collection of the Day 1 fasted samples indicated above, subjects who are participating 
in the PK assessment will each receive a single dose of their assigned investigational product 
with water.  Serial blood samples will be obtained for measurement of OCA and its conjugates 
30 minutes prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose.  Subjects 
should not drink additional water for 1 hour after taking the dose of investigational product and 
will remain fasted until the 1-hour sample is collected.  Meal will be provided following 
collection of the 1-hour PK sample, and will be a meal replacement drink with nutrition 
information that has been submitted to and approved by the Sponsor in advance. 
9.7.6. 
Week 2 Visit Procedures 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and eCRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record anthropometric measures:  body weight, waist and hip 
circumference. 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Collect used bottles of investigational product, assess investigational product 
compliance, and perform investigational product accountability. 
• Obtain blood samples for: 
− Serum chemistry (includes basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
− Lipoprotein analyses and reverse cholesterol transport analytes 
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− CPK, if myopathy suspected 
• Perform a urine-based β-hCG pregnancy test in female subjects of childbearing 
potential.  Perform serum pregnancy test in females of childbearing potential if urine 
β-hCG pregnancy test is positive. 
• Schedule the next visit, reiterate dosing instructions and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product on the morning of the next visit  
− To bring the investigational product bottle(s); s/he will dose at the clinic 
− To fast overnight (at least 8 hours) prior to the next visit, but water is permitted 
9.7.7. 
Week 4 Visit Procedures 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and eCRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record anthropometric measures:  body weight, waist and hip 
circumference. 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Collect used bottles of investigational product, assess investigational product 
compliance, and perform investigational product accountability. 
• Obtain blood samples for: 
− Serum chemistry (includes basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
− Lipoprotein analyses and reverse cholesterol transport analytes 
− PD assessments; markers of inflammation, fibrosis and apoptosis; and markers of 
glucose metabolism (see Table 4 and Table 10)  
− Vitamin D 
− CPK, if myopathy suspected 
• Perform a urine-based β-hCG pregnancy test in female subjects of childbearing 
potential.  Perform serum pregnancy test in females of childbearing potential if urine 
β-hCG pregnancy test is positive. 
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• Record the visit in IWRS and dispense investigational product and atorvastatin as 
instructed. 
• Administer the daily dose of investigational product at the study site.  Instruct the 
subject to swallow the tablet whole; s/he must not chew, divide, or crush the tablet. 
• Administer the daily dose of atorvastatin at the study site.  Instruct the subject to 
swallow the tablet whole; s/he must not chew, divide, or crush the tablet. 
• Schedule the next visit, reiterate dosing instructions and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product or atorvastatin on the morning of the next 
visit  
− To bring the investigational product and atorvastatin bottle(s); s/he will dose at 
the clinic 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.8. 
Week 6 Safety Contact 
• This is a telephone contact with the subject to  
− Review and record AEs 
− Review and record concomitant medications 
− Assess investigational product and atorvastatin compliance 
9.7.9. 
Week 8 Visit Procedures 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and eCRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record anthropometric measures:  body weight, waist and hip 
circumference 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Collect used bottles of investigational product, assess investigational product 
compliance, and perform investigational product accountability. 
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• Collect used bottles of atorvastatin, assess atorvastatin compliance, and perform 
atorvastatin accountability.  
• Obtain blood samples for: 
− Serum chemistry (includes basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
− Lipoprotein analyses and reverse cholesterol transport analytes 
− PD assessments; markers of inflammation, fibrosis and apoptosis; and markers of 
glucose metabolism (see Table 4 and Table 10)   
− Vitamin D 
− CPK, if myopathy suspected 
− Blood sample for future exploratory analysis of biomarkers adiponectin, PAI-1, 
and BNP 
• Perform a urine-based β-hCG pregnancy test in female subjects of childbearing 
potential.  Perform serum pregnancy test in females of childbearing potential if urine 
β-hCG pregnancy test is positive. 
• Record the visit in IWRS and dispense investigational product and atorvastatin as 
instructed.  
• Administer the daily dose of investigational product at the study site.  Instruct the 
subject to swallow the tablet whole; s/he must not chew, divide, or crush the tablet. 
• Administer the daily dose of atorvastatin at the study site.  Instruct the subject to 
swallow the tablet whole; s/he must not chew, divide, or crush the tablet. 
• Reiterate dosing instructions and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product or atorvastatin on the morning of the next 
visit 
− To bring the investigational product and atorvastatin bottle(s); s/he will dose at 
the clinic 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.10. 
Week 10 Safety Contact 
• This is a telephone contact with the subject to:  
− Review and record AEs 
− Review and record concomitant medications 
− Assess investigational product and atorvastatin compliance 
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9.7.11. 
Week 12 Visit Procedures 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and eCRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record anthropometric measures:  body weight, waist and hip 
circumference. 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Collect used bottles of investigational product, assess investigational product 
compliance, and perform investigational product accountability. 
• Collect used bottles of atorvastatin, assess atorvastatin compliance, and perform 
atorvastatin accountability. 
• Obtain blood samples for: 
− Serum chemistry (includes basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
− Lipoprotein analyses and reverse cholesterol transport analytes 
− PD assessments; markers of inflammation, fibrosis and apoptosis; and markers of 
glucose metabolism (see Table 4 and Table 10)  
− Vitamin D 
− CPK, if myopathy suspected 
• Perform a urine-based β-hCG pregnancy test in female subjects of childbearing 
potential.  Perform serum pregnancy test in females of childbearing potential if urine 
β-hCG pregnancy test is positive. 
• Record the visit in IWRS and dispense investigational product and atorvastatin as 
instructed.  
• Administer the daily dose of investigational product at the study site.  Instruct the 
subject to swallow the tablet whole; s/he must not chew, divide, or crush the tablet. 
• Administer the daily dose of atorvastatin at the study site.  Instruct the subject to 
swallow the tablet whole; s/he must not chew, divide, or crush the tablet. 
• Reiterate dosing instructions and advise the subject: 
− Take the investigational product at approximately the same time each day 
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− NOT to take investigational product or atorvastatin on the morning of the next 
visit 
− To bring the investigational product and atorvastatin bottle(s); s/he will dose at 
the clinic 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits; water is permitted. 
9.7.12. 
Week 14 Safety Contact 
• This is a telephone contact with the subject to:  
− Review and record AEs 
− Review and record concomitant medications 
− Assess investigational product and atorvastatin compliance 
9.7.13. 
Week 16 Visit Procedures 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and eCRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Perform a physical examination. 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record anthropometric measures:  body weight, waist and hip 
circumference. 
• Perform a standard 12-lead ECG. 
• Determine alcohol consumption (using AUDIT questionnaire). 
• For participating sites only:  perform TE 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Collect all used and unused bottles of investigational product, assess investigational 
product compliance, and perform investigational product accountability. 
• Collect used bottles of atorvastatin, assess atorvastatin compliance, and perform 
atorvastatin accountability.  
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• Obtain blood samples for:  
− Serum chemistry (includes basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
− Lipoprotein analyses and reverse cholesterol transport analytes 
− PD assessments; markers of inflammation, fibrosis and apoptosis; and markers of 
glucose metabolism (see Table 4 and Table 10) 
− Vitamin D 
− CPK, if myopathy suspected 
− Blood sample for future exploratory analysis of biomarkers adiponectin, PAI-1, 
and BNP 
− Thyroid Function Tests:  TSH, T4, and T3 
− Possible analysis of conjugated and unconjugated bile acids 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in female subjects of childbearing 
potential.  Perform serum pregnancy test in females of childbearing potential if urine 
β-hCG pregnancy test is positive. 
• Record the visit in IWRS and indicate if the subject is continuing into the LTSE. 
9.7.13.1. Additional Week 16 Procedures for PK Subjects 
At participating investigational sites, subjects will have the option to consent to participate in an 
additional PK assessment.  This is optional and subjects may decline to participate without 
affecting their involvement in the rest of the study.  Consent to participate in the assessment can 
be given at any point during study participation prior to the Week 16 Visit. 
Following collection of the Week 16 fasted samples indicated above, subjects who are 
participating in the PK assessment will each receive a single dose of their assigned double-blind 
investigational product with water.  Serial blood samples will be obtained for measurement of 
OCA and its conjugates, and atorvastatin and its metabolites, 30 minutes prior to dosing and at 
0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose.  Subjects should not drink additional water 
for 1 hour after taking the dose of investigational product and will remain fasted until the 1-hour 
sample is collected.  The meal will be provided following collection of the 1-hour PK sample, 
and will be a meal replacement drink with nutrition information that has been submitted to and 
approved by the Sponsor in advance. 
9.7.14. 
Additional Procedures at Week 16/LTSE Day 1 Visit for Subjects Continuing 
into the LTSE 
Subjects who continue into the LTSE phase after completing the procedures listed for the 
Week 16 Visit (Section 9.7.13) will undergo the following procedures after signing the 
LTSE-specific ICF: 
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• Record the visit in IWRS, randomize the subject to one of the open-label treatment 
groups, and dispense open-label investigational product according to IWRS 
instructions. 
• If the subject is continuing with atorvastatin therapy, dispense (via IWRS) and 
provide dosing instructions as clinically indicated (Appendix A). 
• Reiterate dosing instructions for investigational product and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product or atorvastatin on the morning of the next 
visit 
− To bring the investigational product and atorvastatin bottle(s); s/he will dose at 
the clinic 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.15. 
Early Termination/End of Study Procedures:  Double-Blind Period 
Subjects who terminate participation in the study prior to the Week 16 Visit should have an early 
termination (ET) Visit as soon as possible following the decision to discontinue therapy.  If the 
study is terminated early by the Sponsor (Section 7.5), the subject will be asked to return to the 
site for ET/EOS procedures as soon as possible.  The procedures to be performed at the double-
blind phase ET/EOS Visit are as follows: 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and eCRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Perform a physical examination. 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record anthropometric measures:  body weight, waist and hip 
circumference. 
• Perform a standard 12-lead ECG. 
• Determine alcohol consumption (using AUDIT questionnaire). 
• For participating sites only:  perform TE 
• Assess and record AEs. 
• Review and record concomitant medications. 
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• Collect used and unused bottles of investigational product, assess investigational 
product compliance, and perform investigational product accountability. 
• Collect used and unused bottles of atorvastatin, assess atorvastatin compliance, and 
perform atorvastatin accountability.  
• Obtain blood samples for:  
− Serum chemistry (will include basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
− Lipoprotein analyses and reverse cholesterol transport analytes 
− PD assessments; markers of inflammation, fibrosis and apoptosis; and markers of 
glucose metabolism (see Table 4 and Table 10)    
− Vitamin D 
− CPK, if myopathy suspected 
− Blood sample for future exploratory analysis of biomarkers adiponectin, PAI-1, 
and BNP 
− Thyroid Function Tests:  TSH, T4, and T3 
− Possible analysis of conjugated and unconjugated bile acids 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in female subjects of childbearing 
potential.  Perform serum pregnancy test in females of childbearing potential if urine 
β-hCG pregnancy test is positive. 
• Obtain urine sample for urinalysis. 
• Record the visit in the IWRS. 
9.7.16. 
LTSE Visits 
LTSE Visits should occur within ±1 week of the visit day and the timing of all visits should be 
relative to the double-blind Week 16 Visit (ie, the start of the LTSE; LTSE Day 1).  For 
example, if the Month 6 Visit occurred 1 week late, the Month 9 Visit should still be 
approximately 9 months after the Week 16 Visit.  
The first LTSE visit following LTSE Day 1 will occur at LTSE Month 1.  The next visit will 
occur at LTSE Month 3 and every 3 months thereafter (eg, at Months 6, 9, and 12) for the 
duration of the LTSE.  The quarterly visit procedures described below will repeat annually for 
the duration of the LTSE.  For example, once a subject completes a year (Month 12 Visit) in the 
LTSE, their next visit should be 3 months later and the procedures described for the Month 3 
LTSE Visit should be followed. 
9.7.17. 
LTSE Month 1 Visit Procedures 
• Verify that the subject has fasted for at least 8 hours. 
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− Record fasting status in the source and eCRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Collect used bottles of investigational product, assess investigational product 
compliance, and perform investigational product accountability.  Following product 
accountability, redispense the same bottle of investigational product for use until the 
next visit. 
• Collect used bottles of atorvastatin, assess atorvastatin compliance, and perform 
atorvastatin accountability.  Following atorvastatin accountability, if the subject is 
continuing with the same dose of atorvastatin, redispense the same bottle for use until 
the next visit.  
− NOTE:  If atorvastatin dose is up-titrated or re-initiated after dose interruption, a 
telephone safety contact must be conducted 2 weeks following the change in dose 
to assess for AEs, concomitant medications, and investigational product and 
atorvastatin compliance. 
• Obtain blood samples for:  
− Serum chemistry (will include basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
− Markers of glucose metabolism 
− CPK, if myopathy suspected 
• Perform a urine based β-hCG pregnancy test in female subjects of childbearing 
potential.  Perform serum pregnancy test in females of childbearing potential if urine 
β-hCG pregnancy test is positive. 
• Reiterate dosing instructions for investigational product and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product or atorvastatin (if applicable) or on the 
morning of the next visit 
− To bring the investigational product and atorvastatin (if applicable) bottle(s); s/he 
will dose at the clinic 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
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9.7.18. 
LTSE Month 3, Month 6, Month 9, Month 15, Month 18, and Month 21 Visit 
Procedures 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and eCRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Perform a physical examination (only at Month 3 and Month 15 Visits). 
• Perform a standard 12-lead ECG. 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record anthropometric measures:  body weight, waist and hip 
circumference. 
• Determine alcohol consumption (using AUDIT questionnaire [only at Month 6 and 
Month 18 Visits]). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Collect used bottles of investigational product, assess investigational product 
compliance, and perform investigational product accountability. 
• Collect used bottles of atorvastatin, assess atorvastatin compliance, and perform 
atorvastatin accountability.   
− NOTE:  If atorvastatin dose is up-titrated or re-initiated after dose interruption, a 
telephone safety contact must be conducted 2 weeks following the change in dose 
to assess for AEs, concomitant medications, and investigational product and 
atorvastatin compliance. 
• Obtain blood samples for:  
− Serum chemistry (will include basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
− Lipoprotein analyses  
− Reverse cholesterol transport analytes (only at Month 6 and Month 18) 
− PD assessments; markers of inflammation, fibrosis and apoptosis; and markers of 
glucose metabolism (see Table 4 and Table 10) 
− Vitamin D 
− CPK, if myopathy suspected 
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• Perform a urine based β-hCG pregnancy test in female subjects of childbearing 
potential.  Perform serum pregnancy test in females of childbearing potential if urine 
β-hCG pregnancy test is positive. 
• Record the visit in IWRS and dispense investigational product and atorvastatin (if 
applicable) as instructed.  
• Reiterate dosing instructions for investigational product and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product or atorvastatin (if applicable) or on the 
morning of the next visit 
− To bring the investigational product and atorvastatin (if applicable) bottle(s); s/he 
will dose at the clinic 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.19. 
LTSE Month 12 Visit Procedures 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and eCRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Perform a physical examination. 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record anthropometric measures:  body weight, waist and hip 
circumference. 
• Perform a standard 12-lead ECG. 
• Determine alcohol consumption (using AUDIT questionnaire). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• For participating sites only:  Perform TE 
• Collect used bottles of investigational product, assess investigational product 
compliance, and perform investigational product accountability. 
• Collect used bottles of atorvastatin, assess atorvastatin compliance, and perform 
atorvastatin accountability.  
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• Obtain blood samples for:  
− Serum chemistry (will include basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
− Lipoprotein analyses and reverse cholesterol transport analytes 
− PD assessments; markers of inflammation, fibrosis and apoptosis; and markers of 
glucose metabolism (see Table 4 and Table 10)   
− Vitamin D 
− CPK, if myopathy suspected 
− Blood sample for future exploratory analysis of biomarkers adiponectin, PAI-1, 
and BNP 
− Thyroid Function Tests:  TSH, T4, and T3 
• Obtain urine sample for urinalysis. 
• Perform a urine based β-hCG pregnancy test in female subjects of childbearing 
potential.  Perform serum pregnancy test in females of childbearing potential if urine 
β-hCG pregnancy test is positive. 
• Record the visit in IWRS and dispense investigational product and atorvastatin (if 
applicable) as instructed.  
• Reiterate dosing instructions for investigational product and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product or on the morning of the next visit, and  
− To bring the investigational product and atorvastatin (if applicable) bottle(s); s/he 
will dose at the clinic, and 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.20. 
LTSE End of Study/Early Termination Procedures 
When the LTSE concludes, subjects will be asked to return to the site for EOS procedures as 
soon as possible.  Subjects who terminate participation in the study during the LTSE should have 
an ET Visit as soon as possible following the decision to discontinue therapy.  If the study is 
terminated by the Sponsor (Section 7.5), the subjects will be asked to return to the site for the 
ET/EOS procedures as soon as possible.  The procedures to be performed at the LTSE ET/EOS 
Visit are as follows 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and eCRF. 
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− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Perform a physical examination. 
• Assess and record vital signs (body temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record anthropometric measures:  body weight, waist and hip 
circumference. 
• Perform a standard 12-lead ECG. 
• Determine alcohol consumption (using AUDIT questionnaire). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• For participating sites only:  Perform TE  
• Collect used and unused bottles of investigational product, assess investigational 
product compliance, and perform investigational product accountability. 
• Collect used and unused bottles of atorvastatin, assess atorvastatin compliance, and 
perform atorvastatin accountability.  
• Obtain blood samples for:  
− Serum chemistry (will include basic lipid panel and liver biochemistry panel), 
hematology, and coagulation 
− Lipoprotein analyses and reverse cholesterol transport analytes 
− PD assessments; markers of inflammation, fibrosis and apoptosis; and markers of 
glucose metabolism (see Table 4 and Table 10) 
− Vitamin D 
− CPK, if myopathy suspected 
− Blood sample for future exploratory analysis of biomarkers adiponectin, PAI-1, 
and BNP 
− Thyroid Function Tests:  TSH, T4, and T3 
• Obtain urine sample for urinalysis. 
• Perform a urine based β-hCG pregnancy test in female subjects of childbearing 
potential.  Perform serum pregnancy test in females of childbearing potential if urine 
β-hCG pregnancy test is positive. 
• Record the visit in IWRS. 
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9.7.21. 
Unscheduled Safety Visits 
The Investigator may schedule an at-clinic Unscheduled/Safety Visit at any time if clinically 
warranted or requested by the Medical Monitor.  Unscheduled and/or repeat assessments, 
including additional laboratory tests or investigations, may be conducted.   
An increase in aminotransferases (ALT or AST) to >3× baseline (and >ULN) or total bilirubin 
>2× baseline (and >ULN) should be followed by repeat testing within 48 to 72 hours of the 
serum chemistry to confirm the abnormalities and to determine if they are increasing or 
decreasing (Appendix B).  AE information should also be collected.  If symptoms persist or 
repeat testing shows ALT >3× baseline (and >ULN) or total bilirubin >2× baseline (and >ULN), 
subjects should be followed until resolution of the abnormality and as clinically indicated 
depending on other laboratory and clinical signs and symptoms. 
As appropriate, the Medical Monitor should be contacted. 
10. 
INVESTIGATIONAL PRODUCT AND STUDY MEDICATION 
10.1. 
Investigational Product (OCA or Placebo) 
Double-Blind Phase: 
Investigational Product will be supplied as white, round, film-coated tablets containing OCA 
5 mg, OCA 10 mg, OCA 25 mg, or placebo.  All tablets will be debossed with “INT” on one side 
and “3547” on the other side, and will be of the same size and appearance.  The tablets contain 
the following inactive ingredients:  microcrystalline cellulose, sodium starch glycolate, and 
magnesium stearate.  The 25-mg tablet also contains silicon dioxide.  The investigational product 
tablets will be provided in high-density polyethylene (HDPE) bottles with an induction seal and 
child-resistant caps.  All investigational product will be manufactured according to Good 
Manufacturing Practice (GMP). 
LTSE Phase: 
10-mg and 25-mg OCA tablets for the LTSE Phase will be supplied as white tablets.   
• White OCA tablets are round and debossed with “INT” on one side and “3547” on 
the other side. 
The tablets contain the following inactive ingredients:  microcrystalline cellulose, sodium starch 
glycolate, and magnesium stearate.  The 25-mg tablet also contains silicon dioxide.  All 
investigational product will be provided as a tablet for oral administration and provided in HDPE 
bottles with an induction seal and child-resistant caps. 
10.2. 
Investigational Product Packaging and Labeling 
The packaging and labeling of investigational product supplies will be performed according to 
GMP standards by designated, qualified vendors.  A designated vendor will also be responsible 
for the distribution of the investigational product and placebo to the clinical sites.   
For the double-blind period, investigational product will be packaged and labeled as single 
bottles containing 30 OCA- or placebo-containing tablets, and should be dispensed to the subject 
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as instructed by the IWRS and according to the visit schedule in Table 1.  Each bottle will be 
labeled with a unique bottle number.  More than one bottle of investigational product may be 
dispensed to the subject at a visit to provide sufficient tablets for daily dosing until the next study 
visit. 
For the LTSE period, investigational product will be packaged and labeled as single bottles 
containing 30 or 100 tablets of OCA and should be dispensed to the subject as instructed by the 
IWRS.  Each bottle will be labeled with a unique bottle number.  More than one bottle of 
investigational product may be dispensed to the subject at a visit to provide sufficient tablets for 
daily dosing until the next study visit. 
10.3. 
Investigational Product Storage 
Investigational product should be stored in the containers in which they are received from the 
Sponsor’s supplier, at 15°C to 25°C. 
10.4. 
Investigational Product Administration 
Subjects will begin dosing at the clinic following Randomization and will be instructed to take 
investigational product at approximately the same time each day with water.  Subjects must be 
instructed to swallow one tablet whole; they must not chew, divide, or crush the tablet. 
10.4.1. 
Investigational Product Dispensation 
On Randomization/Day 1, after confirmation of subject eligibility, the Investigator or designee 
will dispense investigational product to the subject.  Before leaving the clinic, study site staff 
will ensure that the subject fully understands the dosing instructions. 
Investigational product will be dispensed at clinic visits after confirmation of continued subject 
compliance and eligibility.  If necessary, in exceptional circumstances, and only after approval 
by the Sponsor, investigational product may be delivered to subjects by courier, with proper 
precautions and documentation of shipping. 
10.4.2. 
Missed Doses 
Subjects who miss a dose of investigational product should be instructed to take it later the same 
day, as soon as they remember.  “Missed” doses should not be taken on a subsequent day (ie, the 
subject should not take more than the prescribed daily dose).  Subjects will be asked to record the 
day they miss a dose.   
10.5. 
Atorvastatin Tablets 
Atorvastatin tablets for oral administration contain 10 mg, 20 mg, and 40 mg atorvastatin and the 
following inactive ingredients:  calcium carbonate, USP; candelilla wax, FCC; croscarmellose 
sodium, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; 
microcrystalline cellulose, NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, 
talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion. 
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10.5.1. 
Atorvastatin Packaging and Labeling 
Atorvastatin is commercially available and will be supplied as tablets in its commercial 
configuration, though all bottles will have an auxiliary label with study protocol number and 
bottle number for compliance.  A designated vendor will be responsible for the distribution of 
atorvastatin to the Investigator.  
Atorvastatin should be dispensed to the subject and dosed as instructed by the IWRS. 
10.5.1.1. Atorvastatin Storage 
Atorvastatin should be stored in the containers in which they are received from the Sponsor’s 
supplier, at the manufacturer’s recommended storage conditions. 
10.5.2. 
Atorvastatin Administration 
Subjects will be instructed to begin atorvastatin dosing on the day following their Week 4 Visit.  
The first dose will be administered at the study site during the subject’s study visit (Table 1).  
Atorvastatin can be administered as a single dose with water at any time of the day, with or 
without food. 
10.5.3. 
Atorvastatin Dispensation 
At the subject’s Week 4 Visit, the Investigator or designee will dispense a bottle containing 
atorvastatin 10-mg tablets to the subject.  At the subject’s Week 8 Visit, the Investigator or 
designee will dispense atorvastatin 10-mg tablets to the subject advising the subject to take 
2 tablets for a total dose of atorvastatin 20 mg.  At subsequent visits, atorvastatin will be 
dispensed as clinically indicated.  For doses higher than 20 mg, subject may take multiple 
atorvastatin tablets for a total dose of 40 mg or 80 mg, as clinically indicated.  Before leaving the 
clinic, study site staff will ensure that the subject fully understands the dosing instructions.  
Upon confirmation of continued subject compliance and eligibility, atorvastatin will be 
dispensed using IWRS inventory management during study visits. 
10.5.4. 
Missed Doses of Atorvastatin 
Subjects who miss a dose of atorvastatin should be instructed to take it later the same day, as 
soon as they remember. “Missed” doses should not be taken if it has been more than 12 hours 
since when they would normally take it; the next dose should be taken when they would 
normally dose.  Subjects should be instructed not to take 2 doses at the same time.  Subjects 
should be asked to record the day they miss a dose. 
10.5.5. 
Atorvastatin Overdose 
There is no specific treatment for an overdose of atorvastatin.  In the event of an overdose, the 
subject should be treated symptomatically, and supportive measures instituted as required.  Due 
to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly 
enhance atorvastatin clearance. 
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10.6. 
Investigational Product and Atorvastatin Accountability and 
Disposal 
The Sponsor’s representative will ship investigational product and atorvastatin to the study site 
under appropriate storage conditions.  All shipments of investigational product and atorvastatin 
should be unpacked and the contents reviewed immediately upon receipt.  If it is not possible to 
verify the contents immediately, they must be stored under the appropriate storage conditions 
until verification of the contents is possible (ideally, within 1 business day from receipt).  The 
pharmacist or designee should verify the investigational product and atorvastatin against the 
shipment documentation.  The pharmacist or designee should contact the Sponsor immediately to 
report any concerns regarding the shipment.  
All investigational product and atorvastatin will be provided for use only in this study and is not 
to be used for any other purpose.  The Investigator or designee will maintain a full record of 
investigational product and atorvastatin accountability, including records of individual subject 
dispensing and final return or disposition (as directed by the Sponsor).  
The study monitor, also known as the Clinical Research Associate (CRA), will review 
accountability records against dispensed and in stock investigational product and atorvastatin 
during onsite monitoring visits, at study completion, and in the event of premature study 
termination.  The CRA will retrieve documentation detailing and confirming the return or 
destruction of investigational product and atorvastatin. 
11. 
ASSESSMENT OF EFFICACY AND PHARMACOKINETICS 
11.1. 
Efficacy Assessments 
An overview of parameters supporting primary, secondary, and exploratory objectives of the 
study are summarized in Table 4.  Samples for the assessment of efficacy variables will be 
collected according to the schedule of study procedures for the double-blind period (Table 1) and 
LTSE (Table 2).  For a complete list of variables, please refer to Appendix A.  
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Table 4: 
List of Planned Assessments 
The efficacy assessments supporting the primary, secondary, and exploratory objectives of the 
study are as follows: 
 
Parameters 
Primary Endpoints 
LDL metabolism 
LDL cholesterol concentration, particle size, and particle concentration 
Secondary Endpoints 
Lipoprotein metabolism 
HDL cholesterol concentration, particle size and particle concentration; 
VLDL cholesterol concentration, particle size and particle 
concentration; TG and total cholesterol concentrations; ApoA1, ApoB, 
ApoE, ApoCII, ApoCIII and Lp(a) concentrations; PCSK9 
concentration 
Reverse cholesterol transport 
Pre-β1 HDL concentration, macrophage cholesterol efflux; LCAT 
activity; CETP activity 
Exploratory Endpoints 
Liver biochemistry and markers of 
liver functiona 
Albumin, ALP, ALT (isoenzymes), AST, direct bilirubin, GGT, INR, 
total bilirubin 
Markers of liver inflammation 
IL-6, hs-CRP, and TNF-α 
Marker for hepatic apoptosis and 
fibrosis 
CK-18-M30 and CK-18-M65 
Glycemic Controlb 
Glucose, insulin, C-peptide, HbA1c, HOMA-β, and HOMA-IR 
OCA pharmacokinetics  
OCA, tauro-OCA, glyco-OCA, total OCA, potentially other conjugates 
or metabolites not yet identified  
Atorvastatin bioanalytical 
concentrations 
Atorvastatin and its metabolites 
Anthropometric measuresc 
Height, weight, and waist and hip circumference measurements; and 
BMI, and waist-to-hip ratio calculations 
Pharmacodynamics 
C4 (7α-hydroxy-4-cholesten-3-one) and FGF-19; possible analysis of 
conjugated and unconjugated bile acids 
Noninvasive radiological liver fibrosis 
measurements 
By TE (where available) 
Cardiovascular risk scores 
FRS and Reynolds scores 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; ApoA1 = apolipoprotein A1; ApoB = apolipoprotein 
B; ApoCII = apolipoprotein CII; ApoCIII = apolipoprotein CIII; ApoE = apolipoprotein E; AST = aspartate 
aminotransferase; BMI = body mass index; C4 = 7α-hydroxy-4-cholesten-3-one; CK-18-M30 = cytokeratin-18 
neoepitope M30; CK-18-M65 = cytokeratin-18 neoepitope M65; CTEP = cholesterol ester transfer protein;  
ECG = electrocardiogram; FGF-19 = fibroblast growth factor-19; FRS = Framingham Risk Score; GGT = gamma-
glutamyl transferase; HbA1c = hemoglobin-specific A1c fraction; HDL = high-density lipoprotein;  
HOMA-β = homeostatic model assessment–beta-cell function, HOMA-IR = homeostatic model assessment – insulin 
resistance; hs-CRP = high-sensitivity C-reactive protein; IL-6 = interleukin-6; LCAT = lecithin cholesterol 
acyltransferase; LDL = low-density lipoprotein; Lp(a) = lipoprotein(a); PCSK9 = proprotein convertase 
subtilisin/kexin type 9;TE = transient elastography; TEAE = treatment-emergent adverse event; TG = triglycerides; 
TNF-α = tumor necrosis factor-α; VLDL = very low-density lipoprotein 
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a  Liver biochemistry panel will be included in the serum biochemistry (see Table 10). 
b  HOMA-IR is calculated from fasting plasma glucose and fasting serum insulin values. 
c  Height will be measured at Screening only.  BMI and waist-to-hip ratio will be calculated via EDC from waist and 
hip circumference measurements. 
Please note that there are 2 distinct lipid assessments:  the assessment of lipoprotein metabolism 
and the safety lipids assessment measured as part of serum chemistry.  The latter will be used for 
randomization and safety assessments and the lipoprotein analysis samples will be used for the 
efficacy assessment. 
11.1.1. 
Efficacy Laboratory Assessments 
The complete list of planned laboratory assessments supporting primary, secondary, and 
exploratory objectives of the study is shown in Table 4, and includes parameters related to LDL 
metabolism, lipoprotein metabolism, reverse cholesterol transport, liver biochemistry and 
markers of liver function, markers of inflammation, glycemic control, OCA PD markers, and 
NASH disease severity markers CK-18-M30 and CK-18-M65. 
Fasting (8 hours) blood samples are required for efficacy analyses.  During each visit, the 
Investigator or designee will verify that the subject has fasted for at least 8 hours and record 
fasting status in the source and eCRF.  If the subject reports having eaten (water is permitted) 
within 8 hours, the Investigator or designee will document accordingly in the source and eCRF 
and remind the subject that fasting is required prior to onsite visits. 
Blood samples will be collected at visits indicated in the Schedule of Study Procedures (Table 1 
and Table 2).   
11.1.2. 
Liver Biopsy 
Liver biopsy will be scheduled at Screening Visit 1 for confirmation of NASH (inclusion 
criteria) if no biopsy slides or tissue collected within 1 year of the Screening Visit 1 is available 
for central read.  No other biopsy sample will be collected during the double-blind or LTSE 
phase of the study. 
Biopsies should be at least 2 cm in length.  All biopsies will be read centrally by a Sponsor-
designated central reader. 
11.1.2.1. Central Reading of Liver Histology  
Full instructions concerning the number and type of samples to be collected at each visit, the 
sample collection methods, sample processing, labeling, and shipping will be provided by the 
Sponsor in a study-specific histology manual. 
All biopsy assessments, including determination of study eligibility based on NASH diagnosis 
and fibrosis staging during Screening, will be performed centrally by an independent pathologist.  
The central pathologist must confirm histological presence of NASH and a minimum NAS of 4 
with a score of at least 1 in each component of NAS.  Key features of NASH (ie, steatosis, 
lobular inflammation, and hepatocellular ballooning) will be graded in accordance with the 
NASH CRN criteria for scoring (Kleiner 2005) as summarized in Table 5.  Fibrosis staging for 
eligibility will also be performed in accordance with NASH CRN criteria for fibrosis staging.   
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Table 5: 
NASH CRN Scoring System for Determining Eligibility and Primary 
Histological Endpoint Assessment 
NAFLD Activity Score (NAS) 
Fibrosis Staging 
Parameter 
Scoring Criteria 
Parameter 
Staging Criteria 
Steatosis 
0 = <5%  
1 = 5% - 33% 
2 = >33% - 66%  
3 = >66%  
Stage 0 
No Fibrosis 
Lobular 
Inflammation 
0 = No Foci 
1 = <2 Foci per 200 × field  
2 = 2 - 4 Foci per 200 × field   
3 = >4 Foci per 200 × field  
Stage 1  
Stage 1a 
Stage 1b 
Stage 1c  
Perisinusoidal or Periportal 
Mild, zone 3, perisinusoidal 
Moderate, zone 3, perisinusoidal 
Portal / periportal   
Ballooning 
0 = None  
1 = Few balloon cells  
2 = Many cells / prominent ballooning  
Stage 2 
Perisinusoidal and portal / periportal 
Stage 3 
Bridging fibrosis 
Stage 4 
Cirrhosis  
In addition to the primary scoring system of NASH CRN, biopsy samples will also be scored 
based on modified Ishak scoring (Ishak 1995) for all subjects.  Any extra biopsy tissue may 
undergo exploratory histological evaluations. 
11.1.3. 
Noninvasive Radiological Liver Fibrosis Measurements 
Liver stiffness will be assessed during LTSE using a noninvasive radiological method TE at 
study sites where available. 
11.1.4. 
Blood Samples for Future Analysis 
Blood samples for exploratory future analysis may be assessed for analytes such as adiponectin, 
plasminogen activator inhibitor-1(PAI-1), and B-type natriuretic peptide (BNP; Table 10).   
Blood samples may also be used to assess other disease or investigational product characteristics.  
The samples will be stored for up to 1 year after the end of the study and destroyed if not 
analyzed. 
11.2. 
Pharmacokinetic and Pharmacodynamic Assessments 
Parent OCA and its major conjugates (glyco-OCA and tauro-OCA), C4, and FGF-19 
concentrations will be determined for OCA PK and FXR activity in OCA-treated subjects.  
Concentrations of atorvastatin and its metabolites will be assessed in PK sampled subjects.  
Samples will be obtained for possible assessment of conjugated and unconjugated bile acids. 
11.2.1. 
Pharmacodynamic Assessments 
PD assessments will be collected according to the Schedule of Study Procedures (Table 1 and 
Table 2) from all subjects to measure C4, FGF-19, and possibly conjugated and unconjugated 
bile acids (dependent on the results of the C4 and FGF-19 assessments).  
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11.2.2. 
Pharmacokinetic Assessments 
Subjects who opt to participate in the PK assessment will provide blood samples for the 
measurement of OCA and its conjugates, and atorvastatin and its metabolites.  The first sample 
should be collected within 30 minutes prior to administration of investigational product (predose) 
on Day 1 and prior to administration of investigational product or atorvastatin at the Week 16 
Visit.  Subjects will then receive a single dose of investigational product with approximately 
240 mL of water.  Serial blood samples will be obtained for measurement of OCA and its 
conjugates, and atorvastatin and its metabolites, at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours 
postdose.  Subjects should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until after the 1-hour sample is collected.  A meal 
will be provided following collection of the 1-hour PK sample; the meal will be a meal 
replacement drink with nutrition information that has been submitted to and approved by the 
Sponsor in advance.  
11.3. 
Anthropometric Assessments 
Anthropometric measures include height (measured at Screening Visit 1 only), weight, and waist 
and hip circumference measurements.  Waist-to-hip ratio will be calculated by the electronic data 
capture (EDC) system and will be calculated as ([Waist Circumference in Centimeters] / [Hip 
Circumference in Centimeters]).  Height will also be collected at Screening Visit 1.  
Anthropometric measures will be performed during the visits indicated in Table 1 and Table 2.  
11.3.1. 
BMI 
BMI will be calculated as (Weight in Kilograms / [Height in Meters × Height in Meters]).   
Instructions for measuring body weight and waist and hip circumference are described below.  
All three measures are to be obtained after the subject has fasted for at least 8 hours. 
11.3.2. 
Body Weight 
Body weight should be obtained with the subject wearing a hospital gown or similar light 
clothing and no shoes, and with an empty bladder.  The same scale should be used throughout 
the study.  The floor surface on which the scale rests must be hard rather than carpeted or 
covered with other soft material.  The subject should stand in the center of the platform.  The 
weight is to be read and recorded to the first decimal point (eg, 97.1 kg) by study staff.  
11.3.3. 
Waist and Hip Circumference:   
The subject should be wearing little clothing and standing upright during the measurements, with 
arms relaxed at the side, feet close together, and body weight evenly distributed.  Waist 
circumference should be measured at the end of several consecutive natural breaths, midpoint 
between the top of the iliac crest and the lower margin of the last palpable rib in the mid-axillary 
line.  Hip circumference should be measured at the largest circumference of the buttocks.  Both 
measurements should be made with a Sponsor-provided measuring tape that is wrapped snugly 
around the subject, but not to the point that the tape is constricting.  The tape must be level and 
parallel to the floor at the point of measurement.  Each measurement should be repeated twice; if 
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the measurements are within 1 cm of one another, the average should be calculated.  If the 
difference between the 2 measurements exceeds 1 cm, the 2 measurements should be repeated.  
12. 
ASSESSMENT OF SAFETY 
Safety will be monitored and assessed by AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and clinical laboratory assessments.  Refer to 
Section 17.1 for AE reporting procedures.  
12.1. 
Adverse Events and Serious Adverse Events 
12.1.1. 
Definitions 
12.1.1.1. Adverse Event  
An AE is defined as any untoward medical occurrence associated with the use of the 
investigational product in humans, whether or not considered related to investigational product.  
An AE can be any unfavorable and unintended sign (eg, an abnormal laboratory finding), 
symptom, or disease temporally associated with any use of the investigational product, without 
any judgment about causality and irrespective of route of administration, formulation, or dose, 
including an overdose.  For this study, investigational product refers to OCA or placebo, and 
study medication refers to atorvastatin.  
AEs include, but are not limited to: (1) a worsening or change in nature, severity, or frequency of 
condition(s) present at the start of the study; (2) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction. 
Subjects should be questioned in a general way, without leading the subject or asking about the 
occurrence of any specific symptom.  The Investigator should attempt to establish a diagnosis of 
the event based on signs, symptoms, and/or other clinical information.  The diagnosis and not the 
individual signs/symptoms should be documented as the AE.  For example, if the underlying 
disease process is a stroke, it would not be appropriate to record the AE by describing the 
symptoms “sudden numbness, dizziness, and difficulty speaking.”  The AE medical term of 
“stroke or cerebrovascular accident” should be recorded as it more accurately describes the AE. 
12.1.1.2. Treatment-Emergent Adverse Event 
A treatment-emergent AE (TEAE) is any event not present before the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
12.1.1.3. Serious Adverse Event  
An AE is considered ‘serious’ if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
• Death 
• Is immediately life threatening 
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• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above 
Events not considered to be SAEs are hospitalizations for: 
• Routine monitoring of the studied indication and not associated with any deterioration 
in condition or AE; 
• Elective treatment for a pre-existing condition that did not worsen; 
• Respite care or observation when there is no AE associated with the hospitalization. 
12.1.2. 
Relationship to Investigational Product or Study Medication 
The Investigator will document her/his opinion of the relationship of the AE to treatment with 
investigational product and study medication (atorvastatin) using the criteria outlined in Table 6.  
Each AE will be assessed for relationship to investigational product and atorvastatin 
independently.  An AE for which there is a “reasonable possibility” that either investigational 
product or atorvastatin caused the AE is otherwise referred to as a suspected adverse reactions 
(SARs).  “Reasonable possibility” means there is evidence to suggest a causal relationship 
between the investigational product and/or atorvastatin and the AE.   
If the relationship between a SAE and the investigational product is determined to be “definite,” 
“probable,” or “possible,” the event will be considered to be related to the investigational product 
for the purpose of assessing expedited regulatory reporting. 
If the relationship between an SAE and the atorvastatin is determined to be “definite,” 
“probable,” or “possible,” the event will be considered to be related to atorvastatin for the 
purpose of assessing expedited safety reporting and reporting to the manufacturer. 
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Table 6: 
Relationship of Adverse Events to Investigational Product or Study 
Medication 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product or study medication in which the investigational product or study 
medication level has been established in body fluids or tissue; that follows a known or 
expected response pattern to the suspected investigational product or study medication;; and 
that is confirmed by improvement on stopping or reducing the dosage of the investigational 
product or study medication, and reappearance of the reaction on repeated exposure. 
Probable  
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product or study medication; that follows a known or expected response 
pattern to the suspected investigational product or study medication; that is confirmed by 
stopping or reducing the dosage of the investigational product or study medication; and that 
could not be reasonably explained by the known characteristics of the subject’s clinical state. 
Possible 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product or study medication; that follows a known or expected response 
pattern to the suspected investigational product or study medication; but that could readily be 
produced by a number of other factors. 
Unlikely 
An event that does not follow a reasonable temporal sequence from administration of the 
investigational product or study medication; that does not follow a known or suspected 
response pattern to the suspected investigational product or study medication; and that could 
reasonably be explained by known characteristics of the subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
12.1.3. 
Relationship to Liver Biopsy 
The Investigator will document her/his opinion of the relationship of the AE to liver biopsy using 
the criteria outlined in Table 7.  
Table 7: 
Relationship of Adverse Events to Liver Biopsy 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from the liver biopsy, and that 
follows a known or expected response pattern to the liver biopsy. 
Not Related 
Any event that does not meet the above criteria. 
12.1.4. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity) using Common Terminology Criteria for Adverse 
Events (CTCE) Version 4.03 (Appendix C).  A severity category of mild, moderate, severe, 
life-threatening, or death as defined in Table 8, must be entered on the AE eCRF.  It should be 
noted that the term “severe” used to grade intensity is not synonymous with the term “serious.”  
The assessment of severity is made regardless of investigational product relationship or of the 
seriousness of the AE.  When reporting AEs, reference should be made to the CTCAE manual 
for guidance on appropriate grading. 
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Table 8: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Asymptomatic or mild symptoms, clinical or diagnostic observations only, or intervention 
not indicated. 
2 = Moderate 
Minimal, local or noninvasive intervention indicated; or limiting age-appropriate 
instrumental activities of daily living.a 
3 = Severe 
Medically significant but not immediately life-threatening, hospitalization or prolongation 
of hospitalization indicated, disabling, or limiting self-care activities of daily living.b 
4 = Life-
Threatening 
Urgent intervention indicated 
5 = Death 
Death related to AE 
a  Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b  Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
12.1.4.1. Severity of Pruritus (as an AE) 
Pruritus was the most common AE seen in the Phase 2 PBC studies of OCA and thus may occur 
in this study.  
To ensure consistency in reporting, the following guidelines for assessing severity of pruritus 
should be used for AE reporting.  As pruritus is a subjective symptom, clinical judgment should 
be used to determine its severity and management (Table 9).  
Table 9: 
Severity of Pruritus 
Pruritus Grade 
Clinical Description of Severity for Pruritus and Medical Intervention 
1 = Mild 
Generally localized; causing no limitation of usual activities or minimal sleep disturbance; 
the subject may experience slight discomfort.   
Medicinal intervention is not indicated. 
2 = Moderate 
Intense or widespread; causing some limitation of usual activities or sleep disturbance; the 
subject may experience annoying discomfort.   
Medicinal intervention may be indicated. 
3 = Severe 
Intense or widespread and interfering with activities of daily living, ie, causing inability to 
carry out usual activities, or severe sleep disturbance; the subject may experience 
intolerable discomfort.  
Medicinal intervention is typically indicated. 
Since pruritus is a subjective symptom and the occurrence and magnitude of which are not 
readily measured by objective tools, clinical judgment needs to be applied in the management of 
each subject.  Managing OCA-related pruritus may help improve tolerance in those subjects who 
experience problematic pruritus and may otherwise discontinue from the study prematurely.  
General guidance for the management of subjects experiencing significant pruritus includes: 
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• Drug holiday:  A drug holiday is defined as an Investigator ‘prescribed’ complete 
interruption of dosing for 1 or more consecutive days (ie, non-daily dosing does not 
constitute a drug holiday).  Details of drug holidays and/or nondaily dosing regimens 
should be recorded in the CRF.  Per Section 8.4.1.1, subjects with pruritus ≥Grade 3 
in severity and possibly, probably, or definitely related to investigational product 
must discontinue investigational product.     
• Prescribe BAS.  Subjects taking BAS (including colestyramine and its derivatives, 
colestipol, colesevelam, or other sequestrants) should be instructed to stagger their 
dosing of investigational product, ensuring at least 4 hours between doses of the BAS 
and investigational product.   
• Other therapies may be tried as deemed clinically appropriate. 
• Less frequent dosing of investigational product (eg, on alternate days) may be tried, 
after which subjects may return to their original daily dose as soon as tolerated.   
12.1.5. 
Reporting of Adverse Events and Serious Adverse Events 
12.1.5.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
fully completes her/his study participation. 
All AEs, whether believed by the Investigator to be related or unrelated to the investigational 
product, must be documented in the subject’s medical records, in accordance with the 
Investigator’s normal clinical practice and in the eCRF in the EDC system.  Each AE is to be 
evaluated for duration, intensity, frequency, seriousness, outcome, other actions taken, and 
relationship to the investigational product or study medication. 
12.1.5.2. Reporting of Serious Adverse Events 
In agreeing to the provisions of this protocol, the Investigator accepts all legal responsibilities for 
immediate reporting of SAEs to the Sponsor.  Immediate reporting implies within 24 hours of 
becoming aware of the occurrence of an SAE. 
All SAEs must be reported to the Sponsor.  SAEs are reported by entering the SAE data into the 
study specific EDC system.  Entering the SAE data into the EDC system will automatically 
notify the Sponsor of the event.  In the event that the EDC system is inaccessible, an SAE may 
be reported by: 
• E-mail to the SAE email address:  sae@interceptpharma.com 
• Fax using a paper SAE report form:  +1 800 497 8521 
• Telephone:  +1 844 250 6396  
If an SAE is reported by telephone or fax, an SAE Report form must also be completed in the 
EDC system as soon as the EDC system is accessible.  At a minimum, the following information 
should be provided at the time of the initial report: 
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• Subject number  
• Event term  
• At least 1 criterion classifying the event as serious  
• Name and title of the reporting individual  
• Causal relationship to the investigational product or study medication 
The Investigator will assess whether the event is causally related to the investigational product or 
study medication.  The Sponsor will also assess whether the event is causally related to the 
investigational product, in addition to assessing the overall safety profile of the investigational 
product.  The Sponsor will notify the appropriate regulatory agencies as well as all participating 
Investigators of investigational new drug (IND) Safety Reports/Expedited Safety Reports that 
occur during the study within the time frames required by each regulatory agency. 
Following the initial report, any additional information obtained by the Investigator about the 
SAE must be reported promptly to the Sponsor in the same manner as described above for the 
initial SAE report.  Any supporting source documentation should be faxed to +1 800 497 8521 or 
emailed to sae@interceptpharma.com as soon as possible. 
The Investigator is responsible for submitting information on IND Safety Reports/Expedited 
Safety Reports received from the Sponsor to her/his local IRB/IEC, as directed by the local 
country requirements. 
Documentation of the submissions to IRBs/IECs must be retained in the appropriate study file(s).  
As instructed by the Sponsor, IND Safety Reports/Expedited Safety Reports should be retained 
in the appropriate investigative site study files, or with the IB.  
12.1.6. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the EDC represent the official record of all AEs and SAEs reported 
in the study.  The Investigator should comply with requests by the Medical Monitor or other 
Sponsor personnel to record the SAE on the subject’s AE eCRF in the EDC.  Other supporting 
documents such as radiology reports, hospital discharge summaries, and autopsy reports should 
also be provided, when appropriate.  Additionally, upon request by the Sponsor, the Investigator 
should provide input into the SAE narrative and provide timely information to ensure prompt 
follow-up and closure of the SAE report. 
The Investigator and supporting personnel responsible for subject care should discuss with the 
Medical Monitor any need for supplemental investigations of SAEs.  The results of these 
additional assessments must be reported to the Medical Monitor.   
12.1.7. 
Notification of Post-Study SAEs 
If an Investigator becomes aware of an SAE that may be attributable to the investigational 
product at any time after the end of the study, the Sponsor should be notified immediately 
(ie, within 24 hours). 
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All SAEs that occur within 30 days following the cessation of investigational product or study 
medication, whether or not they are related to the study, must be reported to the Sponsor within 
24 hours by following the instructions provided in Section 12.1.5.2. 
12.1.8. 
Follow-Up of Adverse Events and Serious Adverse Events 
All AEs must be followed during the course of the study until the AE resolves, is no longer of 
clinical concern, has stabilized or is otherwise explained, or the subject is lost to follow-up. 
AEs ongoing at the final visit that are deemed to be “possibly, probably, or definitely” related or 
of other clinical significance must be followed for as long as necessary to adequately evaluate 
the safety of the subject or until the event stabilizes, resolves, or is no longer of clinical concern.  
If resolved, a resolution date for the AE should be documented in the EDC.  The Investigator 
must ensure that follow-up includes any supplemental investigations indicated to elucidate the 
nature and/or causality of the AE.  This may include additional laboratory tests or investigations, 
or consultation with other healthcare professionals, as considered clinically appropriate by the 
Investigator. 
All subjects showing possible drug-induced liver injury should be followed until all 
abnormalities return to normal or to the baseline state.  Drug-induced liver injury may develop or 
progress even after the causative drug has been stopped.  Results should be recorded in the CRF.  
Note that longer follow-up can sometimes reveal an off-drug repetition of what had appeared to 
be drug-induced liver injury, indicating that liver injury was related to underlying liver disease. 
12.1.8.1. Pregnancy and Follow-Up  
Pregnancies are not considered AEs in and of themselves; however, if a female study participant 
becomes pregnant while she is enrolled in the clinical study, she must discontinue treatment with 
investigational product and atorvastatin immediately (see Section 8.4.1.1) and the Sponsor must 
be notified within 24 hours of the Investigator’s awareness of the pregnancy by completing the 
Pregnancy eCRF in the EDC system and downloading and completing the Pregnancy Report 
Form.  The Pregnancy Report Form must be emailed to sae@interceptpharma.com or faxed to 
+1-800-497-8521.  The subject and neonate must be followed for outcome information and/or as 
considered appropriate by the Investigator and the Sponsor. 
Women who discontinue the study due to pregnancy may not re-enroll in the study at any point, 
but should continue with the study visit schedule and must be followed by the Investigator 
through pregnancy outcome.  Similarly, if a subject’s pregnancy is terminated early (planned or 
unplanned), the subject will also be removed from the study. 
Completing the Pregnancy Report Form is not a substitute for reporting an AE/SAE if an 
AE/SAE has occurred related to or concurrent with the pregnancy.  In the situation when an 
AE/SAE has occurred, the AE/SAE reporting procedures described in Section 17.1 must also be 
followed. 
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12.2. 
Other Safety Parameters 
12.2.1. 
Medical History/Demographics 
A complete medical history will be obtained from the subject at Screening Visit 1.  Alcohol 
consumption history will be recorded.  Demographic characteristics (age, gender, race, and 
ethnicity) will be recorded. 
12.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the timepoints specified in the Schedule of Study Procedures (Table 1 and Table 2).  This 
includes height, which is only measured and recorded at Screening Visit 1.  The physical 
examination must include the following:  
• General appearance 
• Height (Screening Visit 1 only) 
• Weight (and BMI, if applicable) 
• Skin 
• Head, eyes, ears, nose, and throat 
• Neck 
• Lymph nodes 
• Chest/Respiratory system 
• Cardiovascular system 
• Abdominal region 
• Extremities 
• Musculoskeletal system 
• Mental status 
• Neurological system 
12.2.3. 
Vital Signs 
Vital signs will be assessed at indicated visits (Table 1 and Table 2).  Vital signs include body 
temperature, sitting heart rate, respiratory rate, and sitting blood pressure.  When taking heart 
rate, respiratory rate, and blood pressure readings, subjects should be seated quietly for a 
minimum of 3 minutes before the readings are taken.   
12.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected at the visits specified in Table 1 and Table 2.  The 
Investigator or designee will review the 12-lead ECG and findings will be recorded in the eCRF 
as normal, abnormal but not clinically significant, or abnormal and clinically significant.  Any 
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clinically significant abnormalities on ECGs recorded after Randomization/Day 1 will also be 
documented as AEs and entered on the AE page of the eCRF, whereas abnormalities on ECGs 
up to Randomization/Day 1, prior to administration of the investigational product, will be 
recorded as pre-treatment AEs. 
Investigative sites must retain a copy of all 12-lead ECGs evaluated by the Investigator or 
designee.  These ECGs must be clearly labeled with the Subject ID number, date, and time.  
Full instructions will be provided for forwarding the 12-lead ECGs for central reading. 
12.2.5. 
Alcohol Consumption 
Information about the subject’s alcohol consumption will be collected during the visits indicated 
in Table 1 and Table 2 using the Alcohol Use Disorders Identification Test (AUDIT).  AUDIT is 
a 10-item questionnaire that uses the domains of alcohol consumption, drinking behavior, and 
alcohol-related problems (Saunders 1993).  
12.2.6. 
Laboratory Assessments 
Except for Screening Visit 1, subjects will be instructed to attend each study visit in a fasted 
state, and subjects should remain fasted until their blood samples have been collected.  For visits 
that require fasting, the Investigator or designee will verify that the subject has fasted for at least 
8 hours and record fasting status in the source and eCRF.  If the subject reports having eaten 
(water is permitted) within the past 8 hours, the Investigator or designee will document 
accordingly in the source and eCRF and remind the subject that fasting is required before all 
study visits (see Section 9.6.1). 
Blood, and urine samples for laboratory assessments will be collected at the visits specified in 
Table 1 and Table 2.  Full instructions concerning the number and type of samples to be 
collected at each visit, the required sample volumes, sample collection methods, sample 
processing, labeling, and shipping will be provided in a separate procedural manual.  All 
necessary collection supplies will be provided by the central laboratory and will be appropriately 
assembled for the specific evaluations required at each visit. 
The list of laboratory analytes to be tested is shown in Table 10. 
 
 
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Table 10: 
List of Laboratory Analytes to be Tested 
 
Laboratory Assessment 
Analyte 
All Subjects 
Serum chemistry  
Albumin, BUN, creatinine, conjugated ( direct) bilirubin, total bilirubin, AST, 
ALT, ALP (isoenzymes), GGT, creatine phosphokinase, electrolytes (calcium, 
chloride, magnesium, phosphorus, potassium, sodium), total protein, 
bicarbonate, free fatty acids; and blood lipids (total cholesterol, LDL, HDL, 
and VLDL fractions and TGs) 
Hematology 
Hemoglobin, hematocrit, white blood count with differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils), platelets, red blood cell 
count (including MCV, MCH, MCHC) 
Urinalysis 
pH, specific gravity, protein, glucose, ketones, bilirubin, blood, microscopic 
exam 
Coagulation 
PT, PTT, INR 
Glycemic control measures 
Fasting plasma glucose, insulin, C-peptide, HbA1c, HOMA-β, and HOMA-IR 
Lipoprotein analysisa 
LDL, HDL, VLDL, total cholesterol, triglycerides, ApoA1, ApoB, ApoE, 
ApoCII, ApoCIII and Lp(a), PCSK9 
Reverse Cholesterol Transport 
Pre-β HDL, macrophage cholesterol efflux, LCAT and CETP 
Markers of Inflammation 
IL-6, hs-CRP, and TNF-α 
Markers of fibrosis and apoptosis 
CK-18-M30 and CK-18-M65 
Vitamin D levels 
Vitamin D 
Thyroid function tests 
T3, T4, TSH 
PD Assessment 
C4 and FGF-19; possible analysis of conjugated and unconjugated bile acids 
Blood sample for future analysis, 
including markers of 
cardiovascular risk 
Adiponectin, PAI-1, BNP 
Pregnancy Test (female subjects of 
childbearing potential) 
β-hCG 
Virus screening tests 
Hepatitis B surface antigen, hepatitis C antibody, and HCV ribonucleic acid 
[RNA] 
Subset of Subjects 
PK analytes 
OCA, tauro-OCA, glyco-OCA, and possible other conjugates or metabolites 
not yet identified 
Atorvastatin and its metabolites 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; ApoA1 = apolipoprotein A1;  
ApoB = apolipoprotein B; ApoCI = apolipoprotein CI; ApoCII = apolipoprotein CII; ApoE = apolipoprotein E;  
AST = aspartate aminotransferase; BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; C4 = 7α-hydroxy-
4-cholesten-3-one; CETP = cholesterol ester transfer protein; CK -18-M30 = cytokeratin-18 neoepitope M30;  
CK-18-M65 = cytokeratin-18 neoepitope M65; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin-specific 
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All subjects with laboratory tests containing clinically significant abnormal values are to be 
followed regularly until the values return to normal ranges; until a valid reason, other than 
investigational product related AE, is identified; or until further follow-up is deemed medically 
unnecessary. 
The Investigator should manage subjects with clinically significant lipoprotein abnormalities 
using local standard of care procedures as appropriate after assessing the individual subject’s 
total cardiovascular risk profile. 
Urine-based β-hCG pregnancy tests will be performed for female subjects of childbearing 
potential at the visits specified in Table 1 and Table 2.  If a urine pregnancy test is positive, a 
serum pregnancy test must be performed to confirm the result (Table 1, Table 2, and 
Section 9.7).  If positive, the Sponsor must be notified and the subject will be followed, as 
outlined in Section 12.1.8.1 through pregnancy outcome. 
International normalized ratio (INR) will be calculated based on prothrombin time value by the 
central laboratory.  HOMA-IR values will be calculated based on fasting plasma glucose and 
insulin concentrations.  Total OCA will be calculated based on OCA, tauro-OCA, and glyco-
OCA concentrations. 
13. 
STATISTICS 
13.1. 
Analysis Sets 
The following subject populations will be used for presentation and analysis of data: 
• Intent-to-Treat (ITT) Population:  All randomized subjects who receive any amount 
of investigational product will be included in the ITT Population.  Treatment 
assignment will be based on the randomized treatment allocation.   
• Safety Population:  The Safety Population will include all subjects who receive any 
amount of investigational product.  Treatment assignment will be based on the 
treatment actually received.  The Safety Population will be used for the analysis of all 
safety data. 
• Efficacy Evaluable Population:  All subjects who complete the double-blind phase 
according to the indicated doses of investigational product and atorvastatin without 
A1c fraction; HDL = high-density lipoprotein; HOMA-β = homeostatic model assessment–beta-cell function;  
HOMA-IR = homeostatic model assessment – insulin resistance; hs-CRP = high-sensitivity C-reactive protein;  
IL-6 = interleukin-6; INR = international normalized ratio; LCAT = lecithin cholesterol acyltransferase;  
LDL = low-density lipoprotein; Lp(a) = lipoprotein(a); MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PAI-1 = plasminogen activator 
inhibitor-1; PCSK9 = proprotein convertase subtilisin/kexin type 9; PK = pharmacokinetic; PT = prothrombin time;  
PTT = partial thromboplastin time; Pre-β-HDL = pre-β-high-density lipoprotein; TGs = triglycerides;  
T3 = triiodothyronine; T4 = thyroxine; TNF-α = tumor necrosis factor-α; TSH = thyroid-stimulating hormone; 
VLDL = very low-density lipoprotein  
a  NMR-based panel will be used for LDL, HDL, and VLDL cholesterol concentrations, particle sizes, and particle 
concentrations. ApoA1, ApoB, ApoE, ApoCII, ApoCIII Lp(a), and PCSK9 concentrations will be measured using 
appropriate methods at central or specialty laboratories.  Serum chemistry panel will be used for LDL, HDL, 
VLDL, TG, and total cholesterol concentration. 
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any significant protocol deviations.  The Efficacy Evaluable Population will be the 
primary population used for efficacy analyses. 
• Pharmacokinetic Populations:  The OCA PK Population will include all OCA 
subjects who consent to participate in the PK assessments and have at least one 
confirmed fasted analyzable sample.  Subjects must have been fasting for 
approximately 8 hours before the visit and must not have any major protocol 
deviations that potentially affect exposure levels.  The Atorvastatin PK Population 
will include all subjects who consent to participate in the PK assessments and have at 
least one confirmed fasted analyzable sample. 
• LTSE Population:  All subjects who receive any amount of investigational product as 
part of the LTSE will be included in the LTSE Population. 
13.2. 
Determination of Sample Size 
It is the intent of this study to characterize the components of LDL metabolism (cholesterol 
concentration, particle size, particle concentration) in subjects with NASH before and after 
treatment with OCA and to assess the changes induced by HMG Coenzyme A reductase inhibitor 
(atorvastatin) therapy.  Assuming, 22 mg/dL increase from baseline with a standard deviation 
of 24 in LDLc in the OCA 25 mg group without atorvastatin therapy after 16 weeks of treatment 
based on data from FLINT, a sample size of 20 subjects per group will provide greater than 
97.3% power to demonstrate the statistically significant difference of LDLc increase from 
baseline with a 2-sided type I error of 0.05.   
13.3. 
General Statistical Considerations 
A Statistical Analysis Plan (SAP), providing details about the specific planned analyses and 
statistical tests for both the double-blind phase and the LTSE phase, will be prepared and 
approved by the Sponsor and its designees prior to study database lock.  
13.4. 
Handling of Dropout and Missing Data 
Primary analysis of efficacy endpoints will be done using observed data only; missing values 
will not be imputed.  A sensitivity analysis using a last observation carried forward approach 
may be considered. 
13.5. 
Subject Population and Demographic Characteristics 
Approximately 80 subjects with a confirmed diagnosis of NASH will be randomized to receive 
investigational product.  Demographic characteristics including age, gender, race, and ethnicity 
will be summarized descriptively. 
13.6. 
Efficacy Analysis 
All efficacy analyses will be conducted using the Efficacy Evaluable Population.  In addition, the 
ITT Population will be used for sensitivity analysis of the primary analyses. 
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The baseline value for efficacy analyses is defined as the last value prior to administration of 
investigational product on Day 1 (predose). 
13.6.1. 
Primary Efficacy Analysis 
The primary efficacy analysis, changes in LDL cholesterol, particle size and particle 
concentration at Week 16 (end of double-blind phase) compared to Baseline will be summarized 
by treatment group. 
Analyses of observed values will be carried out using an analysis of covariance (ANCOVA) 
model at each visit with change from baseline as the dependent variable, including treatment 
group and randomization stratification factor as fixed effects and baseline as a covariate.  The 
same analysis will be carried out using percentage change from baseline as the dependent 
variable. 
Descriptive statistics of the values will be summarized by treatment group and visit.  The results, 
change from baseline, and percentage change from baseline values as well as estimates of least-
square (LS) means, standard errors, and 95% confidence intervals (CIs) will be presented by 
treatment group. 
The comparison of LDLc change from baseline and percentage change from baseline values 
between each active treatment group and placebo group will be performed as exploratory 
analysis.  Estimates of the LS mean difference between each active treatment group and placebo 
group, the standard error of the difference, and 95% CI of the difference will be presented. 
Sensitivity analysis for primary efficacy analysis will be performed using the ITT Population. 
13.6.2. 
Secondary Efficacy Analysis 
The secondary efficacy parameters will be analyzed in the same manner as the primary efficacy 
variables.  Descriptive statistics will be generated and will include change from baseline, 
percentage change from baseline, and estimates of LS means, standard errors, and 95% CIs 
presented by treatment group. 
The secondary parameters related to lipoprotein metabolism include HDL cholesterol 
concentration, particle size and particle concentration; VLDL cholesterol concentration, particle 
size and particle concentration; TG and total cholesterol concentrations; and ApoA1, ApoB, 
ApoE, ApoCII, ApoCIII and Lp(a) concentrations. 
The secondary parameters related to reverse cholesterol metabolism include pre-β1 HDL 
concentration, macrophage cholesterol efflux, lecithin cholesterol acyltransferase (LCAT) 
activity, cholesterol ester transfer protein (CETP) activity, and proprotein convertase 
subtilisin/kexin type 9 (PCSK9) enzyme levels. 
13.6.3. 
Additional Exploratory Efficacy Analyses 
13.6.3.1. Liver Biochemistry, Hepatobiliary Damage, and Liver Function 
The following laboratory parameters will be summarized by treatment group:  ALT, AST, 
gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total and conjugated (direct) 
bilirubin, albumin, INR, and platelets.  
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Analyses of observed laboratory values will be carried out using an ANCOVA model at each 
visit with change from baseline as the dependent variable, including treatment group and 
randomization stratification factor as fixed effects and baseline as a covariate.  The same analysis 
will be carried out using percentage change from baseline as the dependent variable. 
Descriptive statistics will be used to summarize the laboratory values by treatment group and 
visit.  The results, change from baseline, and percentage change from baseline; as well as 
estimates of LS means, standard errors, and 95% CIs will be presented by treatment group.  
Estimates of the mean difference between each active treatment group and placebo group, the 
standard error of the difference, and 95% CI of the difference will be presented. 
13.6.3.2. Markers of Inflammation, Fibrosis, and/or Apoptosis 
Markers of hepatic fibrosis, inflammation, and/or apoptosis include IL-6, hs-CRP, TNF-α, and 
CK-18-M30 and CK-18-M65.  These biomarkers will be summarized by treatment group using 
descriptive statistics at Baseline and at each post-Baseline visit.  The absolute and percentage 
change from baseline will be analyzed using the Wilcoxon Rank Sum Test to compare treatment 
groups.  The median differences and 95% CI of the median differences between treatment groups 
will be constructed using a Hodges-Lehmann estimate.  If the median differences between 
treatments are not symmetrical around the median, the Sign Test may be used. 
13.6.3.3. Glycemic Control Measures 
Glycemic control measures include fasting glucose, fasting insulin, C-peptide, HbA1c, 
HOMA-β, and HOMA-IR.  These measures will be summarized by treatment group using 
descriptive statistics at Baseline and at each on-study evaluation.  The change from baseline will 
also be summarized.  Baseline is defined as the last fasting assessment prior to treatment.  
Treatment groups will be compared using an ANCOVA model at each visit with change from 
baseline as the dependent variable, including treatment group and randomization stratification 
factor as fixed effects and baseline as a covariate.  The same analysis will be carried out using 
percentage change from baseline as the dependent variable.  Estimates of LS means, standard 
errors, and 95% CIs will be presented by treatment group.  Estimates of the mean difference 
between each active treatment group and placebo group, the standard error of the difference, and 
95% CI of the difference will be presented.  The distribution of glycemic control measures will 
be evaluated for normality assumptions.  If normality assumptions are violated, non-parametric 
methods, such as a rank ANCOVA model, will be used. 
Subgroup analyses will also be presented by diabetes status, excluding the randomization 
stratification factor from the ANCOVA model. 
13.6.3.4. Anthropometric Measures and Blood Pressure 
Anthropometric measures include height (measured and recorded only at Screening Visit 1), 
body weight, and waist and hip circumference measurements; and BMI and waist-to-hip ratio 
calculations.  Anthropometric and blood pressure measures will be summarized by treatment 
group using descriptive statistics at Baseline and at each on-study evaluation.  The change from 
Baseline will also be summarized.  Baseline is defined as the last assessment prior to treatment.  
Treatment groups will be compared using an ANCOVA model at each visit with change from 
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baseline as the dependent variable, including treatment group and randomization stratification 
factor as fixed effects and baseline as a covariate.  The same analysis will be carried out using 
percentage change from baseline as the dependent variable.  Estimates of LS means, standard 
errors, and 95% CIs will be presented by treatment group.  Estimates of the mean difference 
between each active treatment group and placebo group, the standard error of the difference, and 
95% CI of the difference will be presented.   
Subgroup analyses will also be presented by diabetes status, excluding the randomization 
stratification factor from the ANCOVA model.  Subgroup analyses of blood pressure will also be 
presented by use of antihypertensive medications. 
13.6.3.5. Noninvasive Radiological Liver Fibrosis Measurements  
Noninvasive radiological methods to assess liver stiffness will be conducted at selected centers 
where the devices are available.  These assessments include TE.  Measurements (based on 
available data) will be summarized by treatment group using descriptive statistics at Baseline and 
at each post-Baseline Visit.  The proportion of fibrosis improvement based on TE measurement 
will be summarized by treatment group at Week 16 of the double-blind phase, and year 1 and 
year 2 of the LTSE phase.  The correlation with histological assessment based on biopsy at 
Baseline will also be assessed. 
13.6.3.6. Pharmacodynamic Analysis 
C4, FGF-19, conjugated and unconjugated bile acids, and total bile acids will be summarized by 
treatment group using descriptive statistics at Baseline and at each scheduled post-Baseline Visit.  
The absolute change from baseline will also be summarized.  Baseline is defined as the mean of 
all available evaluations prior to treatment.   
13.6.3.7. Pharmacokinetic Analysis 
The PK Population will be used for analysis of PK parameters, which include plasma OCA 
(parent) and its conjugates (glyco-OCA and tauro-OCA), total OCA, atorvastatin and its 
metabolites, and potentially other analytes not yet identified.  PK analysis will be conducted 
using standard non-compartmental methodologies.   
For the analysis of OCA and its conjugates, values will be summarized by active treatment group 
using descriptive statistics.  Only samples that have a confirmed fasting of approximately 8 hours 
or more before their visit will be included in the analysis.   
Further details regarding the methods for calculating PK and the specific parameters to be 
reported will be described in the SAP. 
13.6.3.8. Cardiovascular Risk Scores 
The cardiovascular risk score includes the FRS and Reynolds scores.  Each score is derived from 
a subject’s age, sex, smoking status, total cholesterol and HDL levels, and other factors including 
family history, BMI, ethnicity, and medications.  Cardiovascular scores will be calculated at the 
time of data analysis.  These markers will be summarized by treatment group using descriptive 
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statistics at Baseline and at each on-study evaluation.  The change and percentage change from 
Baseline will also be summarized.  
13.6.4. 
LTSE Analyses 
Similar analyses to that which are described above will be conducted for the LTSE using the 
double-blind baseline value.  Analyses based on the double-blind baseline will be performed 
using randomized treatment groups (placebo, OCA 5 mg, OCA 10 mg, or 
OCA 25 mg).  Sensitivity analyses may be conducted using the last value prior to first dose in 
the LTSE for all subjects.  
13.7. 
Safety Analysis 
Safety data, including AEs and clinical laboratory observations, will be summarized by treatment 
group using the Safety Population.  The evaluation of safety data will be conducted for both the 
end of double-blind phase and final analyses at the end of the LTSE.  
13.7.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary of Regulatory Activities (MedDRA).  Summary 
tables of TEAEs will be provided.  The incidence of TEAEs and SAEs will be tabulated by 
system organ class and preferred term for each treatment group, and by severity and relationship 
to treatment.  Tables of TEAEs leading to investigational product discontinuation and SAEs will 
be provided.  The incidence of pre-treatment AEs and pre-treatment SAEs occurring after ICF 
signoff and before the first dosing of investigational product (OCA or placebo) will be tabulated 
in the same manner as above for all subjects participating in the washout period. 
13.7.2. 
Clinical Laboratory Evaluations 
Laboratory parameters will be summarized by treatment group using descriptive statistics at 
Baseline and at each scheduled post-Baseline Visit.  The absolute change from Baseline will also 
be summarized.  Baseline is defined as the mean of all available evaluations (using fasting blood 
sample values for lipids and glucose) prior to treatment. 
In addition, shift tables (ie, low-normal-high at Baseline versus low-normal-high at post-Baseline 
Visit in a 3-by-3 contingency table) from Baseline to worst value, last value, and at each 
scheduled post-Baseline Visit will be provided for hematology, coagulation, and serum 
chemistry by treatment group to assess changes in laboratory values from Baseline to each 
on-study evaluation. 
13.7.3. 
Lipoprotein Evaluations 
Serum chemistry based assessments are the standard safety tool for monitoring subjects’ serum 
lipids.  Baseline is defined as the last fasting assessment prior to treatment.  This analysis will 
only include samples that have a confirmed fasting of approximately 8 hours or more prior to the 
visit at which they were collected.  Further analyses of lipoprotein analytes will be specified in 
the SAP. 
Subgroup analyses will also be presented by use of statin medication. 
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13.7.4. 
Additional Safety Analysis 
13.7.4.1. Vital Signs  
The results and change from baseline to each on-study evaluation visit will be summarized for 
body temperature, sitting heart rate, and respiratory rate.   
13.7.4.2. Electrocardiograms  
The ECG data analysis will be conducted based on methodology recommended in the 
International Conference on Harmonisation (ICH) E14 guideline, The Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs.   
Baseline is defined as the mean of all available evaluations prior to treatment.  Descriptive 
statistics of ECG parameters (time between 2 consecutive R waves [RR], PR, QRS, QT, and QT 
interval corrected by Fridericia’s formula [QTcF]) at baseline and at each post-baseline timepoint 
will be summarized by treatment group; absolute changes from baseline will also be 
summarized.   
A categorical summary of abnormal QTcF values will be presented by treatment group.  The 
number of patients with values of >450 msec, >480 msec, and >500 msec will be presented, and 
the number of patients with change from baseline values of >30 msec and >60 msec will also be 
presented.   
Overall interpretation results for ECGs and the Investigator interpretation results are collected as 
normal, abnormal not clinically significant, and abnormal clinically significant.  Subjects whose 
interpretation shifts from normal to abnormal will be listed separately including description of 
the abnormality and any associated comments. 
13.7.5. 
Adjudicated Cardiovascular Events 
Adjudicated cardiovascular events include core major adverse cardiovascular events (MACE; 
cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) and expanded MACE 
(unstable angina requiring hospitalization, transient ischemic attack, peripheral or coronary 
revascularization procedures, hospitalization for congestive heart failure).  Other events 
potentially related to adverse cardiovascular outcomes are defined in Appendix D and will be 
included in the Cardiovascular Adjudication Committee (CAC) Charter for adjudication.  
Undetermined cause of death will be classified as a cardiovascular death by the CAC. 
Summaries of adjudicated cardiovascular events will include the incidence of TEAEs and the 
incidence of serious TEAEs.  All summaries of incidence will include the associated exact 
binomial 95% CI.  
13.8. 
Data Monitoring Committee 
An independent DMC that includes hepatologists, pharmaceutical physicians, 
epidemiology/cardiology expert(s), and statistician(s) not involved in the study as Investigators, 
or consultants.  The DMC will have oversight over the study conduct as defined by the DMC 
charter.  All members will have considerable experience with clinical study conduct and DMCs.  
Any candidate found to have a conflict of interest or whose name is listed on the FDA debarment 
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list will not be offered membership.  Conflicts of interest will be assessed regularly, and if 
members are found to have a new conflict of interest they would be replaced.   
The DMC will meet approximately quarterly at scheduled meetings and ad hoc meetings will be 
convened, as appropriate, to review safety and efficacy data.  Based on review of these data, the 
DMC will advise the Sponsor on the validity and scientific merit of continuing the study.   
Written minutes of both the open and closed DMC sessions will be prepared.  The closed 
minutes will be made available to the appointed Sponsor representatives only after the double-
blind database is locked and unblinded. 
Data listings provided to the DMC do not contain individual subject treatment information; 
however, the DMC will have access to the database and may unblind individual subject data as 
appropriate.  Summary tables reviewed by the DMC during closed sessions will include an 
overall column containing information regarding all subjects and separate treatment columns 
with fake labels, ie, the actual treatment groups are used, but are not identified.  Data reviewed 
during the meetings will include, at a minimum, disposition, demographics, exposure, clinical 
laboratory results, MedDRA coded AEs, and AEs leading to early withdrawal of investigational 
product.  At each meeting, detailed narratives of interval SAEs (including events resulting in 
death) are reviewed by the DMC in addition to a cumulative list of all SAEs. 
The DMC may agree to adjust meeting frequency based upon actual and projected safety and 
efficacy data availability. 
All Investigators and responsible IRBs/IECs will be informed of any decisions made by the 
Sponsor based on recommendations from the DMC relating to subject safety that alter the 
conduct of this study.  The Investigators will inform the subjects of such actions and the 
protocol, patient information sheet, and ICF will be revised, as appropriate. 
13.9. 
Adjudication Committees 
All suspected MACE, and drug-related hepatic injury events that occur after administration of 
the first dose of investigational product will be reviewed by the following blinded adjudication 
committees, depending on event type, before inclusion in any analysis.  The 2 committees and 
event types they are responsible for adjudicating are as follows: 
• Cardiovascular Adjudication Committee (CAC):  Adjudicates all suspected MACE 
(Appendix D), including all deaths 
• Hepatic Safety Committee:  Adjudicates all suspected drug-related hepatic injury events 
Each adjudication committee will have a charter that documents the reporting of events by the 
study site; definition of the suspected events to be adjudicated; supply of source documentation 
to the committee; and the entire data flow and process from committee membership, review of 
the events by the committee, reporting of the final assessment, and the working procedures of the 
committee.   
The adjudication committee members will include experts with relevant adjudication experience; 
they will not be involved in the study as Investigators, DMC members, or consultants.  Any 
candidate found to have a conflict or whose name is listed on the FDA debarment list will not be 
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offered membership.  Conflicts of interest are assessed regularly, and if members are found to 
have a new conflict of interest they will be replaced. 
The adjudication of suspected events will be based on available source documentation, including 
but not limited to individual clinical study data, hospital records, histology, discharge summaries, 
and/or death certificates.  The adjudication committees will not receive any individual subject 
treatment or site-specific information.  The assessment of events will be conducted in 
compliance with study-specific procedures, manuals, GCP, and all other applicable regulatory 
requirements, including the archiving of essential documents.    
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Study records at each site will be monitored at regular intervals by a representative of the 
Sponsor, the CRA.  The role of the CRA is to aid the Investigator in the maintenance and 
documentation of complete, accurate, legible, well organized and easily retrievable data.  In 
addition, the CRA will ensure the Investigator's understanding of all applicable regulations 
concerning the clinical evaluation of the investigational product and will ensure an understanding 
of the protocol, reporting responsibilities and the validity of the data.  This will include ensuring 
that full and appropriate essential documentation is available. 
In order to perform this role, the CRA must perform source data verification and as such, must 
be given access to the subject’s primary source documentation (eg, paper or electronic medical 
records such as consent to participate in the study, visit dates, screening and randomization 
numbers, demographic information, medical history, disease history, physical examination, vital 
signs, laboratory assessments [copy of laboratory reports], AEs, concomitant medications, dates 
of dispensing investigational product, ECGs, etc) that support data entries in the eCRF.  The 
eCRF must be completed promptly after each visit to allow the progress and results of the study 
to be closely followed by the Medical Monitor. 
The Investigator may exercise judgment in allowing the CRA access to particular sections of the 
subject's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
14.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IRB/IEC and/or 
a regulatory agency to conduct one or more site audits during or after the study and agrees to 
allow access to all study-related documentation and information and be available for discussion 
about the study.   
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the eCRF or ultimately 
transferred into the database to ensure accuracy and completeness.   
Training sessions, regular monitoring of the study at the study site by the Sponsor or designated 
personnel (eg, CRA), instruction manuals, data verification, cross-checking and data audits will 
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be performed to ensure quality of all study data.  Investigators’ meetings and/or onsite study 
initiations will be performed to prepare Investigators and other study site personnel for 
appropriate collection of study data. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit. 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF and/or other subject information, 
must be approved or given a favorable opinion in writing by an IRB/IEC as appropriate.  The 
Investigator must submit written IRB/IEC approval to the Sponsor before he or she can enroll 
any subject into the study.  The Investigator is responsible for providing the IB and any other 
available safety information and information about payments and compensation available to 
study subjects to the ethics committee for review. 
The Investigator is responsible for informing the IRB/IEC of any amendment to the protocol in 
accordance with local requirements.  A favorable opinion on substantial amendments will be 
obtained prior to implementation, unless the amendment is necessary to reduce immediate risk to 
study participants.  In addition, the IRB/IEC must approve all advertising used to recruit subjects 
for the study.  The protocol must be reapproved by the IRB/IEC upon receipt of amendments and 
annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product.  
The Sponsor will provide this information to the Investigator. 
Progress reports and notifications of SARs will be provided to the IRB/IEC according to local 
regulations and guidelines.  Investigators or the Sponsor or its designee will provide reports to 
the IRB/IEC as requested, as a minimum annually, and after the study is complete. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements, 
and the Sponsor’s policies. 
16.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The subject’s signed and dated ICF must be obtained before conducting any study procedures. 
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The Investigator(s) must maintain the original, signed ICF.  A copy of the ICF must be given to 
the subject. 
16.4. 
Subject Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the subject will be 
regarded as confidential and confidentiality of all subjects will be maintained.  Monitors (eg, 
CRA, Medical Monitor), auditors and inspectors will require access to a subject’s medical notes 
for the purpose of source document verification but the subject’s confidentiality will be 
maintained at all times.  An agreement for disclosure of any such information will be obtained in 
writing and is included in the statement of informed consent.  The study data shall not be 
disclosed to a third party (with the exception of auditors and/or regulatory authorities) without 
the written consent of the Sponsor.  All reports and communications relating to subjects in this 
study that are disclosed to an authorized third party will identify subjects only by protocol and 
assigned number and will be shared in a secure manner.  All data shall be secured against 
unauthorized access. 
The Investigator will maintain a list of subject names and identifying information (eg, subjects’ 
hospital numbers, unique subject numbers).  This list will not be collected by the Sponsor. 
The written information sheet will explain that study data will be stored in a computer database, 
maintaining confidentiality in accordance with national data protection legislation.  All data 
computer processed by the Sponsor or designee will be identified by unique subject 
number/randomization code/site number, only.   
When personal subject data are stored or processed by computer, the data must be protected to 
prevent their disclosure to unauthorized third parties.  The pertinent sections of the data 
protection laws in which the country is being conducted will be complied with in full. 
The written information sheet and ICF will explain that, for data verification purposes, 
authorized representatives of the Sponsor, a regulatory authority, or an IRB/IEC may require 
direct access to parts of the hospital or study site records relevant to the study, including subject 
medical history. 
17. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the subjects for the duration of the study.  If the Investigator 
is not present at the study site during the assessment, he or she will leave instructions for the 
study site staff and a telephone number where he or she can be reached. 
Named physician(s) will be responsible for the medical follow-up of subjects, as applicable. 
17.1. 
AE Reporting 
The Investigator is responsible for recording AEs reported by the subject or discovered by any 
other means during the study.  In agreeing to the provisions of this protocol, the Investigator 
accepts all legal responsibilities for immediate reporting of SAEs to the Sponsor. 
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17.2. 
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol in any significant way without 
proper notification to the Sponsor (or designee).  Only the Sponsor may amend the protocol.  
Any change in study conduct considered necessary by the Investigator will be made only after 
consultation with the Sponsor, who will then issue a formal protocol amendment to implement 
the change and obtain regulatory approval.  The only exception is when the Investigator 
considers a subject’s safety to be compromised if immediate action is not taken. 
17.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
• Approved Patient Information Sheets and ICF (all versions) 
• IRB/IEC approvals (of protocol/amendments, subject questionnaires, etc.) 
• Form FDA 1572  
• Current medical license of Principal Investigators 
• Curriculum vitae of Principal Investigators 
• Laboratory certification and reference ranges 
• Financial disclosure forms 
17.4. 
Ethics Review 
Please see Section 16.1 for the Investigator’s responsibilities regarding ethics review. 
17.5. 
Archiving and Record Retention 
The Investigator should retain all correspondence relating to this study in the Investigator Site 
File (ISF).  Any study documents stored elsewhere should have their location referenced in the 
ISF. 
All documents relating to the study including the ISF itself, source documents and subject 
medical files, completed study subject log and confidential subject identification list will be 
retained by the Investigator in accordance with regulations.  US Federal regulations require that 
records of drug disposition, eCRFs, source documents, and all reports of this investigation shall 
be retained by the Investigator for a minimum of 2 years following notification by the Sponsor 
that the regulatory authorities have been notified of the study's termination, or 2 years following 
approval of the marketing application.  If the Investigator is unable to retain the study documents 
for the required amount of time, the Sponsor must be notified of the individual who will be 
assuming this responsibility.  In the event that storage of records becomes a problem at any time 
during this period, the Sponsor should be consulted for assistance.  At the end of the minimum 
period, the Investigator should obtain written authorization from the Sponsor prior to the 
destruction of any records.  The Investigator will notify the Sponsor if ownership of documents 
or responsibility for the study site is transferred.  The Sponsor will inform Investigators should it 
become aware of any changes in storage requirements. 
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18. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it Sponsors consistent 
with the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, 
October 2013).  Consistent with the recommendations of the editors of several leading medical 
journals, the International Committee of Medical Journal Editors (ICMJE), authorship of 
publications resulting from Intercept sponsored studies should fairly recognize the activities of 
those that have made a significant contribution to the study (http://www.icmje.org).  Thus, it is 
anticipated that authorship will reflect the contribution made by the Sponsor personnel, the 
Investigators and others involved, such as statisticians. 
In recent years, issues about conflicts of interest and accuracy of the study data have been raised 
in the medical press.  Accordingly, the Sponsor has developed publication guidelines for clinical 
studies that are appropriate for this study.  Key issues include the following: 
• Clinical Study Registries (eg, clinicaltrials.gov):  A description of the study and 
relevant design elements (eg, basic design, objectives and endpoints, sample size, 
study population, and key inclusion/exclusion criteria) and results (when available) 
will be published online in a manner consistent with applicable regulatory guidelines. 
• Overview:  Investigators, reviewers, and editors will have the right to audit the data to 
verify its accuracy. 
• Responsibility:  Each Investigator is responsible for the accuracy and completeness of 
all data from her/his site.  The Sponsor (or its representatives) is responsible for the 
accuracy of the data entered into the study databases and the analyses conducted. 
• Data Management:  The Sponsor will establish data management and the SAP.  The 
Investigators will have the opportunity to provide input into the plans.  The 
Investigators will have the right to review the audit reports and data resolution 
decisions before the establishment of a clean file.  The Investigators will have the 
right to appoint appropriately qualified auditors, with GCP experience, to audit the 
Sponsor’s data before the establishment of a clean file.  The Investigators must 
provide adequate notice (at least 2 months) to the Sponsor of their intention to audit a 
study.  The audit should be conducted in a timely manner to allow the resolution of 
discrepancies before a clean file is established.  The Investigators will bear all the 
costs for the conduct of audits that they initiate, except those related to the resolution 
of data queries which the Sponsor will bear.  Such audits must be conducted in such a 
manner as to minimize the time to create the clean file. 
• Authorship:  The Sponsor, in collaboration with the Investigators, will establish the 
appropriate authorship and responsibility for drafting study documents in accordance 
with the principles of the ICMJE.  All manuscripts will be reviewed and agreed upon 
before submission for publication by all authors. 
• Single Center Publication and Additional Publications:  This is a multicenter study 
and is designed to be published with complete data from all the study sites.  Single 
center publications are therefore not considered appropriate.  Any such publications 
should clearly state that the data are “extracted” from a multicenter study and that the 
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study was not intended, or statistically powered, for data presentation by a single 
study site. 
• Intercept Review of External Manuscripts:  Consistent with this, Investigators must 
submit any drafts of any publications or presentations that may arise from this study 
to the Sponsor for review and approval and to ensure consistency with the policy in 
this protocol at least 30 days before submission for publication or presentation.  The 
Sponsor will have the right to request appropriate modification to correct facts and to 
represent its, or the Publication Committee’s, opinion if these differ with the proposed 
publication. 
• Confidentiality:  Investigators will conduct all interactions with the company and 
with third parties consistent with the executed confidentiality agreements.  While 
publication, by intention, presents the critical scientific data in a public forum, some 
information (such as future plans, results of preclinical studies, or chemical formulae) 
may still need to remain confidential. 
• Medical Journal Review:  Upon request, all pertinent study data and information will 
be made available as supplemental information for journal editors and reviewers to 
evaluate and audit (eg, protocol and amendments, data tabulations, etc).  
Arrangements will be made to maintain the confidentiality of such supplemental 
information.  Arrangements will also be made to maintain the confidentiality of the 
identity of journal reviewers.  Records will be maintained of which documents and 
datasets were reviewed. 
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19. 
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APPENDIX A. AMERICAN COLLEGE OF CARDIOLOGY/AMERICAN 
HEART ASSOCIATION GUIDANCE FOR THE USE OF 
STATINS 
 
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PRACTICE GUIDELINE
2013 ACC/AHA Guideline on the
Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adultsq
A Report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines
Endorsed by the American Academy of Physician Assistants, American Association of Cardiovascular and
Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive Cardiology,
Association of Black Cardiologists, Preventive Cardiovascular Nurses Association, and
WomenHeart: The National Coalition for Women With Heart Disease
Expert Panel
Members
Neil J. Stone, MD, MACP, FAHA, FACC,
Chair
Jennifer G. Robinson, MD, MPH, FAHA,
Vice Chair
Alice H. Lichtenstein, DSC, FAHA, Vice Chair
C. Noel Bairey Merz, MD, FAHA, FACC
Conrad B. Blum, MD, FAHA
Robert H. Eckel, MD, FAHA
Anne C. Goldberg, MD, FACP, FAHA
David Gordon, MD*
Daniel Levy, MD*
Donald M. Lloyd-Jones, MD, SCM, FACC,
FAHA
Patrick McBride, MD, MPH, FAHA
J. Sanford Schwartz, MD
Susan T. Shero, MS, RN*
Sidney C. Smith, JR, MD, FACC, FAHA
Karol Watson, MD, PHD, FACC, FAHA
Peter W. F. Wilson, MD, FAHA
*Ex-Ofﬁcio Members.
Methodology
Members
Karen M. Eddleman, BS
Nicole M. Jarrett
Ken LaBresh, MD
Lev Nevo, MD
Janusz Wnek, PHD
ACC/AHA Task
Force Members
Jeffrey L. Anderson, MD, FACC, FAHA, Chair
Jonathan L. Halperin, MD, FACC, FAHA,
Chair-Elect
Nancy M. Albert, PHD, CCNS, CCRN, FAHA
Biykem Bozkurt, MD, PHD, FACC, FAHA
Ralph G. Brindis, MD, MPH, MACC
Lesley H. Curtis, PHD, FAHA
David DeMets, PHD
Judith S. Hochman, MD, FACC, FAHA
Richard J. Kovacs, MD, FACC, FAHA
E. Magnus Ohman, MD, FACC
Susan J. Pressler, PHD, RN, FAAN, FAHA
Frank W. Sellke, MD, FACC, FAHA
Win-Kuang Shen, MD, FACC, FAHA
Subcommittee on
Prevention
Guidelines
Sidney C. Smith, JR, MD, FACC, FAHA, Chair
Gordon F. Tomaselli, MD, FACC, FAHA, Co-Chair
qThe Journal of the American College of Cardiology is published on behalf of
the American College of Cardiology Foundation by Elsevier Inc.; Circulation
is published on behalf of the American Heart Association, Inc., by Wolters
Kluwer. This is an open access article under the terms of the Creative Commons
Attribution Non-Commercial-NoDervis License, which permits use, distribu-
tion, and reproduction in any medium, provided that the Contribution is
properly cited, the use is noncommercial, and no modiﬁcations or adaptations
are made.
This document was approved by the American College of Cardiology Board of
Trustees and the American Heart Association Science Advisory and Coordinating
Committee in November 2013. The Academy of Nutrition and Dietetics afﬁrms the
value of this guideline.
The American College of Cardiology requests that this document be cited as fol-
lows: Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel
RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS,
Shero ST, Smith SC Jr, Watson K, Wilson PWF. 2013 ACC/AHA guideline on the
treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a
report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889–934.
This article is copublished in Circulation.
Copies: This document is available on the World Wide Web sites of the American
College of Cardiology (http://www.cardiosource.org) and the American Heart As-
sociation (my.americanheart.org). For copies of this document, please contact the
Elsevier Inc. Reprint Department, fax (212) 462-1935, e-mail reprints@elsevier.com.
Journal of the American College of Cardiology
 2014 The Expert Panel Members
Published by Elsevier Inc.
Vol. 63, No. 25, 2014
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2013.11.002
Page 117 of 356
Page 119 of 364


TABLE OF CONTENTS
Preamble and Transition to ACC/AHA Guidelines to
Reduce Cardiovascular Risk . . . . . . . . . . . . . . . . . . . . . . 2890
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2891
1.1. Organization of the Panel . . . . . . . . . . . . . . . . 2891
1.2. Document Review and Approval . . . . . . . . . . 2891
1.3. Scope of Guideline . . . . . . . . . . . . . . . . . . . . . . . 2892
1.4. Methodology and Evidence Review . . . . . . . 2894
2.
Overview of the Guideline . . . . . . . . . . . . . . . . . . . . 2895
2.1. Lifestyle as the Foundation for
ASCVD Risk-Reduction Efforts . . . . . . . . . . . . 2895
2.2. Initiation of Statin Therapy . . . . . . . . . . . . . . . 2897
3.
Critical Questions and Conclusions . . . . . . . . . . . 2897
3.1. Identiﬁcation of CQs . . . . . . . . . . . . . . . . . . . . . 2897
3.1.1. CQ1: LDL-C and Non–HDL-C Goals in
Secondary Prevention . . . . . . . . . . . . . . . . . 2899
3.1.2. CQ2: LDL-C and Non–HDL-C Goals in
Primary Prevention . . . . . . . . . . . . . . . . . . . 2899
3.1.3. CQ3: Efﬁcacy and Safety of
Cholesterol-Lowering Medications . . . . . 2899
4.
Statin Treatment: Recommendations . . . . . . . . . 2899
4.1. Intensity of Statin Therapy in Primary and
Secondary Prevention . . . . . . . . . . . . . . . . . . . . 2899
4.2. LDL-C and Non–HDL-C Treatment Goals . . . . 2901
4.3. Secondary Prevention . . . . . . . . . . . . . . . . . . . . 2902
4.4. Primary Prevention in Individuals ‡21 Years of
Age With LDL-C ‡190 mg/dL . . . . . . . . . . . . . . 2903
4.5. Primary Prevention in Individuals With
Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2905
4.6. Primary Prevention in Individuals Without
Diabetes and With LDL-C 70 to 189 mg/dL 2905
4.7. Risk Assessment in Primary Prevention . . . 2906
4.8. Heart Failure and Hemodialysis . . . . . . . . . . . 2907
5.
Safety: Recommendations . . . . . . . . . . . . . . . . . . . 2907
6.
Managing Statin Therapy:
Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2911
6.1. Monitoring Statin Therapy . . . . . . . . . . . . . . . . 2911
6.2. Optimizing Statin Therapy . . . . . . . . . . . . . . . . 2912
6.3. Insufﬁcient Response to Statin Therapy . . 2912
6.3.1. Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2912
6.3.2. Nonstatins Added to Statins or in
Statin-Intolerant Individuals . . . . . . . . . . . 2913
7.
Selected Clinical and Population
Subgroups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2913
7.1. Sex and Racial and Ethnic Subgroups . . . . . 2913
7.2. Individuals >75 Years of Age . . . . . . . . . . . . . 2913
8.
Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2914
9.
Evidence Gaps and Future Research Needs . . 2914
10.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2914
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2915
Appendix 1. Author Relationships With Industry
and Other Entities (Relevant) . . . . . . . . . . . . . . . . . . . . . 2919
Appendix 2. Expert Reviewer Relationships With
Industry and Other Entities . . . . . . . . . . . . . . . . . . . . . . . 2922
Appendix 3. Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . 2923
Appendix 4. Evidence Statements . . . . . . . . . . . . . . . . 2923
Appendix 5. Expanded Discussion of
What’s New in the Guideline . . . . . . . . . . . . . . . . . . . . . . 2932
Preamble and Transition to ACC/AHA
Guidelines to Reduce Cardiovascular Risk
The goals of the American College of Cardiology (ACC)
and the American Heart Association (AHA) are to prevent
cardiovascular diseases; improve the management of people
who have these diseases through professional education
and research; and develop guidelines, standards, and pol-
icies that promote optimal patient care and cardiovascular
health. Toward these objectives, the ACC and AHA have
collaborated with the National Heart, Lung, and Blood
Institute (NHLBI) and stakeholder and professional or-
ganizations to develop clinical practice guidelines for
assessment of cardiovascular risk, lifestyle modiﬁcations to
reduce cardiovascular risk, management of blood choles-
terol in adults, and management of overweight and obesity
in adults.
In 2008, the NHLBI initiated these guidelines by
sponsoring rigorous systematic evidence reviews for each
topic by expert panels convened to develop critical ques-
tions (CQs), interpret the evidence, and craft recommen-
dations. In response to the 2011 report from the Institute
of Medicine on the development of trustworthy clinical
guidelines (1), the NHLBI Advisory Council recom-
mended that the NHLBI focus speciﬁcally on reviewing
the highest-quality evidence and partner with other orga-
nizations to develop recommendations (2,3). Accordingly,
in June 2013 the NHLBI initiated collaboration with the
ACC and AHA to work with other organizations to
complete and publish the 4 guidelines noted above and
make them available to the widest possible constituency.
Recognizing that the Expert Panels/Work Groups did not
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consider evidence beyond 2011 (except as speciﬁed in the
methodology), the ACC, AHA, and collaborating societies
plan to begin updating these guidelines starting in 2014.
The joint ACC/AHA Task Force on Practice Guide-
lines (Task Force) appointed a subcommittee to shepherd
this transition, communicate the rationale and expectations
to the writing panels and partnering organizations, and
expeditiously publish the documents. The ACC/AHA and
partner organizations recruited a limited number of expert
reviewers for ﬁduciary examination of content, recognizing
that each document had undergone extensive peer review
by representatives of the NHLBI Advisory Council, key
federal agencies, and scientiﬁc experts. Each writing panel
responded to comments from these reviewers. Clariﬁca-
tions were incorporated where appropriate, but there were
no substantive changes because the bulk of the content was
undisputed.
Although the Task Force led the ﬁnal development of
these prevention guidelines, they differ from other ACC/
AHA guidelines. First, as opposed to an extensive com-
pendium of clinical information, these documents are
signiﬁcantly more limited in scope and focus on selected
CQs on each topic, based on the highest-quality evidence
available. Recommendations were derived from randomized
trials, meta-analyses, and observational studies evaluated for
quality and were not formulated when sufﬁcient evidence
was not available. Second, the text accompanying each
recommendation is succinct, summarizing the evidence for
each question. The Full Panel/Work Group Reports include
more detailed information about the evidence statements
that serve as the basis for recommendations. Third, the
format of the recommendations differs from other ACC/
AHA guidelines. Each recommendation has been mapped
from the NHLBI grading format to the ACC/AHA Clas-
siﬁcation of Recommendation/Level of Evidence (COR/
LOE) construct (Table 1) and is expressed in both formats.
Because of the inherent differences in grading systems and
the clinical questions driving the recommendations, align-
ment between the NHLBI and ACC/AHA formats is in
some cases imperfect. Explanations of these variations are
noted in the recommendation tables, where applicable.
In consultation with NHLBI, the policies adopted by
the writing panels to manage relationships of authors with
industry and other entities (RWI) are outlined in the
methods section of each panel report. These policies were
in effect when this effort began in 2008 and throughout
the writing process and voting on recommendations, until
the process was transferred to ACC/AHA in 2013. In the
interest of transparency, the ACC/AHA requested that
panel authors resubmit RWI disclosures as of July 2013.
Relationships relevant to this guideline are disclosed in
Appendix 1. None of the ACC/AHA expert reviewers had
relevant RWI (Appendix 2). See Appendix 3 for a list of
abbreviations used in the guideline.
Systematic evidence reports and accompanying sum-
mary tables were developed by the expert panels and
NHLBI. The guideline was reviewed by the ACC/
AHA Task Force and approved by the ACC Board
of Trustees, and the AHA Science Advisory and Coor-
dinating Committee. In addition, ACC/AHA sought
endorsement from other stakeholders, including profes-
sional organizations. It is the hope of the writing panels,
stakeholders, professional organizations, NHLBI, and
Task Force that the guidelines will garner the widest
possible readership for the beneﬁt of patients, providers,
and the public health.
These guidelines are meant to deﬁne practices that
meet the needs of patients in most circumstances and
are not a replacement for clinical judgment. The ulti-
mate decision about care of a particular patient must be
made by the healthcare provider and patient in light of
the circumstances presented by that patient. As a result,
situations might arise in which deviations from these
guidelines may be appropriate. These considerations
notwithstanding, in caring for most patients, clinicians
can employ the recommendations conﬁdently to reduce
the
risks
of
atherosclerotic
cardiovascular
disease
(ASCVD) events.
See Tables 1a and 1b for an explanation of the NHLBI
recommendation grading methodology.
1. Introduction
1.1. Organization of the Panel
The Blood Cholesterol Expert Panel (Expert Panel) was
originally convened as the Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol
in Adults (Adult Treatment Panel IV) appointed by
the NHLBI. The Expert Panel was composed of 13
members and 3 ex-ofﬁcio members, which included pri-
mary care physicians, cardiologists, endocrinologists, and
experts in clinical lipidology, clinical trials, cardiovascular
epidemiology and nutrition, and guideline development.
The Expert Panel chair asked all panel members to disclose
any conﬂict-of-interest information to the full panel in
advance of the deliberations; members with conﬂicts were
asked to recuse themselves from voting on any aspect
of the guideline for which a conﬂict might exist. All 16
members of the NHLBI Adult Treatment Panel IV Panel
transitioned to the ACC/AHA guideline Expert Panel.
Independent contractors performed the systematic review
with the assistance of the Expert Panel and provided
methodological guidance to the Expert Panel.
1.2. Document Review and Approval
A formal peer review process was initially completed under
the auspices of the NHLBI and included 23 expert re-
viewers and representatives of federal agencies. This doc-
ument was also reviewed by 4 expert reviewers nominated
by the ACC and the AHA when the management of the
guideline transitioned to the ACC/AHA. The ACC and
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AHA reviewers’ RWI information is published in this
document (Appendix 2).
This document was approved for publication by the
governing bodies of the ACC and AHA and endorsed by
the American Academy of Physician Assistants, American
Association of Cardiovascular and Pulmonary Rehabilita-
tion, American Pharmacists Association, American Society
for Preventive Cardiology, Association of Black Cardiol-
ogists, Preventive Cardiovascular Nurses Association, and
WomenHeart: The National Coalition for Women with
Heart Disease.
1.3. Scope of Guideline
This guideline is based on the Full Panel Report, which
is provided as an online-only data supplement to the
guideline. The Full Panel Report contains background and
additional material related to content, methodology, evi-
dence synthesis, rationale, and references and is supported
by the NHLBI Systematic Evidence Review, which can be
found at http://www.nhlbi.nih.gov/guidelines/cholesterol/ser/.
Table 2 provides an overview to facilitate understanding
what is new in the present guideline.
The Expert Panel was charged with using data from
randomized controlled trials (RCTs) and systematic reviews
and meta-analyses of RCTs to update the clinical practice
recommendations for the treatment of blood cholesterol
levels to reduce ASCVD risk. For this guideline, ASCVD
includes coronary heart disease (CHD), stroke, and pe-
ripheral arterial disease, all of presumed atherosclerotic
origin. These recommendations are intended to provide a
Table 1. Applying Classiﬁcation of Recommendation and Level of Evidence
A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials.
Even when randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.
*Data available from clinical trials or registries about the usefulness/efﬁcacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart
failure, and prior aspirin use.
yFor comparative-effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments
or strategies being evaluated.
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strong, evidence-based foundation for the treatment of
cholesterol for the primary and secondary prevention of
ASCVD in women and men.
Because RCT data were used to identify those most likely
to beneﬁt from cholesterol-lowering statin therapy, the
recommendations will be of value to primary care clinicians
as well as specialists concerned with ASCVD prevention.
Importantly, the recommendations were designed to be
easy to use in the clinical setting, facilitating the imple-
mentation of a strategy of risk assessment and treatment
focused on the prevention of ASCVD. The present
guideline is intended to address treatment of adults (21
years of age) to complement the NHLBI cardiovascular
health risk-reduction guideline for children and adoles-
cents (4).
The members of the Expert Panel acknowledge the
important contributions arising from decades of genetic
and biochemical studies, observational epidemiological
and ecological studies, and in vitro and animal experi-
ments that associated higher low-density lipoprotein
cholesterol (LDL-C) levels with greater ASCVD risk.
These studies provided the rationale for RCTs, which in
turn demonstrated that lowering cholesterol levels reduced
ASCVD events and thereby established a central, causal
role
of
atherogenic
cholesterol-containing
lipoprotein
particles, particularly LDL, in the genesis of CHD and
ASCVD.
Other strategies for using drug therapy to reduce
ASCVD events have been advocated, including treat-
to-cholesterol target, lowest-is-best, and risk-based treat-
ment approaches. However, only 1 approach has been
evaluated in multiple RCTsdthe use of ﬁxed doses of
cholesterol-lowering drugs to reduce ASCVD risk. Because
the overwhelming body of evidence came from statin
Table 1a. NHLBI Grading of the Strength of
Recommendations
Grade
Strength of Recommendation*
A
Strong recommendation
There is high certainty based on evidence that the net beneﬁty
is substantial.
B
Moderate recommendation
There is moderate certainty based on evidence that the net beneﬁt is
moderate to substantial, or there is high certainty that the net
beneﬁt is moderate.
C
Weak recommendation
There is at least moderate certainty based on evidence that there is a
small net beneﬁt.
D
Recommendation against
There is at least moderate certainty based on evidence that
there is no net beneﬁt or that risks/harms outweigh beneﬁts.
E
Expert opinion (“There is insufﬁcient evidence or evidence is
unclear or conﬂicting, but this is what the Work Group
recommends.”)
Net beneﬁt is unclear. Balance of beneﬁts and harms cannot be
determined because of no evidence, insufﬁcient evidence,
unclear evidence, or conﬂicting evidence, but the Work Group
thought it was important to provide clinical guidance and
make a recommendation. Further research is recommended
in this area.
N
No recommendation for or against (“There is insufﬁcient evidence or
evidence is unclear or conﬂicting.”)
Net beneﬁt is unclear. Balance of beneﬁts and harms cannot be
determined because of no evidence, insufﬁcient evidence, unclear
evidence, or conﬂicting evidence, and the Work Group thought
no recommendation should be made. Further research is
recommended in this area.
*In most cases, the strength of the recommendation should be closely aligned with the quality
of the evidence; however, under some circumstances, there may be valid reasons for making
recommendations that are not closely aligned with the quality of the evidence (e.g., strong
recommendation when the evidence quality is moderate, such as smoking cessation to reduce
cardiovascular disease risk or ordering an ECG as part of the initial diagnostic work-up for a
patient presenting with possible MI). Those situations should be limited and the rationale
explained clearly by the Work Group.
yNet beneﬁt is deﬁned as beneﬁts minus risks/harms of the service/intervention.
ECG indicates electrocardiogram; MI, myocardial infarction; and NHLBI, National Heart, Lung,
and Blood Institute.
Table 1b. NHLBI Quality Rating of the Strength of Evidence
Type of Evidence
Quality Rating*
 Well-designed, well-executedy RCT that adequately
represent populations to which the results are applied
and directly assess effects on health outcomes.
 Meta-analyses of such studies.
Highly certain about the estimate of effect. Further
research is unlikely to change our conﬁdence in the
estimate of effect.
High
 RCT with minor limitationsz affecting conﬁdence in,
or applicability of, the results.
 Well-designed, well-executed nonrandomized controlled
studiesx and well-designed, well-executed observational
studiesk.
 Meta-analyses of such studies.
Moderately certain about the estimate of effect. Further
research may have an impact on our conﬁdence in the
estimate of effect and may change the estimate.
Moderate
 RCT with major limitations.
 Nonrandomized controlled studies and observational
studies with major limitations affecting conﬁdence in,
or applicability of, the results.
 Uncontrolled clinical observations without an appropriate
comparison group (e.g., case series, case reports).
 Physiological studies in humans.
 Meta-analyses of such studies.
Low certainty about the estimate of effect. Further
research is likely to have an impact on our conﬁdence
in the estimate of effect and is likely to change the
estimate.
Low
*In some cases, other evidence, such as large all-or-none case series (e.g., jumping from air-
planes or tall structures), can represent high- or moderate-quality evidence. In such cases, the
rationale for the evidence rating exception should be explained by the Work Group and clearly
justiﬁed.
y“Well-designed, well-executed” refers to studies that directly address the question; use
adequate randomization, blinding, and allocation concealment; are adequately powered; use
intention-to-treat analyses; and have high follow-up rates.
zLimitations include concerns with the design and execution of a study that result in decreased
conﬁdence in the true estimate of the effect. Examples of such limitations include but are not
limited to: inadequate randomization, lack of blinding of study participants or outcome asses-
sors, inadequate power, outcomes of interest that are not prespeciﬁed for the primary out-
comes, low follow-up rates, and ﬁndings based on subgroup analyses. Whether the limitations
are considered minor or major is based on the number and severity of ﬂaws in design or
execution. Rules for determining whether the limitations are considered minor or major and how
they will affect rating of the individual studies will be developed collaboratively with the meth-
odology team.
xNonrandomized controlled studies refer to intervention studies where assignment to inter-
vention and comparison groups is not random (e.g., quasi-experimental study design).
jjObservational studies include prospective and retrospective cohort, case-control, and cross-
sectional studies.
NHLBI indicates National Heart, Lung, and Blood Institute; and RCT, randomized controlled
trials.
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RCTs, the Expert Panel appropriately focused on these
statin RCTs to develop evidence-based guidelines for the
reduction of ASCVD risk. We recognize that this repre-
sents a signiﬁcant departure from current strategies. This
should not come as a surprise to clinicians. The recent
guideline on heart failure has changed long-standing para-
digms on the basis of the evidence, and this guideline does
as well (5). Future RCTs will be needed to determine the
optimal treatment strategy to provide the greatest reduction
in ASCVD events with best margin of safety.
The Expert Panel acknowledges that our process did not
provide for a comprehensive approach to the detection,
evaluation, and treatment of lipid disorders as was done in
the prior Adult Treatment Panel III Report (6). However,
the present guideline was never intended to be a compre-
hensive approach to lipid management for purposes other
than ASCVD risk reduction. A limited number of expert
opinion recommendations were made only when RCT
evidence was not present and after a thorough consider-
ation of what the Expert Panel had learned from the
RCTs. For the many questions about complex lipid dis-
orders that are beyond the scope of our systematic evidence
review, or for which little or no RCT data are available, it
is anticipated that clinicians with lipid expertise can
contribute to their management.
1.4. Methodology and Evidence Review
Although the Expert Panel was convened before the
Institute of Medicine reports on practice guidelines, our
evidence-based process followed most of the standards
from the Institute of Medicine report, “Clinical Practice
Guidelines We Can Trust” (1). The systematic review was
limited to RCTs with ASCVD outcomes and systematic
reviews and meta-analyses of RCTs with ASCVD out-
comes. Observational studies and those with <18 months
(CQ1 and CQ2) or <12 months (CQ3) of follow-up were
excluded. Support was provided by a methodology con-
tractor and a systematic review and general support con-
tractor and included the following steps:
 The Expert Panel constructed CQs relevant to
clinical practice.
 The Expert Panel identiﬁed (a priori) inclusion/
exclusion criteria for each CQ.
 An independent contractor developed a literature
search strategy, based on inclusion/exclusion criteria,
for each CQ.
 An independent contractor executed a systematic
electronic search of the published literature from
relevant bibliographic databases for each CQ. The
date range for the overall literature search was
January 1, 1995, through December 1, 2009. How-
ever, RCTs with hard ASCVD outcomes of myo-
cardial infarction (MI), stroke, and cardiovascular
death published after that date range were eligible
for consideration until the Expert Panel began de-
liberations on relevant recommendations.
 RCTs that met the inclusion criteria and were
independently graded as fair or good quality were
included in the evidence tables for the consideration
of the Expert Panel. RCTs that were graded as poor
quality were excluded.
 With the assistance of independent methodologists,
this evidence base was used to develop a series of
evidence statements graded on the level of the evi-
dence (high, medium, or low).
 The Expert Panel then synthesized the evidence state-
ments into treatment recommendations/summaries
Table 2. What’s New in the Guideline?*
1
Focus on ASCVD Risk Reduction: 4 Statin Beneﬁt Groups
1. This guideline is based on a comprehensive set of data from RCTs
from which 4 statin beneﬁt groups were identiﬁed that focus efforts
to reduce ASCVD events in secondary and primary prevention.
2. This guideline identiﬁes high-intensity and moderate-intensity
statin therapy for use in secondary and primary prevention.
2
A New Perspective on LDL-C and/or Non–HDL-C Treatment Goals
1. The Expert Panel was unable to ﬁnd RCT evidence to support
continued use of speciﬁc LDL-C or non–HDL-C treatment targets.
2. The appropriate intensity of statin therapy should be used to
reduce ASCVD risk in those most likely to beneﬁt.
3. Nonstatin therapies, as compared with statin therapy,
do not provide acceptable ASCVD risk-reduction beneﬁts relative
to their potential for adverse effects in the routine prevention
of ASCVD.
3
Global Risk Assessment for Primary Prevention
1. This guideline recommends use of the new Pooled Cohort Equations
to estimate 10-year ASCVD risk in both white and black men and
women.
2. By more accurately identifying higher-risk individuals for statin
therapy, the guideline focuses statin therapy on those most likely
to beneﬁt.
3. It also indicates, on the basis of RCT data, those high-risk groups
that might not beneﬁt.
4. This guideline recommends a discussion between clinicians
and patients before initiation of statin therapy.
4
Safety Recommendations
1. This guideline used RCTs to identify important safety
considerations in individuals receiving treatment of blood
cholesterol to reduce ASCVD risk.
2. Using RCTs to determine statin adverse effects facilitates
understanding of the net beneﬁt from statin therapy.
3. This guideline provides expert guidance on management of
statin-associated adverse effects, including muscle symptoms.
5
Role of Biomarkers and Noninvasive Tests
1. Treatment decisions in selected individuals who are not included
in the 4 statin beneﬁt groups may be informed by other factors as
recommended by the Risk Assessment Work Group and
Blood Cholesterol Expert Panel.
6
Future Updates to the Blood Cholesterol Guideline
1. This is a comprehensive guideline for the evidence-based treatment
of blood cholesterol to reduce ASCVD risk.
2. Future updates will build on this foundation to provide expert
guidance on the management of complex lipid disorders and
incorporate reﬁnements in risk stratiﬁcation based on critical
review of emerging data.
3. RCTs comparing alternative treatment strategies are needed in
order to inform future evidence-based guidelines for the optimum
ASCVD risk-reduction approach.
*See Appendix 5, for an expanded discussion of what’s new in the guideline.
ASCVD indicates atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein
cholesterol; LDL-C, low-density lipoprotein cholesterol; and RCT, randomized controlled trial.
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graded as A (strong), B (moderate), C (weak), D
(recommend
against), E (expert), and N
(no
recommendation).
 The ﬁnal evidence statements and treatment rec-
ommendations were approved by at least a majority
of voting members of the Expert Panel.
 Guideline implementability appraisals, planned and
coordinated by the NHLBI Implementation Work
Group, were performed to identify and address bar-
riers to guideline implementation.
In addition, the Expert Panel was able to include major
RCTs and meta-analyses of RCTs published through July
2013 in our discussion and as part of the process of
determining ACC/AHA grading of the NHLBI expert-
level recommendations.
2. Overview of the Guideline
The RCTs identiﬁed in the systematic evidence review
indicated a consistent reduction in ASCVD events from
3-hydroxy-3-methylglutaryl-coenzyme A reductase inhib-
itor (statin) therapy in secondary- and primary-prevention
populations, with the exception of no ASCVD event
reduction when statin therapy was initiated in those with
New York Heart Association class II to IV heart failure or
those receiving maintenance hemodialysis. The RCTs
either compared ﬁxed doses of statins with placebo or
untreated controls, or compared ﬁxed doses of higher-
intensity statins with moderate-intensity statins. These
trials were not designed to evaluate the effect of titrated
(dose-adjusted) statin treatment to achieve prespeciﬁed
LDL-C or non–HDL-C goals.
Therefore, the Expert Panel was unable to ﬁnd RCT
evidence to support titrating cholesterol-lowering drug
therapy to achieve target LDL-C or non–HDL-C levels,
as recommended by Adult Treatment Panel III (6–8).
Notably, the Expert Panel did ﬁnd RCT evidence that use
of therapy (e.g., niacin) to additionally lower non–HDL-C,
once an LDL-C target was achieved, did not further
reduce ASCVD outcomes (9). The Expert Panel also
found extensive RCT evidence that the appropriate in-
tensity of statin therapy should be used to reduce
ASCVD risk in those most likely to beneﬁt. The work of
the Expert Panel was informed by the reports of the
Lifestyle Management (10) and Risk Assessment Work
Groups (11) (Figure 1). A summary of the major rec-
ommendations for the treatment of cholesterol to reduce
ASCVD risk is provided in Table 3.
2.1. Lifestyle as the Foundation for
ASCVD Risk-Reduction Efforts
It must be emphasized that lifestyle modiﬁcation (i.e.,
adhering to a heart-healthy diet, regular exercise habits,
avoidance of tobacco products, and maintenance of a
healthy weight) remains a crucial component of health
promotion and ASCVD risk reduction, both prior to and in
concert with the use of cholesterol-lowering drug therapies.
Healthy diet or lifestyle modiﬁcations were recommended
as background therapy for the RCTs of cholesterol-
lowering drug therapy. See the “2013 AHA/ACC Guide-
line on Lifestyle Management to Reduce Cardiovascular
Risk” (10) for lifestyle recommendations for healthy adults.
Drug therapy for lifestyle-related risk factors such as hy-
pertension is often needed and smoking should be avoided.
Figure 1. Overview of the Expert Panel’s Guideline
RCTs indicates randomized controlled trials.
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Table 3. Summary of Key Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults
(See Tables 4, 8, 9, and 10 for the complete recommendations; and Table 5 for deﬁnition of statin intensity)
Recommendations
ACC/AHA COR
ACC/AHA LOE
A. Heart-healthy lifestyle habits should be encouraged for all individuals
B. The appropriate intensity of statin therapy should be initiated or continued:
1. Clinical ASCVD*
a. Age 75 y and no safety concerns: High-intensity statin
I
A
b. Age >75 y or safety concerns: Moderate-intensity statin
I
A
2. Primary prevention – Primary LDL-C ‡190 mg/dL
a. Rule out secondary causes of hyperlipidemia (Table 6)
I
B
b. Age 21 y: High-intensity statin
I
B
c. Achieve at least a 50% reduction in LDL-C
IIa
B
d. LDL-C lowering nonstatin therapy may be considered to further reduce LDL-C
IIb
C
3. Primary preventiondDiabetes 40–75 years of age and LDL-C 70–189 mg/dL
a. Moderate-intensity statin
I
A
b. Consider high-intensity statin when 7.5% 10-y ASCVD risk using the Pooled Cohort Equationsy
IIa
B
4. Primary prevention – No diabetes 40–75 years of age and LDL-C 70–189 mg/dL
a. Estimate 10-y ASCVD risk using the Risk Calculator based on the Pooled Cohort Equationsy in those NOT receiving a statin;
estimate risk every 4–6 y
I
B
b. To determine whether to initiate a statin, engage in a clinician-patient discussion of the potential for ASCVD risk reduction,
adverse effects, drug–drug interactions, and patient preferences
c. Re-emphasize heart-healthy lifestyle habits and address other risk factors
IIa
C
i. ‡7.5% 10-y ASCVD risk: Moderate- or high-intensity statin
I
A
ii. 5 to <7.5% 10-y ASCVD risk: Consider moderate-intensity statin
IIa
B
iii. Other factors may be consideredz: LDL-C 160 mg/dL, family history of premature ASCVD, hs-CRP 2.0 mg/L,
CAC score 300 Agaston units, ABI <0.9, or lifetime ASCVD risk
IIb
C
5. Primary prevention when LDL-C <190 mg/dL and age <40 or >75 y, or <5% 10-y ASCVD risk
a. Statin therapy may be considered in selected individualsz
IIb
C
6. Statin therapy is not routinely recommended for individuals with NYHA class II-IV heart failure or who are receiving
maintenance hemodialysis
C. Regularly monitor adherence to lifestyle and drug therapy with lipid and safety assessments
1. Assess adherence, response to therapy, and adverse effects within 4–12 wk following statin initiation or change in therapy
I
A
a. Measure a fasting lipid panel
I
A
b. Do not routinely monitor ALT or CK unless symptomatic
IIa
C
c. Screen and treat type 2 diabetes according to current practice guidelines. Heart-healthy lifestyle habits should be encouraged
to prevent progression to diabetes
I
B
d. Anticipated therapeutic response: approximately 50% reduction in LDL-C from baseline for high-intensity statin and
30% to <50% for moderate-intensity statin
IIa
B
i. Insufﬁcient evidence for LDL-C or non–HDL-C treatment targets from RCTs
ii. For those with unknown baseline LDL-C, an LDL-C <100 mg/dL was observed in RCTs of high-intensity statin therapy
e. Less than anticipated therapeutic response:
i. Reinforce improved adherence to lifestyle and drug therapy
I
A
ii. Evaluate for secondary causes of hyperlipidemia if indicated (Table 6)
I
A
iii. Increase statin intensity, or if on maximally-tolerated statin intensity, consider addition of nonstatin therapy in selected
high-risk individualsx
IIb
C
f. Regularly monitor adherence to lifestyle and drug therapy every 3–12 mo once adherence has been established. Continue
assessment of adherence for optimal ASCVD risk reduction and safety
I
A
D. In individuals intolerant of the recommended intensity of statin therapy, use the maximally tolerated intensity of
statin.
I
B
1. If there are muscle or other symptoms, establish that they are related to the statin
IIa
B
2. For speciﬁc recommendations on managing muscle symptoms (Table 8)
*Clinical ASCVD includes acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of
atherosclerotic origin.
yEstimated 10-year or “hard” ASCVD risk includes ﬁrst occurrence of nonfatal MI, CHD death, and nonfatal and fatal stroke as used by the Risk Assessment Work Group in developing the Pooled Cohort
Equations (http://my.americanheart.org/cvriskcalculator and http://www.cardiosource.org/en/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/2013-Prevention-Guideline-Tools.aspx).
zThese factors may include primary LDL-C 160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset <55 years of age in a ﬁrst-degree male relative or <65
years of age in a ﬁrst-degree female relative; hs-CRP 2 mg/L; CAC score 300 Agatston units or 75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/
CACReference.aspx); ABI <0.9; or lifetime risk of ASCVD. Additional factors that might aid in individual risk assessment could be identiﬁed in the future.
xHigh-risk individuals include those with clinical ASCVD, an untreated LDL-C 190 mg/dL suggesting genetic hypercholesterolemia, or individuals with diabetes 40 to 75 years of age and LDL-C 70 to
189 mg/dL.
ABI indicates ankle-brachial index; ACC, American College of Cardiology; AHA, American Heart Association; ALT, alanine aminotransferase, a test of hepatic function; ASCVD, atherosclerotic cardiovascular
disease; CAC, coronary artery calcium; CHD, coronary heart disease; CK, creatine kinase, a test of muscle injury; COR, Class of Recommendation; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-
sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; LOE, Level of Evidence; NHLBI, National Heart, Lung, and Blood Institute; NYHA, New York Heart Association; RCTs, randomized
controlled trials; and TIA, transient ischemic attack.
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2.2. Initiation of Statin Therapy
The Expert Panel found extensive and consistent evidence
supporting the use of statins for the prevention of ASCVD
in many higher-risk primary- and all secondary-prevention
individuals without New York Heart Association class
II–IV heart failure who were not receiving hemodialysis.
In the RCTs reviewed, initiation of moderate-intensity
therapy
(lowering
LDL-C
by
approximately
30%
to <50%) or high-intensity statin therapy (lowering LDL-C
by approximately 50%) is a critical factor in reducing
ASCVD events. Moreover, statin therapy reduces ASCVD
events
across
the
spectrum
of
baseline
LDL-C
levels 70 mg/dL. In addition, the relative reduction
in ASCVD risk is consistent for primary and secondary
prevention and for various patient subgroups. Of note,
the absolute reduction in ASCVD events is proportional
to baseline absolute ASCVD risk. Therefore, statin
therapy is recommended for individuals at increased
ASCVD risk who are most likely to experience a net
beneﬁt in terms of the potential for ASCVD risk
reduction and the potential for adverse effects (Table 3;
Figure 2).
On the basis of this large and consistent body of evi-
dence, 4 major statin beneﬁt groups were identiﬁed for
whom the ASCVD risk reduction clearly outweighs the
risk of adverse events based on a strong body of evidence.
These are 1) secondary prevention in individuals with
clinical ASCVD, 2) primary prevention in individuals with
primary elevations of LDL-C 190 mg/dL, 3) primary
prevention in individuals with diabetes 40 to 75 years of
age who have LDL-C 70 to 189 mg/dL, and 4) primary
prevention in individuals without diabetes and with esti-
mated 10-year ASCVD risk 7.5%, 40 to 75 years of age
who have LDL-C 70 to 189 mg/dL. Moderate evidence
supports the use of statins for primary prevention in in-
dividuals with 5% to <7.5% 10-year ASCVD risk, 40 to
75 years of age with LDL-C 70 to 189 mg/dL. Selected
individuals with <5% 10-year ASCVD risk, or <40 or
>75 years of age may also beneﬁt from statin therapy.
Clinicians and patients should engage in a discussion of the
potential for ASCVD risk-reduction beneﬁts, adverse ef-
fects, drug–drug interactions, and consider patient prefer-
ences for treatment. This discussion also provides the
opportunity to re-emphasize healthy-lifestyle habits and
address other risk factors.
Clinical ASCVD is deﬁned by the inclusion criteria for
the secondary-prevention statin RCTs (acute coronary
syndromes, a history of MI, stable or unstable angina,
coronary or other arterial revascularization, stroke, tran-
sient ischemic attack, or peripheral arterial disease pre-
sumed to be of atherosclerotic origin). For primary
prevention in individuals without clinical ASCVD or
diabetes who have an LDL-C 70 to 189 mg/dL, the
estimated absolute 10-year risk of ASCVD (deﬁned as
nonfatal MI, CHD death, or nonfatal and fatal stroke)
should be used to guide the initiation of statin therapy.
The 10-year ASCVD risk should be estimated with the
Pooled Cohort Equations (Section 4.7). For the primary
prevention of ASCVD in individuals with diabetes
(diabetes mellitus type 1 and type 2), estimated 10-year
ASCVD risk can also be used to guide the intensity of
statin therapy. For those with clinical ASCVD or with
LDL-C 190 mg/dL who are already in a statin beneﬁt
group, it is not appropriate to estimate 10-year ASCVD
risk. In primary prevention, additional factors may in-
ﬂuence ASCVD risk in those for whom a risk-based
decision is unclear. These include a primary LDL-
C 160 mg/dL or other evidence of genetic hyperlip-
idemias, family history of premature ASCVD with
onset <55 years of age in a ﬁrst-degree male relative
or <65 years of age in a ﬁrst-degree female relative, high-
sensitivity C-reactive protein 2 mg/L, coronary artery
calcium score 300 Agatston units or 75th percentile
for age, sex, and ethnicity (for additional information,
see http://www.mesa-nhlbi.org/CACReference.aspx.), ankle-
brachial index <0.9, and elevated lifetime risk of
ASCVD.
The ﬁndings support the use of statins to prevent both
nonfatal and fatal ASCVD events. Such an approach can
reduce the large burden of disability from nonfatal stroke
(for which women are at higher risk than men) and
nonfatal CHD events. Primary and secondary prevention
of ASCVD with statins can positively impact rising
healthcare costs. In addition, a high level of evidence was
found that statins reduce total mortality in individuals with
a history of prior ASCVD events (e.g., secondary-
prevention settings). In individuals with no prior history
of ASCVD events (e.g., primary-prevention settings),
there is moderate evidence that statins reduce total mor-
tality in individuals at increased ASCVD risk. It should be
noted that 2 meta-analyses published after the completion
of the Expert Panel’s systematic review provide strong
evidence that statins reduce total mortality in primary
prevention (12,13).
3. Critical Questions and Conclusions
3.1. Identiﬁcation of CQs
Although limited to 3 CQs, these questions were consid-
ered the most important to answer in order to identify
whom to treat and with what treatment(s) and to consider
how intensively the treatments should be used. The ﬁrst 2
CQs evaluated the evidence for LDL-C and non–HDL-C
goals for the secondary and primary prevention of ASCVD
with cholesterol-lowering drug therapy. Titration to spe-
ciﬁc LDL-C goals has been considered a fundamental
therapeutic strategy in deciding on the adequacy of
cholesterol-lowering therapy for secondary and primary
prevention. Therefore, a comprehensive systematic review
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Yes
Age ≤75 y
High-intensity statin
(Moderate-intensity statin if not 
candidate for high-intensity statin)
Age ≥21 y and a candidate 
for statin therapy
Yes
High-intensity statin
(Moderate-intensity statin if not 
candidate for high-intensity statin)
Yes
No
Moderate-intensity statin
No
Primary prevention 
(No diabetes, LDL-C 70 to 189 mg/dL, and not receiving statin therapy)
Estimate 10-y ASCVD risk every 4-6 y
using Pooled Cohort Equations†
No
In selected individuals, additional 
factors may be considered to inform 
treatment decision making§
Heart-healthy lifestyle habits are the foundation of ASCVD prevention
(See 2013 AHA/ACC Lifestyle Management Guideline)
Yes
Estimated 10-y ASCVD risk ≥7.5%†
High-intensity statin
Age >75 y OR if not candidate for 
high-intensity statin
Moderate-intensity statin
Yes
Yes
Clinical 
ASCVD
LDL-C ≥190 
mg/dL
Diabetes
LDL-C 70-189 mg/dL
Age 40-75 y
Definitions of High- and Moderate-
Intensity Statin Therapy*
(See Table 5)
High
Daily dose lowers 
LDL-C by approx. 
≥50%
Moderate
Daily dose lowers 
LDL-C by approx. 
30% to <50%
≥7.5%
10-y ASCVD risk
(Moderate- or high-
intensity statin)
5% to <7.5%
10-y ASCVD risk
(Moderate-intensity 
statin)
<5%
10-y ASCVD 
risk‡
Age <40 or >75 y 
and LDL-C <190 
mg/dL‡
Clinician-Patient Discussion
Prior to initiating statin therapy, discuss:
    1. Potential for ASCVD risk-reduction benefits║
    2. Potential for adverse effects and drug–drug interactions¶
    3. Heart-healthy lifestyle
    4. Management of other risk factors
    5. Patient preferences
    6. If decision is unclear, consider primary LDL-C ≥160 mg/dL, family history of premature 
        ASCVD, lifetime ASCVD risk, abnormal CAC score or ABI, or hs-CRP ≥2 mg/L§
No to statin
Yes to statin
 Encourage adherence to lifestyle 
 Initiate statin at appropriate intensity
 Manage other risk factors
 Monitor adherence* (See Fig 5)
 Emphasize adherence to lifestyle 
 Manage other risk factors
 Monitor adherence
DM age <40 
or >75 y or 
LDL-C <70 
mg/dL
Regularly monitor adherence to 
lifestyle and drug therapy with 
lipid and safety assessments 
(See Fig 5)
Figure 2. Summary of Statin Initiation Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults
(See Figures 3, 4, and 5 for More Detailed Management Information)
Colors correspond to the Classes of Recommendation in Table 1. Assessment of the potential for beneﬁt and risk from statin therapy for ASCVD prevention provides the
framework for clinical decision making incorporating patient preferences.
*Percent reduction in LDL-C can be used as an indication of response and adherence to therapy, but is not in itself a treatment goal.
yThe Pooled Cohort Equations can be used to estimate 10-year ASCVD risk in individuals with and without diabetes. The estimator within this application should be used to
inform decision making in primary prevention patients not on a statin.
zConsider moderate-intensity statin as more appropriate in low-risk individuals.
xFor those in whom a risk assessment is uncertain, consider factors such as primary LDL-C 160 mg/dL or other evidence of genetic hyperlipidemias, family history of
premature ASCVD with onset <55 years of age in a ﬁrst-degree male relative or <65 years of age in a ﬁrst-degree female relative, hs-CRP 2 mg/L, CAC score 300 Agatston
units, or 75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx), ABI <0.9, or lifetime risk of ASCVD.
Additional factors that may aid in individual risk assessment may be identiﬁed in the future.
kPotential ASCVD risk-reduction beneﬁts. The absolute reduction in ASCVD events from moderate- or high-intensity statin therapy can be approximated by multiplying the estimated
10-year ASCVD risk by the anticipated relative-risk reduction from the intensity of statin initiated (w30% for moderate-intensity statin or w45% for high-intensity statin therapy).
The net ASCVD risk-reduction beneﬁt is estimated from the number of potential ASCVD events prevented with a statin, compared to the number of potential excess adverse effects.
{Potential adverse effects. The excess risk of diabetes is the main consideration in w0.1 excess cases per 100 individuals treated with a moderate-intensity statin for
1 year and w0.3 excess cases per 100 individuals treated with a high-intensity statin for 1 year. In RCTs, both statin-treated and placebo-treated participants experienced the
same rate of muscle symptoms. The actual rate of statin-related muscle symptoms in the clinical population is unclear. Muscle symptoms attributed to statin therapy should
be evaluated (see Table 8, Safety Recommendation 8).
ABI indicates ankle-brachial index; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density
lipoprotein cholesterol; MI, myocardial infarction; and RCT, randomized controlled trial.
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of the evidence base supporting this concept was essential.
The third CQ had several objectives:
 Identify groups of patients who will beneﬁt from
pharmacological treatment,
 Deﬁne the pharmacological treatment(s) for which
there is the best evidence of net beneﬁt, and
 Provide guidance on the appropriate intensity of
pharmacological treatment to reduce ASCVD risk.
3.1.1. CQ1: LDL-C and Non–HDL-C Goals
in Secondary Prevention
CQ1: What is the evidence for LDL-C and non–HDL-C
goals for the secondary prevention of ASCVD?
The Expert Panel reviewed 19 RCTs to answer CQ1.
Although CQ1 is supported conceptually by an extrapo-
lation of observational studies and observational data from
RCTs, no data were identiﬁed for treatment or titration
to a speciﬁc LDL-C goal in adults with clinical ASCVD.
The majority of studies conﬁrming the efﬁcacy of
cholesterol reduction in improving clinical outcomes in
patients with clinical ASCVD used a single ﬁxed-dose
statin to lower LDL-C levels. In the 4S trial, 37% had
the dose of simvastatin raised from 20 mg/d to 40 mg/d to
achieve a total cholesterol level <200 mg/dL (16). The
Expert Panel was unable to ﬁnd any RCTs that evaluated
titration of all individuals in a treatment group to speciﬁc
LDL-C targets <100 mg/dL or <70 mg/dL, nor were any
RCTs comparing 2 LDL-C treatment targets identiﬁed.
No statin RCTs reporting on-treatment non–HDL-C
levels were identiﬁed. (In CQ3, statin-nonstatin combina-
tion therapy was evaluated.)
3.1.2. CQ2: LDL-C and Non–HDL-C Goals in
Primary Prevention
CQ2: What is the evidence for LDL-C and non–HDL-C
goals for the primary prevention of ASCVD?
The Expert Panel reviewed 6 RCTs. The 4 studies con-
ﬁrming the efﬁcacy of cholesterol reduction in improving
clinical outcomes in patients without ASCVD used ﬁxed-
dose statin therapy to lower LDL-C levels. In the
AFCAPS-TEXCAPS
(Air
Force/Texas
Coronary
Atherosclerosis Prevention Study) trial (17), in 50% of
participants, the lovastatin dose was raised from 20 mg to
40 mg to achieve an LDL-C level <110 mg/dL. In the
MEGA (Management of Elevated Cholesterol in the
Primary Prevention Group of Adult Japanese) trial (18),
the dose of pravastatin could be uptitrated from 10 mg to
20 mg to achieve a total cholesterol level <220 mg/dL.
The Expert Panel did not ﬁnd any RCTs that evaluated
titration of all individuals in a treatment group to speciﬁc
LDL-C targets <100 mg/dL or <70 mg/dL, nor were any
RCTs comparing 2 LDL-C treatment targets identiﬁed.
No trials reported on-treatment non–HDL-C levels.
3.1.3. CQ3: Efﬁcacy and Safety of
Cholesterol-Lowering Medications
CQ3: For primary and secondary prevention, what is
the impact on lipid levels, effectiveness, and safety of
speciﬁc cholesterol-modifying drugs used for lipid
management in general and in selected subgroups?
The populations examined included primary-prevention
adult patients who could not have a diagnosis of CHD
or cardiovascular disease. Interventions included pharma-
cotherapy with single-drug therapies or combination-drug
therapies with any drug therapy used for treating blood
cholesterol, including statins, ﬁbrates (fenoﬁbrate, gemﬁ-
brozil), nicotinic acid (niacin in immediate-, slow-, or
extended-release form), bile acid sequestrants, ezetimibe,
omega-3 fatty acids (also called marine fatty acids, in-
cluding eicosapentaenoic acid alone, docosahexanoic acid
alone, eicosapentaenoic acid plus docosahexanoic acid, and
alpha-linolenic acid). There were no ASCVD outcomes
identiﬁed for plant sterols, sterol esters, stanols, or stanol
esters. A single ASCVD outcomes trial (19) used Xuez-
hikang, an extract from red yeast Chinese rice, which was
not available in the United States during the timeframe
for evidence review, so no recommendations were made
regarding its use.
The recommendations synthesize the evidence retrieved
for answering CQ3, along with the evidence from the trials
included in CQ1 and CQ2, to guide the use of cholesterol-
lowering drugs for secondary or primary prevention of
ASCVD.
4. Statin Treatment: Recommendations
For each recommendation, the grades of the recom-
mendation
by
both
the
NHLBI
and
ACC/AHA
methods are provided. Major treatment recommenda-
tions are listed in Table 4, and statin intensities are
deﬁned in Table 5. The safety (statin and nonstatin)
recommendations are in Section 5. A complete listing
of the evidence statements supporting each recom-
mendation, along with the references, is provided in
Appendix 4.
4.1. Intensity of Statin Therapy in
Primary and Secondary Prevention
The Expert Panel deﬁnes the intensity of statin therapy
on the basis of the average expected LDL-C response to
a speciﬁc statin and dose. “High-intensity,” “moderate-
intensity,” and “low-intensity” statin therapy deﬁnitions
were derived from the systematic reviews for CQ1 and
CQ2. The basis for differentiation among speciﬁc statins
and doses arose from the RCTs included in CQ1, where
there was a high level of evidence that high-intensity
statin therapy with atorvastatin 40 mg to 80 mg
reduced ASCVD risk more than moderate-intensity
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Table 4. Recommendations for Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adultsd
Statin Treatment (High, Moderate, and Low Statin Intensities are Deﬁned in Table 5)
Recommendations
NHLBI Grade
NHLBI Evidence
Statements
ACC/AHA COR
ACC/AHA LOE
Treatment Targets
1. The Expert Panel makes no recommendations for or
against speciﬁc LDL-C or non–HDL-C targets for the
primary or secondary prevention of ASCVD.
N (No recommendation)
1–4
d
d
Secondary Prevention
1. High-intensity statin therapy should be initiated or
continued as ﬁrst-line therapy in women and men
75 years of age who have clinical ASCVD*, unless
contraindicated.
A (Strong)
1,6–8,10–23,26–28
I
A
2. In individuals with clinical ASCVD* in whom high-
intensity statin therapy would otherwise be used, when
high-intensity statin therapy is contraindicatedy or
when characteristics predisposing to statin-associated
adverse effects are present, moderate-intensity statin
should be used as the second option if tolerated
(Table 8 for Safety of Statins, Recommendation 1).
A (Strong)
13–22,24,27,28
I
A
3. In individuals with clinical ASCVD >75 years of age, it
is reasonable to evaluate the potential for ASCVD risk-
reduction beneﬁts and for adverse effects and drug–drug
interactions and to consider patient preferences when
initiating a moderate- or high-intensity statin. It is
reasonable to continue statin therapy in those who are
tolerating it.
E (Expert Opinion)
d
IIa
B
(16,20–43)
Primary Prevention in Individuals ‡21 Years of Age With LDL-C ‡190 mg/dL
1. Individuals with LDL-C 190 mg/dL or triglycerides
500 mg/dL should be evaluated for secondary causes
of hyperlipidemia (Table 6).
B (Moderate)
75
Iz
B
(44,45)
2. Adults 21 years of age with primary LDL-C 190 mg/
dL should be treated with statin therapy (10-year ASCVD
risk estimation is not required):
 Use high-intensity statin therapy unless
contraindicated.
 For individuals unable to tolerate high-intensity statin
therapy, use the maximum tolerated statin intensity.
B (Moderate)
6,19,28,33–35,37,38
Ix
B
3. For individuals 21 years of age with an untreated
primary LDL-C 190 mg/dL, it is reasonable to intensify
statin therapy to achieve at least a 50% LDL-C reduction.
E (Expert Opinion)
d
IIa
B
(20,46–50)
4. For individuals 21 years of age with an untreated pri-
mary LDL-C 190 mg/dL, after the maximum intensity
of statin therapy has been achieved, addition of a non-
statin drug may be considered to further lower LDL-C.
Evaluate the potential for ASCVD risk-reduction beneﬁts,
adverse effects, and drug–drug interactions, and consider
patient preferences.
E (Expert Opinion)
d
IIb
C
(51)
Primary Prevention in Individuals With Diabetes and LDL-C 70–189 mg/dL
1. Moderate-intensity statin therapy should be initiated
or continued for adults 40–75 years of age with diabetes.
A (Strong)
19,29–34,40
I
A
2. High-intensity statin therapy is reasonable for adults
40–75 years of age with diabetes with a 7.5%
estimated 10-year ASCVD riskk unless contraindicated.
E (Expert Opinion)
d
IIa
B
(49,52)
3. In adults with diabetes, who are <40 years of age or
>75 years of age, or with LDL <70 mg/dL it is reason-
able to evaluate the potential for ASCVD beneﬁts and for
adverse effects and drug–drug interactions and to
consider patient preferences when deciding to initiate,
continue, or intensify statin therapy.
E (Expert Opinion)
d
IIa
C
(53–62)
Continued on the next page
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statin therapy with atorvastatin 10 mg, pravastatin 40 mg,
or simvastatin 20 mg to 40 mg twice daily. Classifying
speciﬁc statins and doses by the percent reduction in
LDL-C level is based on evidence that the relative
reduction in ASCVD risk from statin therapy is related to
the degree by which LDL-C is lowered. However, no
variation in the relative reduction in ASCVD risk was
observed after the data were adjusted for LDL-C reduc-
tion. Furthermore, there is no differentiation between the
speciﬁc statins and doses used in primary- and secondary-
prevention RCTs, according to a high level of evidence
that statins reduce
ASCVD risk similarly in both
populations.
Percent reductions in LDL-C for a speciﬁc statin and
dose were calculated for the RCTs included in individual
meta-analyses conducted by the Cholesterol Treatment
Trialists (CTT) in 2010 (20), in which statin therapy
reduced ASCVD events. High-intensity statin therapy
on average lowers LDL-C by approximately 50%,
moderate-intensity
statin
therapy
lowers
LDL-C
by
approximately 30% to <50%, and lower-intensity statin
therapy lowers LDL-C by <30% (Table 5).
4.2. LDL-C and Non–HDL-C Treatment Goals
The Expert Panel did not ﬁnd evidence to support titrating
cholesterol-lowering drug therapy to achieve optimal
Table 4. Continued
Recommendations
NHLBI Grade
NHLBI Evidence
Statements
ACC/AHA COR
ACC/AHA LOE
Primary Prevention in Individuals Without Diabetes and With LDL-C 70–189 mg/dL
1. The Pooled Cohort Equations should be used to estimate
10-year ASCVDk risk for individuals with LDL-C 70–189
mg/dL without clinical ASCVD* to guide initiation of
statin therapy for the primary prevention of ASCVD.
E (Expert Opinion)
d
I
B
(11)
2. Adults 40–75 years of age with LDL-C 70–189 mg/dL,
without clinical ASCVD* or diabetes, and with an
estimated 10-year ASCVDk risk 7.5% should be treated
with moderate- to high-intensity statin therapy.
A (Strong)
28,34–36,38,42–44,
47,49–56,76
I
A
3. It is reasonable to offer treatment with a moderate-
intensity statin to adults 40–75 years of age, with LDL-C
70–189 mg/dL, without clinical ASCVD* or diabetes, and
with an estimated 10-year ASCVDk risk of 5% to <7.5%.
C (Weak)
28,34–36,38,42–44,
47,49–56,76
IIa
B
4. Before initiation of statin therapy for the primary pre-
vention of ASCVD in adults with LDL-C 70–189 mg/dL
without clinical ASCVD* or diabetes, it is reasonable for
clinicians and patients to engage in a discussion that
considers the potential for ASCVD risk-reduction beneﬁts
and for adverse effects and drug–drug interactions, as
well as patient preferences for treatment.
E (Expert Opinion)
d
IIa
C
(63)
5. In adults with LDL-C <190 mg/dL who are not otherwise
identiﬁed in a statin beneﬁt group, or for whom after
quantitative risk assessment a risk-based treatment
decision is uncertain, additional factors{ may be
considered to inform treatment decision making. In
these individuals, statin therapy for primary prevention
may be considered after evaluation of the potential for
ASCVD risk-reduction beneﬁts, adverse effects, and drug–
drug interactions and consider patient preferences.
E (Expert Opinion)
d
IIb
C
(11,13)
Heart Failure and Hemodialysis
1. The Expert Panel makes no recommendations regarding
the initiation or discontinuation of statins in patients with
NYHA class II–IV ischemic systolic heart failure or in pa-
tients on maintenance hemodialysis.
N (No Recommendation)
71,72
d
d
*Clinical ASCVD includes acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of
atherosclerotic origin.
yContraindications, warnings, and precautions are deﬁned for each statin according to the manufacturer’s prescribing information (64–70).
zIndividuals with secondary causes of hyperlipidemia were excluded from RCTs reviewed. A triglyceride level 500 mg/dL was an exclusion criterion for almost all RCTs. Therefore, ruling out secondary
causes is necessary to avoid inappropriate statin therapy.
xNo RCTs included only individuals with LDL-C 190 mg/dL. However, many trials did include individuals with LDL-C 190 mg/dL, and all of these trials consistently demonstrated a reduction in ASCVD
events. In addition, the Cholesterol Treatment Trialists meta-analyses have shown that each 39-mg/dL reduction in LDL-C with statin therapy reduced ASCVD events by 22%, and the relative reductions in
ASCVD events were consistent across the range of LDL-C levels. Therefore, individuals with primary LDL-C 190 mg/dL should be treated with statin therapy.
kEstimated 10-year or “hard” ASCVD risk includes ﬁrst occurrence of nonfatal MI, coronary heart disease death, and nonfatal and fatal stroke as used by the Risk Assessment Work Group in developing
the Pooled Cohort Equations.
{These factors may include primary LDL-C 160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset <55 years of age in a ﬁrst-degree male relative or <65
years of age in a ﬁrst-degree female relative; high-sensitivity C-reactive protein 2 mg/L; CAC score 300 Agatston units or 75th percentile for age, sex, and ethnicity (for additional information, see
http://www.mesa-nhlbi.org/CACReference.aspx); ABI <0.9; or lifetime risk of ASCVD. Additional factors that might aid in individual risk assessment could be identiﬁed in the future.
ABI indicates ankle-brachial index; ACC, American College of Cardiology; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; COR, Class of
Recommendation; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LOE, Level of Evidence; NHLBI, National Heart, Lung, and Blood Institute; NYHA, New York Heart
Association; RCTs, randomized controlled trials; TIA, transient ischemic attack; and d, not applicable.
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LDL-C or non–HDL-C levels because the clinical trials
were essentially ﬁxed-dose trials (CQ1 and CQ2). Dosage
increases did occur in a few RCTs with the intent of
maximizing statin therapy. Therefore, these were not truly
tests of deﬁning optimal goals for LDL-C in primary and
secondary prevention because not all individuals in the
statin treatment groups received drug therapy titrated
to achieve a speciﬁc LDL-C or non–HDL-C goal, nor
were speciﬁc treatment targets compared. One RCT in
CQ3 was identiﬁed that showed no additional ASCVD
event reduction from the addition of nonstatin therapy to
further lower non–HDL-C levels once an LDL-C goal
had been reached. In AIM-HIGH (Atherothrombosis
Intervention in Metabolic Syndrome With Low HDL/
High Triglycerides and Impact on Global Health Out-
comes), the additional reduction in non–HDL-C levels
(as well as further reductions in apolipoprotein B, lipo-
protein[a], and triglycerides in addition to HDL-C
increases) with niacin therapy did not further reduce
ASCVD risk in individuals treated to LDL-C levels of 40
to 80 mg/dL (9).
Therefore, given the absence of data on titration of drug
therapy to speciﬁc goals, no recommendations are made for
or against speciﬁc LDL-C or non–HDL-C goals for the
primary or secondary prevention of ASCVD.
4.3. Secondary Prevention
Women and men with clinical ASCVD (deﬁned from the
RCT inclusion criteria as acute coronary syndromes; history
of MI, stable or unstable angina, coronary or other arterial
revascularization, stroke, transient ischemic attack, or pe-
ripheral arterial disease presumed to be of atherosclerotic
origin) arterial revascularization, stroke, transient ischemic
attack, or peripheral arterial disease presumed to be of
atherosclerotic origin are at increased risk for recurrent
ASCVD and ASCVD death. An extensive body of evi-
dence demonstrates that high-intensity statin therapy re-
duces ASCVD events more than moderate-intensity statin
therapy (Table 4) in individuals with clinical ASCVD.
High-intensity statin therapy should be initiated for
adults 75 years of age with clinical ASCVD who are not
receiving statin therapy, or the intensity should be increased
in those receiving a low- or moderate-intensity statin, un-
less they have a history of intolerance to high-intensity
statin therapy or other characteristics that could inﬂuence
safety (Section 5). This is consistent with RCT data. In
2 trials, patients were previously treated with a moderately
intensive statin (46,47), and in 2 trials, 75% to 97% of
patients had not received prior statin therapy (48,78). The
high-intensity statins atorvastatin 80 mg and rosuvastatin
20 mg daily reduce LDL-C 50% on average and have
been shown to reduce ASCVD events in RCTs.
Although atorvastatin 40 mg reduces LDL-C by app-
roximately 50%, this dose was used in only 1 RCT if the
participant was unable to tolerate atorvastatin 80 mg/dL.
Whether an individual receiving atorvastatin 40 mg should
be uptitrated to atorvastatin 80 mg should be based on the
potential for an ASCVD risk-reduction beneﬁt and the
potential for adverse effects, drug–drug interactions, and
consider patient preferences.
In individuals with clinical ASCVD in whom high-
intensity statin therapy would otherwise be used, either
when high-intensity statintherapy iscontraindicated or when
characteristics predisposing to statin-associated adverse ef-
fects are present, moderate-intensity statin should be used as
the second option, if tolerated (Section 5). In the relatively
few individuals >75 years of age who were included in
RCTs of high- versus moderate-intensity statin therapy,
there was no clear evidence of an additional reduction in
ASCVD events from high-intensity statin therapy. In
contrast, individuals >75 years of age did experience a
reduction in ASCVD events in the trials of mostly moderate-
intensity statin therapy, as compared with control. Therefore,
moderate-intensity statin therapy should be considered for
individuals >75 years of age with clinical ASCVD. However,
in acknowledgment that older participants in RCTs were
likelytobehealthierthanmanyolderindividualsinthegeneral
population, the use of statin therapy should be individualized
Table 5. High-, Moderate-, and Low-Intensity Statin Therapy (Used in the RCTs Reviewed by the Expert Panel)*
High-Intensity Statin Therapy
Moderate-Intensity Statin Therapy
Low-Intensity Statin Therapy
Daily dose lowers LDL-C, on average,
by approximately 50%
Daily dose lowers LDL-C, on average,
by approximately 30% to <50%
Daily dose lowers LDL-C,
on average, by <30%
Atorvastatin (40y)–80 mg
Rosuvastatin 20 (40) mg
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20–40 mgz
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg BID
Pitavastatin 2–4 mg
Simvastatin 10 mg
Pravastatin 10–20 mg
Lovastatin 20 mg
Fluvastatin 20–40 mg
Pitavastatin 1 mg
Boldface type indicates speciﬁc statins and doses that were evaluated in RCTs (16–18,46–49,64–75,77) included in CQ1, CQ2, and the Cholesterol Treatment Trialists 2010 meta-analysis included in
CQ3 (20). All of these RCTs demonstrated a reduction in major cardiovascular events. Italic type indicates statins and doses that have been approved by the FDA but were not tested in the RCTs reviewed.
*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biological basis for a less-than-average response.
yEvidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in the IDEAL (Incremental Decrease through Aggressive Lipid Lowering) study (47).
zAlthough simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA because of the increased risk of myopathy, including
rhabdomyolysis.
BID indicates twice daily; CQ, critical question; FDA, Food and Drug Administration; LDL-C, low-density lipoprotein cholesterol; and RCTs, randomized controlled trials.
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in persons >75 years of age with clinical ASCVD, according
to the potential for ASCVD risk-reduction beneﬁts, adverse
effects, drug–drug interactions, and consider patient prefer-
ences. The Expert Panel considers it reasonable to continue
statin therapy in persons >75 years of age who have clinical
ASCVD and are tolerating statin therapy.
The ﬂow diagram for the initiation and management of
statin therapy in individuals with clinical ASCVD is pro-
vided in Figure 3.
4.4. Primary Prevention in Individuals
‡21 Years of Age With LDL-C ‡190 mg/dL
This guideline recognizes that individuals 21 years of age
with primary, severe elevations of LDL-C (190 mg/dL)
have a high lifetime risk for ASCVD events. This is due to
their lifetime exposure to markedly elevated LDL-C
levels arising from genetic causes. Thus, at age 21, these
individuals should receive statin therapy if they have
not already been diagnosed and treated before this
age. Although in most clinical trials individuals with
LDL-C 190 mg/dL were not included because of their
need for treatment, extensive evidence shows that each 39-
mg/dL reduction in LDL-C by statin therapy reduces
ASCVD risk by about 20%. Patients with primary elevations
of LDL-C 190 mg/dL require even more substantial re-
ductions in their LDL-C levels and intensive management
Figure 3. Initiating Statin Therapy in Individuals With Clinical ASCVD
Colors correspond to the Classes of Recommendation in Table 1.
*Fasting lipid panel preferred. In a nonfasting individual, a non–HDL-C level 220 mg/dL could indicate genetic hypercholesterolemia that requires further evaluation or a
secondary etiology. If nonfasting triglycerides are 500 mg/dL, a fasting lipid panel is required.
yIt is reasonable to evaluate the potential for ASCVD beneﬁts and for adverse effects, and to consider patient preferences, in initiating or continuing a moderate- or high-intensity
statin in individuals with ASCVD who are >75 years of age.
ALT indicates alanine transaminase; ASCVD, atherosclerotic cardiovascular disease; CK, creatine kinase; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein
cholesterol; and ULN, upper limit of normal.
Table 6. Secondary Causes of Hyperlipidemia Most
Commonly Encountered in Clinical Practice
Secondary Cause
Elevated LDL-C
Elevated
Triglycerides
Diet
Saturated or trans fats,
weight gain, anorexia
nervosa
Weight gain, very-low-fat
diets, high intake
of reﬁned carbohydrates,
excessive alcohol intake
Drugs
Diuretics, cyclosporine,
glucocorticoids,
amiodarone
Oral estrogens,
glucocorticoids, bile acid
sequestrants,
protease inhibitors,
retinoic acid, anabolic
steroids, sirolimus,
raloxifene, tamoxifen,
beta blockers
(not carvedilol), thiazides
Diseases
Biliary obstruction,
nephrotic syndrome
Nephrotic syndrome,
chronic renal failure,
lipodystrophies
Disorders and
altered states
of metabolism
Hypothyroidism,
obesity, pregnancy*
Diabetes (poorly controlled),
hypothyroidism, obesity;
pregnancy*
Adapted with permission from Stone et al (80).
*Cholesterol and triglycerides rise progressively throughout pregnancy (80); treatment with
statins, niacin, and ezetimibe are contraindicated during pregnancy and lactation.
LDL-C indicates low-density lipoprotein cholesterol.
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Figure 4. Initiating Statin Therapy in Individuals Without Clinical ASCVD
Colors correspond to the Classes of Recommendation in Table 1.
*Fasting lipid panel preferred. In a nonfasting individual, a non–HDL-C level 220 mg/dL could indicate genetic hypercholesterolemia that requires further evaluation or a
secondary etiology. If nonfasting triglycerides are 500 mg/dL, a fasting lipid panel is required.
yThe Pooled Cohort Equations can be used to estimate 10-year ASCVD risk in individuals with and without diabetes.
A downloadable spreadsheet enabling estimation of 10-year and lifetime risk for ASCVD and a Web-based calculator are available at http://my.americanheart.org/cvriskcalculator
and http://www.cardiosource.org/en/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/2013-Prevention-Guideline-Tools.aspx.
zFor those in whom a risk assessment is uncertain, consider factors such as primary LDL-C 160 mg/dL or other evidence of genetic hyperlipidemias; family history of
premature ASCVD with onset <55 years of age in a ﬁrst-degree male relative or <65 years of age in a ﬁrst-degree female relative, high-sensitivity C-reactive protein 2 mg/L;
CAC 300 Agatston units or 75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx); ABI <0.9; or lifetime
risk of ASCVD. Additional factors that may aid in individual risk assessment could be identiﬁed in the future.
x1) Potential ASCVD risk-reduction beneﬁts. The absolute reduction in ASCVD events from moderate- or high-intensity statin therapy can be approximated by multiplying the
estimated 10-year ASCVD risk by the anticipated relative-risk reduction from the intensity of statin initiated (w30% for moderate-intensity statin or w45% for high-intensity statin
therapy). The net ASCVD risk-reduction beneﬁt is estimated from the number of potential ASCVD events prevented with a statin, compared to the number of potential excess
adverse effects. 2) Potential adverse effects. The excess risk of diabetes is the main consideration in w0.1 excess cases per 100 individuals treated with a moderate-intensity
statin for 1 year and w0.3 excess cases per 100 individuals treated with a high-intensity statin for 1 year. In RCTs, both statin-treated and placebo-treated participants expe-
rienced the same rate of muscle symptoms. The actual rate of statin-related muscle symptoms in the clinical population is unclear. Muscle symptoms attributed to statin therapy
should be evaluated (see Table 8, Safety Recommendation 8).
ABI indicates ankle-brachial index; ALT, alanine transaminase; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CK, creatine kinase; FH, familial
hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; RCT, randomized controlled trial; and ULN, upper limit of normal.
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of other risk factors to reduce their ASCVD event rates.
Therefore, it is reasonable to use high-intensity statin ther-
apy to achieve at least a 50% reduction. It is recognized that
maximal statin therapy might not be adequate to lower
LDL-C sufﬁciently to reduce ASCVD event risk in in-
dividuals with primary severe elevations of LDL-C. In
addition to a maximally tolerated dose of statin, nonstatin
cholesterol-lowering medications are often needed to lower
LDL-C to acceptable levels in these individuals. Because
the hypercholesterolemia in these high-risk individuals is
often genetically determined, family screening is especially
important in this group to identify additional family mem-
bers who would beneﬁt from assessment and early treatment.
Secondary causes of severe elevations of LDL-C 190
mg/dL and triglycerides 500 mg/dL often contribute to
the magnitude of the hyperlipidemia and should be eval-
uated and treated appropriately. For guidance, we note that
in a lipid specialty clinic, the most frequently encountered
secondary conditions were excessive alcohol intake, un-
controlled diabetes, and overt albuminuria (79). Table 6
focuses on secondary causes of hyperlipidemia most likely
encountered in clinical practice (80). Management of in-
dividuals with fasting triglycerides 500 mg/dL has been
addressed in an AHA statement (45).
The ﬂow diagram for the initiation and management of
statin therapy in individuals with LDL-C 190 mg/dL is
provided in Figure 4.
4.5. Primary Prevention in
Individuals With Diabetes
A high level of evidence supports the use of moderate-
intensity statin therapy in persons with diabetes who are
40 to 75 years of age. The only trial of high-intensity statin
therapy in primary prevention was performed in a popu-
lation without diabetes. However, a high level of evidence
existed for event reduction with statin therapy in in-
dividuals with a 7.5% estimated 10-year ASCVD risk
(Section 4.6) who did not have diabetes to recommend
high-intensity statin therapy preferentially for individuals
with diabetes and a 7.5% estimated 10-year ASCVD risk
(Section 4.7). This consideration for those with diabetes
who are 40 to 75 years of age recognizes that these in-
dividuals are at substantially increased lifetime risk for
ASCVD events and death. Moreover, individuals with
diabetes experience greater morbidity and worse survival
after the onset of clinical ASCVD. In persons with dia-
betes who are <40 years of age or >75 years of age, or
whose LDL-C is <70 mg/dL, statin therapy should be
individualized on the basis of considerations of ASCVD
risk-reduction beneﬁts, the potential for adverse effects and
drug–drug interactions, and patient preferences (Figure 4).
4.6. Primary Prevention in Individuals Without
Diabetes and With LDL-C 70 to 189 mg/dL
In individuals 40 to 75 years of age with LDL-C 70 to
189 mg/dL who do not have clinical ASCVD or diabetes,
Table 7. Rationale for the Expert Panel Approach to
Primary-Prevention Guidelines
1. Cholesterol-lowering medications, particularly statins, are efﬁcacious and
effective for reducing risk of initial cardiovascular events.
2. Statins are associated with similar relative risk reductions for cardiovas-
cular events across the majority of primary-prevention patient groups
studied.*
3. The extent of relative risk reduction for ASCVD is proportional to the degree
of LDL-C lowering observed on statin therapy. Therefore, more intensive
statin therapy could reduce risk more than moderate- or lower-intensity
statin therapy.
4. According to consistent ﬁndings, the absolute beneﬁt in ASCVD risk
reduction is proportional to the baseline risk of the patient group or indi-
vidual and to the intensity of statin therapy.
5. Patients or groups at higher baseline absolute risk, therefore, will derive
greater absolute beneﬁt from initiation of statin therapy over a period of
5 to 10 years.
6. The absolute risk for adverse outcomes, including a small excess in cases
of newly diagnosed diabetes, also appears to be proportional to the in-
tensity of statin therapy. However, the adverse outcome of incident (or
earlier diagnosis of) diabetes must be weighed in the context of the
potentially fatal or debilitating occurrence of MI or stroke that could be
prevented by statin therapy.
7. The Expert Panel emphasizes that the occurrence of a major ASCVD event
(MI or stroke) represents a much greater harm to health status than does
an increase in blood glucose leading to a diagnosis of diabetes. The net
absolute beneﬁt of statin therapy can be considered as a comparison of the
absolute risk reduction for ASCVD with the absolute excess risks, including
that for diabetes. Beneﬁt also could be understood as a comparison of the
number of statin-treated patients that would result in the prevention of 1
case of major ASCVD (NNT) with the number of statin-treated patients that
would result in 1 excess case of diabetes (NNH).
8. Because the absolute beneﬁt in terms of ASCVD risk reduction depends on
the baseline absolute risk for ASCVD, the absolute beneﬁt from initiation of
statin therapy is lower and would approach the risk for adverse effects in
patients with lower baseline levels of predicted ASCVD risk.
9. Available RCT evidence indicates a clear net absolute beneﬁt of initiation of
moderate-to-intensive statin therapy at a baseline estimated 10-year
ASCVD risk of 7.5%.
10.Available RCT evidence indicates that when baseline ASCVD risk is 5.0%
to <7.5%, there is still net absolute beneﬁt with moderate-intensity statin
therapy. However, the tradeoffs between the ASCVD risk-reduction beneﬁt
and adverse effects are less clear. Thus, a clinician-patient discussion is
even more important for individuals with this range of ASCVD risk. The net
beneﬁt of high-intensity statin therapy may be marginal in such individuals.
Conclusion
On the basis of the above tenets and its review of the evidence, this
guideline recommends initiation of moderate or intensive statin therapy for
patients who are eligible for primary ASCVD prevention and have a
predicted 10-year “hard” ASCVD risk of 7.5%. This guideline recommends
that initiation of moderate-intensity statin therapy be considered for
patients with predicted 10-year “hard” ASCVD risk of 5.0% to <7.5%.
*Available evidence suggests that initiation of statin therapy might not achieve a signiﬁcant
reduction of CVD risk in patients with higher classes of NYHA heart failure or who are receiving
maintenance hemodialysis.
ASCVD indicates atherosclerotic cardiovascular disease; CVD, cardiovascular disease; LDL-C,
low-density lipoprotein cholesterol; MI, myocardial infarction; NNH, number needed to harm;
NNT, number needed to treat; NYHA, New York Heart Association; and RCT, randomized
controlled trial.
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initiation of statin therapy based on estimated 10-year
ASCVD risk is recommended, regardless of sex, race, or
ethnicity (Section 4.7). Point estimates of statin-associated
reductions in the relative risk of ASCVD in primary pre-
vention are similar for both women and men. There also is
no evidence that the ASCVD risk-reduction beneﬁt or
adverse-effect proﬁles differ by race.
To better identify those individuals without ASCVD
who would most beneﬁt from statin therapy to reduce
ASCVD risk, data were used from the 3 exclusively
primary-prevention RCTs that included individuals with
LDL-C levels <190 mg/dL, almost all of whom had
LDL-C levels 70 mg/dL (17,18,49). From these trials,
an estimate of the expected 10-year ASCVD event rates
was derived from the placebo groups. The rates of excess
adverse events in the statin treatment groups were obtained
from meta-analyses of statin RCTs. A high level of evi-
dence for an ASCVD risk-reduction beneﬁt from initia-
tion of moderate- or high-intensity statin therapy in
individuals 40 to 75 years of age with 7.5% estimated 10-
year ASCVD risk was found (Section 4.7). The reduction
in ASCVD risk clearly outweighs the potential for adverse
effects (Table 7). Thus, it is recommended that individuals
40 to 75 years of age, who are not already candidates for
statin therapy on the basis of the presence of clinical
ASCVD, diabetes, or LDL-C 190 mg/dL, receive statin
therapy if they have a 7.5% estimated 10-year risk for
ASCVD and LDL-C 70 to 189 mg/dL. Although only 1
exclusively primary-prevention RCT included individuals
with LDL-C 70 to <100 mg/dL, the Cholesterol Treat-
ment Trialists 2010 meta-analysis found a relative reduc-
tion in ASCVD events of similar magnitude across the
spectrum of LDL-C levels 70 mg/dL (20). Given that
the relative risk reduction is similar across the range of
LDL-C 70 to 189 mg/dL, the absolute beneﬁt of statin
therapy in primary prevention is determined by the global
risk estimate using all the risk factor information and is
reﬂected in the estimated 10-year ASCVD risk.
A conservative estimate of adverse events includes excess
cases of new-onset diabetes and rare cases of myopathy
and hemorrhagic stroke. The rate of excess diabetes varies
by statin intensity. For moderate-intensity statins, approxi-
mately 0.1 excess case of diabetes per 100 statin-treated
individuals per year has been observed, and for high-
intensity statins, approximately 0.3 excess case of diabetes
per 100 statin-treated individuals per year has been observed
(52,81). The long-term adverse effects of statin-associated
cases of diabetes over a 10-year period are unclear and are
unlikely to be equivalent to an MI, stroke, or ASCVD
death. Myopathy (w0.01 excess case per 100) and hemor-
rhagic stroke (w0.01 excess case per 100) make minimal
contributions to excess risk from statin therapy (13).
Although a similar level of evidence of a reduction in
ASCVD events from moderate- and high-intensity statin
therapy is present for those with a 5% to <7.5% estimated
10-year ASCVD risk, the potential for adverse effects may
outweigh the potential for ASCVD risk-reduction beneﬁt
when high-intensity statin therapy is used in this risk group.
However, for moderate-intensity statin therapy, the ASCVD
risk reduction clearly exceeds the potential for adverse effects.
Before initiating statin therapy for the primary preven-
tion of ASCVD in adults with 7.5% or 5% to <7.5%
estimated 10-year ASCVD risk, it is reasonable for clini-
cians and patients to engage in a discussion of the proposed
therapy. This discussion should include the potential for
ASCVD beneﬁt, the potential for adverse effects and
drug–drug interactions, and consideration of patient pref-
erences for treatment.
No primary-prevention RCT data were available for
individuals 21 to 39 years of age, and few data were
available for individuals >75 years of age. Additionally, in
individuals 40 to 75 years of age with <5% estimated 10-
year ASCVD risk, the net beneﬁt from statin therapy over
a 10-year period may be small. Therefore, in adults with
LDL-C <190 mg/dL who are not otherwise identiﬁed in
a statin beneﬁt group or for whom a risk-based treatment
decision is uncertain after quantitative risk assessment,
clinician knowledge, experience, and skill (“the art of
medicine”) and patient preferences all contribute to the
decision to initiate statin therapy (82). Before initiation of
statin therapy, the clinician-patient discussion should
include consideration of the potential for ASCVD risk-
reduction beneﬁts, adverse effects, and drug–drug in-
teractions. Additional factors may also be considered to
inform treatment decision making in selected individuals.
Factors that can contribute to assessment of ASCVD risk
include primary LDL-C 160 mg/dL or other evidence of
genetic
hyperlipidemias;
family
history
of
premature
ASCVD with onset <55 years of age in a ﬁrst-degree male
relative or <65 years of age in a ﬁrst-degree female relative;
high-sensitivity C-reactive protein 2 mg/L, coronary
artery calcium score 300 Agatston units or 75th
percentile for age, sex, and ethnicity (for additional infor-
mation, see http://www.mesa-nhlbi.org/CACReference.aspx);
ankle-brachial index <0.9; or elevated lifetime risk of
ASCVD. Additional factors that might aid in individual
risk assessment could be identiﬁed in the future.
For an individual <40 years of age, the 10-year horizon
might not be optimal for predicting lifetime risk of
ASCVD
(see
2013
ACC/AHA
Guideline
on
the
Assessment of Cardiovascular Risk) (11). Future RCTs
will be needed to determine the optimal age at which to
initiate statin therapy to reduce ASCVD risk, as well as to
determine the optimum duration of statin therapy.
4.7. Risk Assessment in Primary Prevention
To estimate more closely the total burden of ASCVD, this
guideline recommends a comprehensive assessment of the
estimated 10-year risk for an ASCVD event that includes
both CHD and stroke. This is in contrast to the use of an
estimated 10-year risk for hard CHD (deﬁned as nonfatal
MI and CHD death) (83).
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This guideline recommends using the new Pooled
Cohort Risk Assessment Equations developed by the Risk
Assessment Work Group to estimate the 10-year ASCVD
risk (deﬁned as ﬁrst-occurrence nonfatal and fatal MI and
nonfatal and fatal stroke) for the identiﬁcation of candi-
dates for statin therapy (see http://my.americanheart.org/
cvriskcalculator
and
http://www.cardiosource.org/en/
Science-And-Quality/Practice-Guidelines-and-Quality-
Standards/2013-Prevention-Guideline-Tools.aspx for risk
calculator). These equations should be used to predict
stroke as well as CHD events in non-Hispanic, Caucasian,
and African-American women and men 40 to 79 years of
age with or without diabetes who have LDL-C levels 70 to
189 mg/dL and are not receiving statin therapy. A more
complete discussion of risk assessment is provided in the
Full Panel Report Supplement.
This guideline does not require speciﬁc risk factor
counting for risk assessment or the use of RCT risk factor
inclusion criteria to determine statin eligibility. Rather, a
global ASCVD risk assessment to guide initiation of statin
therapy was chosen for several important reasons (see
rationale in Table 7 and further discussion in Section 7.3 of
the Full Panel Report Supplement): 1) The Cholesterol
Treatment Trialists individual-level meta-analyses were
used to evaluate the effect of statins in various important
patient subgroups, including risk factor cutpoints used for
RCT eligibility. The Expert Panel found that statin ther-
apy reduces ASCVD events regardless of risk factor
characteristics in both primary and secondary prevention.
Therefore, the rationale for using ﬁxed cutpoints to
determine whether statin therapy should be used is refuted
by a consideration of the total body of evidence. 2) Use of
absolute ASCVD risk facilitates a quantitative assessment
of the potential for an ASCVD risk-reduction beneﬁt as
compared with the potential for adverse effects. 3) Use of
an RCT eligibility criteria–based approach results in failure
to identify a substantial proportion of higher-risk in-
dividuals who could beneﬁt from statin therapy and over-
identiﬁcation of very-low-risk individuals who might not
experience a net beneﬁt from statin therapy over a 10-year
period.
4.8. Heart Failure and Hemodialysis
No recommendation was made with regard to the initia-
tion or continuation of statin therapy in 2 speciﬁc groups:
1) individuals with New York Heart Association class II–
IV heart failure, and 2) individuals undergoing mainte-
nance hemodialysis. In the 4 RCTs reviewed that specif-
ically addressed statin treatment in these groups, there
were individuals with and without heart disease (84–87).
Although statin therapy did not reduce ASCVD events in
2 RCTs for each condition (84–87), there was insufﬁcient
information on which to base recommendations for or
against statin treatment. Future research may identify
subgroups of patients with these conditions that may
beneﬁt from statin therapy. In individuals with these
conditions, the potential for ASCVD risk-reduction ben-
eﬁts, adverse effects, and drug–drug interactions, along
with other cautions and contraindications to statin therapy
and choice of statin dose, must also be considered by the
treating clinician.
5. Safety: Recommendations
See safety recommendations for statins (Table 8) and
nonstatin drugs (Table 9).
RCT data were also used to examine the safety of lipid
medications. From the statin RCTs and meta-analyses,
patient characteristics and monitoring strategies were
identiﬁed that should enhance the safe use of high- and
moderate-intensity statin therapy. Patient characteristics
that may inﬂuence statin safety include but are not limited
to: multiple or serious comorbidities, including impaired
renal or hepatic function; a history of previous statin
intolerance or muscle disorders; concomitant use of drugs
affecting statin metabolism; a history of hemorrhagic
stroke; and age >75 years. Asian ancestry may also inﬂu-
ence the initial choice of statin intensity.
This guideline recommends against routine measure-
ment of creatine kinase in individuals receiving statin
therapy. This measurement should be reserved for those
with muscle symptoms. However, measurement of a base-
line creatine kinase may be useful in those at increased risk
of adverse muscle events. Such individuals include those
with a personal or family history of statin intolerance or
muscle disease, clinical presentation, or concomitant drug
therapy that might increase the likelihood of myopathy.
Expert recommendations are also provided for managing
muscle symptoms while a patient is on statin therapy.
These useful management suggestions were derived from
other clinical trial data and clinical experience to enhance
the safety and tolerability of statin therapy. Consistent with
the protocols of the RCTs, patients should be asked at each
visit, both before and after initiation of statin therapy,
about muscle symptoms such as muscle weakness or fa-
tigue, aching, pain, tenderness, cramps, or stiffness. The
recommended
approach
for
management
of
muscle
symptoms is described in Table 8, Recommendation 8.
This guideline recommends that baseline measurement
of transaminase (alanine transaminase; ALT) levels should
be performed before initiation of statin therapy. This
approach was taken in the RCTs reviewed for this report.
There is no recommendation to monitor transaminase
(ALT) levels because ALT monitoring was performed in
the RCTs, and there was no signiﬁcant difference between
placebo groups and statin treatment groups in the rates of
ALT elevations. In addition, the U.S. Food and Drug
Administration has indicated that if the baseline hepatic
transaminases are normal, further hepatic monitoring is
not needed. During statin therapy, it is reasonable to
measure
hepatic
function
if
symptoms
suggesting
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hepatotoxicity arise (e.g., unusual fatigue or weakness, loss
of appetite, abdominal pain, dark-colored urine, or yel-
lowing of the skin or sclera).
Decreasing the statin dose may be considered when
2 consecutive values of LDL-C are <40 mg/dL. This
recommendation was based on the approach taken in 2
RCTs. However, no data were identiﬁed that suggest an
excess of adverse events occurred when LDL-C levels were
below this level.
Statins modestly increase the excess risk of type 2 dia-
betes
in
individuals
with
risk
factors
for
diabetes.
The potential for an ASCVD risk-reduction beneﬁt out-
weighs the excess risk of diabetes in all but the lowest-risk
individuals (Section 4.5). All individuals receiving statins
should be counseled on healthy-lifestyle habits. In-
dividuals receiving statin therapy should be evaluated for
new-onset diabetes according to the current diabetes
screening guidelines (91). Those who develop diabetes
Table 8. Statin Safety Recommendations
Recommendations
NHLBI Grade
NHLBI Evidence
Statements
ACC/AHA COR
ACC/AHA LOE
Safety
1. To maximize the safety of statins, selection of the appropriate statin and dose
in men and nonpregnant/nonnursing women should be based on patient
characteristics, level of ASCVD* risk, and potential for adverse effects.
Moderate-intensity statin therapy should be used in individuals in whom
high-intensity statin therapy would otherwise be recommended when
characteristics predisposing them to statin-associated adverse effects are
present.
Characteristics predisposing individuals to statin adverse effects include but
are not limited to:
 Multiple or serious comorbidities, including impaired renal or hepatic
function.
 History of previous statin intolerance or muscle disorders.
 Unexplained ALT elevations 3 times ULN.
 Patient characteristics or concomitant use of drugs affecting statin
metabolism.
 Age >75 years.
Additional characteristics that could modify the decision to use higher statin
intensities might include but are not limited to:
 History of hemorrhagic stroke.
 Asian ancestry.
A (Strong)
46–55
I
B
2a. CK should not be routinely measured in individuals receiving statin therapy.
A (Strong)
45,49–51,54,55
III: No Beneﬁt
A
2b. Baseline measurement of CK is reasonable for individuals believed to be at
increased risk for adverse muscle events because of a personal or family
history of statin intolerance or muscle disease, clinical presentation, or
concomitant drug therapy that might increase the risk of myopathy.
E (Expert Opinion)
d
IIa
C
(88)
2c. During statin therapy, it is reasonable to measure CK in individuals with
muscle symptoms, including pain, tenderness, stiffness, cramping,
weakness, or generalized fatigue.
E (Expert Opinion)
d
IIa
C
(88)
3a. Baseline measurement of hepatic transaminase levels (ALT) should be
performed before initiation of statin therapy.
B (Moderate)
46,52,53
Iy
B
3b. During statin therapy, it is reasonable to measure hepatic function if
symptoms suggesting hepatotoxicity arise (e.g., unusual fatigue or weakness,
loss of appetite, abdominal pain, dark-colored urine, or yellowing of the skin
or sclera).
E (Expert Opinion)
d
IIa
C
(89)
4. Decreasing the statin dose may be considered when 2 consecutive values
of LDL-C levels are <40 mg/dL.
C (Weak)
45
IIb
C
5. It may be harmful to initiate simvastatin at 80 mg daily or increase the
dose of simvastatin to 80 mg daily.
B (Moderate)
6,54
III: Harm
A
(67,90)
6. Individuals receiving statin therapy should be evaluated for new-onset diabetes
according to the current diabetes screening guidelines (91). Those who
develop diabetes during statin therapy should be encouraged to adhere to
a heart-healthy dietary pattern, engage in physical activity, achieve and
maintain a healthy body weight, cease tobacco use, and continue statin
therapy to reduce their risk of ASCVD events.
B (Moderate)
44
Iz
B
7. For individuals taking any dose of statins, it is reasonable to use caution in
individuals >75 years of age, as well as in individuals who are taking
concomitant medications that alter drug metabolism, taking multiple drugs,
or taking drugs for conditions that require complex medication regimens
(e.g., those who have undergone solid organ transplantation or are receiving
treatment for HIV). A review of the manufacturer’s prescribing information may
be useful before initiation of any cholesterol-lowering drug.
E (Expert Opinion)
d
IIa
C
(16,64–70,
89,92–94)
Continued on the next page
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during statin therapy should be encouraged to adhere to a
heart-healthy dietary pattern, engage in physical activity,
achieve and maintain a healthy body weight, cease tobacco
use, and continue statin therapy to reduce their risk of
ASCVD events.
Statins are listed as pregnancy category X and should
not be used in women of childbearing potential unless
these women are using effective contraception and are not
nursing.
For individuals taking any dose of statins, it is reason-
able to use caution in individuals >75 years of age, as well
as in individuals who are taking concomitant medications
that alter drug metabolism, taking multiple drugs, or
taking drugs for conditions that require complex medi-
cation regimens (e.g., those who have undergone solid
organ transplantation or are receiving treatment for HIV).
A review of the manufacturer’s prescribing information
might be useful before initiation of any cholesterol-
lowering drug, because RCTs considered deﬁned pop-
ulations and many patients in everyday practice would not
qualify for clinical trials. Thus, clinicians should also
consult other sources of safety data, such as pharmacists,
drug information centers, and manufacturers’ prescribing
information on a regular basis for up-to-date guidance
about lipid medications and medication interactions.
Statins used in combination with other cholesterol-
lowering drug therapies might require more intensive
monitoring. The safety of nonstatin agents was reviewed,
and that information is included in Table 9 and the Full
Panel Report Supplement. Warnings about the use of
Table 8. Continued
Recommendations
NHLBI Grade
NHLBI Evidence
Statements
ACC/AHA COR
ACC/AHA LOE
8. It is reasonable to evaluate and treat muscle symptoms, including pain,
tenderness, stiffness, cramping, weakness, or fatigue, in statin-treated
patients according to the following management algorithm:
 To avoid unnecessary discontinuation of statins, obtain a history of prior or
current muscle symptoms to establish a baseline before initiation of statin
therapy.
 If unexplained severe muscle symptoms or fatigue develop during statin
therapy, promptly discontinue the statin and address the possibility of
rhabdomyolysis by evaluating CK and creatinine and performing urinalysis
for myoglobinuria.
 If mild to moderate muscle symptoms develop during statin therapy:
– Discontinue the statin until the symptoms can be evaluated.
– Evaluate the patient for other conditions that might increase the risk for
muscle symptoms (e.g., hypothyroidism, reduced renal or hepatic func-
tion, rheumatologic disorders such as polymyalgia rheumatica, steroid
myopathy, vitamin D deﬁciency, or primary muscle diseases).
– If muscle symptoms resolve, and if no contraindication exists, give the
patient the original or a lower dose of the same statin to establish a
causal relationship between the muscle symptoms and statin therapy.
– If a causal relationship exists, discontinue the original statin. Once
muscle symptoms resolve, use a low dose of a different statin.
– Once a low dose of a statin is tolerated, gradually increase the dose as
tolerated.
– If, after 2 months without statin treatment, muscle symptoms or
elevated CK levels do not resolve completely, consider other causes of
muscle symptoms listed above.
– If persistent muscle symptoms are determined to arise from a condition
unrelated to statin therapy, or if the predisposing condition has been
treated, resume statin therapy at the original dose.
E (Expert Opinion)
d
IIa
B
(15,88,96–98)
9. For individuals presenting with a confusional state or memory impairment
while on statin therapy, it may be reasonable to evaluate the patient for
nonstatin causes, such as exposure to other drugs, as well as for systemic and
neuropsychiatric causes, in addition to the possibility of adverse effects
associated with statin drug therapy.
E (Expert Opinion)
d
IIb
C
(38,89,99,100)
*Based on the presence of clinical ASCVD, diabetes, LDL-C 190 mg/dL, or level of estimated 10-year ASCVD risk.
yIndividuals with elevated ALT levels (usually >1.5 or 2 times ULN) were excluded from RCT participation. Unexplained ALT 3 times ULN is a contraindication to statin therapy as listed in manufacturer’s
prescribing information.
zStatin use is associated with a very modest excess risk of new-onset diabetes in RCTs and meta-analyses of RCTs (i.e., w0.1 excess cases per 100 individuals treated for 1 year with moderate-intensity
statin therapy and w0.3 excess cases per 100 individuals treated for 1 year with high-intensity statin therapy. The increased risk of new-onset diabetes appears to be conﬁned to those with risk factors
for diabetes. These individuals are also at higher risk of ASCVD because of these risk factors. Therefore, if a statin-treated individual develops diabetes as detected by current diabetes screening
guidelines, he or she should be counseled to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin
therapy to reduce the risk of ASCVD events.
ACC indicates American College of Cardiology; AHA, American Heart Association; ALT, alanine transaminase; ASCVD, atherosclerotic cardiovascular disease; CK, creatine kinase; COR, Class of
Recommendation; NHLBI, National Heart, Lung, and Blood Institute; LDL-C, low-density lipoprotein cholesterol; LOE, Level of Evidence; RCTs, randomized controlled trials; ULN, upper limit of normal;
and d, not applicable.
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Table 9. Nonstatin Safety Recommendations
Recommendations
NHLBI Grade
NHLBI Evidence
Statements
ACC/AHA COR
ACC/AHA LOE
Safety of Niacin
1. Baseline hepatic transaminases, fasting blood glucose or hemoglobin A1c,
and uric acid should be obtained before initiation of niacin, and again during
up-titration to a maintenance dose and every 6 months thereafter.
B (Moderate)
77
I
B
2. Niacin should not be used if:
 Hepatic transaminase elevations are higher than 2 to 3 times ULN.
A (Strong)
79
III: Harm
B
 Persistent severe cutaneous symptoms, persistent hyperglycemia, acute
gout, or unexplained abdominal pain or gastrointestinal symptoms occur.
B (Moderate)
78,79
III: Harm
B
 New-onset atrial ﬁbrillation or weight loss occurs.
C (Weak)
80
III: Harm
B
3. In individuals with adverse effects from niacin, the potential for ASCVD
beneﬁts and the potential for adverse effects should be reconsidered before
reinitiation of niacin therapy.
E (Expert)
d
I
B
(9,101–104)
4. To reduce the frequency and severity of adverse cutaneous symptoms, it is
reasonable to:
 Start niacin at a low dose and titrate to a higher dose over a period of
weeks as tolerated.
 Take niacin with food or premedicate with aspirin 325 mg 30 minutes
before niacin dosing to alleviate ﬂushing symptoms.
 If an extended-release preparation is used, increase the dose of extended-
release niacin from 500 mg to a maximum of 2,000 mg/day over 4 to
8 weeks, with the dose of extended-release niacin increasing not more
than weekly.
 If immediate-release niacin is chosen, start at a dose of 100 mg 3 times
daily and up-titrate to 3 g/day, divided into 2 or 3 doses.
E (Expert)
d
IIa
C
(9,101–104)
Safety of BAS
1. BAS should not be used in individuals with baseline fasting triglyceride
levels 300 mg/dL or type III hyperlipoproteinemia, because severe
triglyceride elevations might occur. (A fasting lipid panel should be obtained
before BAS is initiated, 3 months after initiation, and every 6 to 12 months
thereafter.)
C (Weak)
60
III: Harm
B
2. It is reasonable to use BAS with caution if baseline triglyceride levels are
250 to 299 mg/dL, and evaluate a fasting lipid panel in 4 to 6 weeks after
initiation. Discontinue the BAS if triglycerides exceed 400 mg/dL.
E (Expert)
d
IIa
C
(105)
Safety of Cholesterol-Absorption Inhibitors
1. It is reasonable to obtain baseline hepatic transaminases before initiation of
ezetimibe. When ezetimibe is coadministered with a statin, monitor trans-
aminase levels as clinically indicated, and discontinue ezetimibe if persistent
ALT elevations 3 times ULN occur.
C (Weak)
61–64
IIa
B
Safety of Fibrates
1. Gemﬁbrozil should not be initiated in patients on statin therapy because of an
increased risk for muscle symptoms and rhabdomyolysis.
B (Moderate)
46
III: Harm
B
2. Fenoﬁbrate may be considered concomitantly with a low- or moderate-
intensity statin only if the beneﬁts from ASCVD risk reduction or triglyceride
lowering when triglycerides are 500 mg/dL are judged to outweigh the
potential risk for adverse effects.
E (Expert)
d
IIb
C
(14)
3. Renal status should be evaluated before fenoﬁbrate initiation, within 3
months after initiation, and every 6 months thereafter. Assess renal safety
with both a serum creatinine level and an eGFR based on creatinine.
B (Moderate)
66,67
I
B
 Fenoﬁbrate should not be used if moderate or severe renal impairment,
deﬁned as eGFR <30 mL/min per 1.73 m2, is present.
 If eGFR is between 30 and 59 mL/min per 1.73 m2, the dose of fenoﬁbrate
should not exceed 54 mg/day.*
 If, during follow-up, the eGFR decreases persistently to 30 mL/min per
1.73 m2, fenoﬁbrate should be discontinued.
III: Harm
B
Safety of Omega-3 Fatty Acids
1. If EPA and/or DHA are used for the management of severe
hypertriglyceridemia, deﬁned as triglycerides 500 mg/dL, it is reasonable to
evaluate the patient for gastrointestinal disturbances, skin changes, and
bleeding.
C (Weak)
70
IIa
B
*Consult the manufacturer’s prescribing information as there are several forms of fenoﬁbrate available.
ACC indicates American College of Cardiology; AHA, American Heart Association; ALT, alanine transaminase; ASCVD, atherosclerotic cardiovascular disease; BAS, bile acid sequestrants; COR, Class of
Recommendation; DHA, docosahexanoic acid; EPA, eicosapentaenoic acid; eGFR, estimated glomerular ﬁltration rate; LOE, Level of Evidence; NHLBI, National Heart, Lung, and Blood Institute; ULN,
upper limit of normal; and d, not applicable.
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cholesterol-lowering agents in pregnancy and lactation also
apply to nonstatins, and the manufacturer’s prescribing
information should be consulted.
6. Managing Statin Therapy:
Recommendations
See Table 10 for a summary of recommendations for
monitoring,
optimizing,
and
addressing
insufﬁcient
response to statin therapy.
6.1. Monitoring Statin Therapy
A high level of RCT evidence supports the use of an
initial fasting lipid panel (total cholesterol, triglycerides,
HDL-C, and calculated LDL-C), followed by a second
lipid panel 4 to 12 weeks after initiation of statin therapy,
to determine a patient’s adherence. Thereafter, assess-
ments should be performed every 3 to 12 months as
clinically indicated. Adherence to both medication and
lifestyle regimens are required for ASCVD risk reduc-
tion. After statin therapy has been initiated, some
Table 10. Recommendations for Monitoring, Optimizing, and Addressing Insufﬁcient Response to Statin Therapy
Recommendations
NHLBI Grade
NHLBI Evidence
Statements
ACC/AHA COR
ACC/AHA LOE
Monitoring Statin Therapy
1. Adherence to medication and lifestyle, therapeutic response to statin
therapy, and safety should be regularly assessed. This should also
include a fasting lipid panel performed within 4–12 weeks after initiation
or dose adjustment, and every 3–12 months thereafter. Other safety
measurements should be measured as clinically indicated.
A (Strong)
45
I
A
Optimizing Statin Therapy
1. The maximum tolerated intensity of statin should be used in individuals for
whom a high- or moderate-intensity statin is recommended but not tolerated.
B (Moderate)
25,26,27,45
I*
B
Insufﬁcient Response to Statin Therapy
1. In individuals who have a less-than-anticipated therapeutic response or are
intolerant of the recommended intensity of statin therapy, the following should
be performed:
 Reinforce medication adherence.
 Reinforce adherence to intensive lifestyle changes.
 Exclude secondary causes of hyperlipidemia.
A (Strong)
45
I
A
2. It is reasonable to use the following as indicators of anticipated therapeutic
response to the recommended intensity of statin therapy. Focus is on the
intensity of the statin therapy. As an aid to monitoring:
 High-intensity statin therapyy generally results in an average LDL-C
reduction of 50% from the untreated baseline.
 Moderate-intensity statin therapy generally results in an average
LDL-C reduction of 30% to <50% from the untreated baseline.
 LDL-C levels and percents reduction are to be used only to assess
response to therapy and adherence. They are not to be used as
performance standards.
E (Expert Opinion)
d
IIa
B
(46–48,78,
106,107)
3. In individuals at higher ASCVD risk receiving the maximum tolerated
intensity of statin therapy who continue to have a less-than-anticipated
therapeutic response, addition of nonstatin cholesterol-lowering drug(s) may
be considered if the ASCVD risk-reduction beneﬁts outweigh the potential for
adverse effects.
Higher-risk individuals include:
 Individuals with clinical ASCVDz <75 years of age.
 Individuals with baseline LDL-C 190 mg/dL.
 Individuals 40–75 years of age with diabetes.
Preference should be given to nonstatin cholesterol-lowering drugs shown to
reduce ASCVD events in RCTs.
E (Expert Opinion)
d
IIb
C
(9,14,108–110)
4. In individuals who are candidates for statin treatment but are completely
statin intolerant, it is reasonable to use nonstatin cholesterol-lowering drugs
that have been shown to reduce ASCVD events in RCTs if the ASCVD risk-
reduction beneﬁts outweigh the potential for adverse effects.
E (Expert Opinion)
d
IIa
B
(88,101,111–116)
*Several RCTs found that low-intensity and low-moderate–intensity statin therapy reduced ASCVD events. In addition, the Cholesterol Treatment Trialists meta-analyses found that each 39-mg/dL
reduction in LDL-C reduces ASCVD risk by 22%. Therefore, the Panel considered that submaximal statin therapy should be used to reduce ASCVD risk in those unable to tolerate moderate- or high-
intensity statin therapy.
yIn those already on a statin, in whom baseline LDL-C is unknown, an LDL-C level <100 mg/dL was observed in most individuals receiving high-intensity statin therapy.
zClinical ASCVD includes acute coronary syndromes, or a history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or
peripheral arterial disease presumed to be of atherosclerotic origin.
ACC indicates American College of Cardiology; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; COR, Class of Recommendation; LDL-C, low-density lipoprotein
cholesterol; LOE, Level of Evidence; NHLBI, National Heart, Lung, and Blood Institute; RCTs, randomized controlled trials; and d, not applicable.
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individuals experience unacceptable adverse effects when
taking the recommended intensity of statin therapy.
Once the severity and association of adverse effects with
statin therapy has been established, and once factors
potentially contributing to statin intolerance are resolved,
the patient should be given lower doses of the same statin
or an alternative appropriate statin, until a statin and dose
that have no adverse effects have been identiﬁed (Table 8,
Recommendation 8).
See Figure 5 for a ﬂow diagram on monitoring statin
response for the initiation of nonstatin therapy.
6.2. Optimizing Statin Therapy
Although high-intensity statin therapy reduces ASCVD
events
more
than
moderate-intensity
statin
therapy,
lower-intensity statin therapy has also been shown to
reduce ASCVD events, although to a lesser degree.
Therefore, individuals who merit guideline-recommended
statin therapy should be treated with the maximum-
appropriate intensity of a statin that does not cause
adverse effects.
6.3. Insufﬁcient Response to Statin Therapy
6.3.1. Testing
The evidence is less clear with regard to the most appropriate
tests for determining whether an anticipated therapeutic
response to statin therapy has occurred on the maximally
tolerated dose. RCT evidence to support the use of speciﬁc
LDL-C or non–HDL-C targets was not identiﬁed. The
focus is on the intensity of the statin therapy, but as an aid to
monitoring response to therapy and adherence, it is reason-
able to use the following as indicators of anticipated thera-
peutic response to statin therapy:
 High-intensity statin therapy generally results in an
average LDL-C reduction of 50% from the un-
treated baseline.
 Moderate-intensity statin therapy generally results in
an average LDL-C reduction of 30% to <50% from
the untreated baseline.
 LDL-C levels and percent reduction are to be
used only to assess response to therapy and adherence.
They are not to be used as performance standards.
Figure 5. Statin Therapy: Monitoring Therapeutic Response and Adherence
Colors correspond to the Classes of Recommendation in Table 1.
*Fasting lipid panel preferred. In a nonfasting individual, a non–HDL-C level 220 mg/dL may indicate genetic hypercholesterolemia that requires further evaluation or a secondary
etiology. If nonfasting triglycerides are 500 mg/dL, a fasting lipid panel is required.
yIn those already on a statin, in whom baseline LDL-C is unknown, an LDL-C <100 mg/dL was observed in most individuals receiving high-intensity statin therapy in RCTs.
zSee Section 6.3.1.
HDL-C indicates high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; and RCTs, randomized clinical trials.
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In those already on a statin, in whom the baseline LDL-
C is unknown, an LDL-C <100 mg/dL was observed in
most individuals receiving high-intensity statin therapy in
RCTs.
However, there are many limitations of using LDL-C
<100 mg/dL as a ﬁxed target. If a moderate- or low-intensity
statin results in an LDL-C level <100 mg/dL in a patient
with ASCVD, the evidence suggests that a high-intensity
statin, if tolerated, provides a greater reduction in ASCVD
events. Conversely, in those with LDL-C levels slightly
>100 mg/dL on a high-intensity statin, some options such as
niacin might require down-titration of the statin intensity in
an effort to improve safety. This would result in a suboptimal
intensity of evidence-based statin therapy. Additional limi-
tationstousing LDL-C treatmenttargets arediscussed inthe
Full Panel Report Supplement.
No evidence was found that titration or combination-
drug therapy to achieve speciﬁc LDL-C or non–HDL-C
levels or percent reductions improved ASCVD outcomes.
Therefore, this guideline does not recommend their use as
performance measures.
The percent LDL-C reduction may not only indicate
adherence, but also may reﬂect biological variability in
the response to statin therapy. This acknowledges that some
individuals mayhave less than an average response. Attention
to adherence of statin and lifestyle therapy and evaluation
and treatment of secondary causes (Table 6) that might el-
evate LDL-C, may address less-than-anticipated responses
to a speciﬁc statin dosage. Whether the dose of statin therapy
should be increased on the basis of a less-than-anticipated
average response should be left to clinical judgment.
6.3.2. Nonstatins Added to Statins or
in Statin-Intolerant Individuals
Adherence to lifestyle changes and to statin therapy should
be reemphasized before the addition of a nonstatin drug is
considered (Figure 5). RCTs evaluating the ASCVD event
reductions from nonstatins used as monotherapy were
reviewed, as were RCTs evaluating the additional reduc-
tion in ASCVD events from nonstatin therapy added to
statin therapy. The Expert Panel could ﬁnd no data sup-
porting the routine use of nonstatin drugs combined with
statin therapy to further reduce ASCVD events. In addi-
tion, no RCTs that assessed ASCVD outcomes in statin-
intolerant patients were found.
Clinicians treating high-risk patients who have a less-
than-anticipated response to statins, who are unable to
tolerate a less-than-recommended intensity of a statin, or
who are completely statin intolerant, may consider the
addition of a nonstatin cholesterol-lowering therapy.
High-risk individuals include those with ASCVD, those
with LDL-C 190 mg/dL, and those with diabetes
40–75 years of age. In this situation, this guideline rec-
ommends clinicians preferentially prescribe drugs that
have been shown in RCTs to provide ASCVD risk-
reduction beneﬁts that outweigh the potential for adverse
effects and drug–drug interactions, and consider patient
preferences.
7. Selected Clinical and
Population Subgroups
7.1. Sex and Racial and Ethnic Subgroups
Because the RCT evidence shows that the absolute beneﬁt
of statin treatment is proportional to baseline ASCVD
risk, treatment decisions for women and racial and ethnic
subgroups should be based on the level of ASCVD risk.
This conclusion is a departure from previous approaches
that focused on LDL-C levels to guide treatment de-
cisions. Statin treatment based on estimated 10-year
ASCVD risk avoids the overtreatment of lower-risk
groups, such as younger, non-Hispanic white women
who, despite moderate elevations in LDL-C, are typically
not at signiﬁcantly increased risk for ASCVD in the next
10 years in the absence of substantial risk factor burden.
However, ignoring the increased ASCVD risk in African
American women and men might result in the under-
treatment of some individuals who are at signiﬁcantly
higher ASCVD risk at the same LDL-C level. Thus, this
guideline recommends statin therapy for individuals in
whom it is most likely to provide ASCVD risk reduction
on the basis of the estimated 10-year risk of ASCVD.
7.2. Individuals >75 Years of Age
Fewer people >75 years of age were enrolled in the statin
RCTs reviewed. RCT evidence does support the contin-
uation of statins beyond 75 years of age in persons who are
already taking and tolerating these drugs. A larger amount
of data supports the use of moderate-intensity statin
therapy for secondary prevention in individuals with clin-
ical ASCVD who are >75 years of age. However, the
limited information available did not clearly support
initiation of high-intensity statin therapy for secondary
prevention in individuals >75 years of age.
Few data were available to indicate an ASCVD event
reduction beneﬁt in primary prevention among individuals
>75 years of age who do not have clinical ASCVD.
Therefore, initiation of statins for primary prevention of
ASCVD in individuals >75 years of age requires consid-
eration of additional factors, including increasing comor-
bidities, safety considerations, and priorities of care. The
Pooled Cohort Equations can also provide information on
expected 10-year ASCVD risk for those 76 to 79 years of
age that may inform the treatment decision. These factors
may inﬂuence decisions about cholesterol-lowering drug
therapy, especially in the primary-prevention setting.
Accordingly, a discussion of the potential ASCVD risk-
reduction beneﬁts, risk of adverse effects, drug–drug in-
teractions, and consideration of patient preferences should
precede the initiation of statin therapy for primary pre-
vention in older individuals.
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8. Limitations
The evidence-based recommendations in this guideline
focus on patient groups who are well represented in RCTs
and/or are highly likely to have high-risk genetic condi-
tions, so the recommendations are designed to inform
rather than replace clinical judgment. However, there are
other patient groups for which a robust evidence base is
lacking but that may nevertheless include some persons for
whom statin treatment should be considered (after taking
patient preferences into account) on the basis of the po-
tential for ASCVD beneﬁts to exceed the risk of adverse
events and drug–drug interactions. Clinician judgment is
especially important for several patient groups for which
the RCT evidence is insufﬁcient for guiding clinical rec-
ommendations. These patient groups include younger
adults (<40 years of age) who have a low estimated 10-year
ASCVD risk but a high lifetime ASCVD risk based
on single strong factors or multiple risk factors. Other
groups include those with serious comorbidities and
increased ASCVD risk (e.g., individuals with HIV or
rheumatologic or inﬂammatory diseases, or who have un-
dergone a solid organ transplantation). This guideline
encourages clinicians to use clinical judgment in these
situations, weighing potential beneﬁts, adverse effects,
drug–drug interactions, and consider patient preferences.
Previous guidelines have taken less rigorous approaches
to identifying the evidence to support their recommen-
dations. In contrast, to minimize various sources of bias,
the present recommendations are based on data available
from RCTs and systematic reviews and meta-analyses of
RCTs that were graded as fair to good quality by an
independent contractor and were reviewed by the Expert
Panel, with the assistance of an independent methodolo-
gist. To avoid biases, evidence from post-hoc analyses of
included RCTs, from poor-quality RCTs, and from
observational studies was not considered. This approach
resulted in a comprehensive set of evidence-based clinical
recommendations for the treatment of blood cholesterol to
reduce ASCVD risk.
9. Evidence Gaps and
Future Research Needs
After a systematic review of the literature, several research
priorities are suggested that address existing evidence gaps
and offer the greatest potential to inform and inﬂuence
clinical practice and reduce ASCVD morbidity and mor-
tality. High-priority research areas are:
1. Outcomes of RCTs to evaluate statins for the pri-
mary prevention of ASCVD in adults >75 years of
age.
2. Outcomes of RCTs to evaluate alternative treatment
strategies for ASCVD risk reduction. These RCTs
may compare titration to speciﬁc cholesterol or
apolipoprotein goals versus ﬁxed-dose statin therapy
in high-risk patients.
3. RCTs to determine whether submaximal statin
doses, combined with nonstatin therapies, reduce
ASCVD risk in statin-intolerant patients.
4. Evaluation of the incidence, pathophysiology, clin-
ical course, and clinical outcomes of new-onset
diabetes associated with statin therapy.
5. Outcomes of RCTs of new lipid-modifying agents to
determine the incremental ASCVD event-reduction
beneﬁts when added to evidence-based statin therapy.
Additional research recommendations are included in
the Full Panel Report Supplement.
10. Conclusions
These recommendations arose from careful consideration
of an extensive body of higher-quality evidence derived
from RCTs and systematic reviews and meta-analyses of
RCTs. Rather than LDL-C or non–HDL-C targets, this
guideline used the intensity of statin therapy as the goal of
treatment. Through a rigorous process, 4 groups of in-
dividuals were identiﬁed for whom an extensive body of
RCT evidence demonstrated a reduction in ASCVD
events with a good margin of safety from moderate- or
high-intensity statin therapy:
Four Statin Beneﬁt Groups:
1. Individuals with clinical ASCVD
2. Individuals with primary elevations of LDL-C 190
mg/dL
3. Individuals 40 to 75 years of age with diabetes and
LDL-C 70 to 189 mg/dL without clinical ASCVD
4. Individuals without clinical ASCVD or diabetes
who are 40 to 75 years of age and have LDL-C 70 to
189 mg/dL and an estimated 10-year ASCVD risk of
7.5%. This requires a clinician-patient discussion.
Individuals in the last group can be identiﬁed by using
the Pooled Cohort Equations for ASCVD risk prediction
developed by the Risk Assessment Work Group. Lifestyle
counseling should occur at the initial and follow-up visits
as the foundation for statin therapy and may improve the
overall risk factor proﬁle.
Most importantly, our focus is on those individuals most
likely to beneﬁt from evidence-based statin therapy to
reduce ASCVD risk. Implementation of these ASCVD
risk-reduction guidelines will help to substantially address
the large burden of fatal and nonfatal ASCVD in the
United States. We realize that these guidelines represent a
change from previous guidelines, but clinicians have become
accustomed to change when that change is consistent with
the current evidence. Continued accumulation of quality
trial data will inform future cholesterol treatment guidelines.
Stone et al.
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July 1, 2014:2889–934
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Presidents and Staff
American College of Cardiology
John Gordon Harold, MD, MACC, President
Shalom Jacobovitz, Chief Executive Ofﬁcer
William J. Oetgen, MD, MBA, FACC, Executive Vice
President, Science, Education, & Quality
Charlene May, Senior Director, Science and Clinical Policy
American College of Cardiology/American Heart Association
Lisa Bradﬁeld, CAE, Director, Science and Clinical Policy
Emily Schiller, Specialist, Science and Clinical Policy
American Heart Association
Mariell Jessup, MD, FACC, FAHA, President
Nancy Brown, Chief Executive Ofﬁcer
Rose Marie Robertson, MD, FAHA, Chief Science
Ofﬁcer
Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior
Vice President, Ofﬁce of Science Operations
Marco Di Buono, PhD, Vice President of Science and
Research
Jody Hundley, Production Manager, Scientiﬁc Publications,
Ofﬁce of Science Operations
National Heart, Lung, and Blood Institute
Glen Bennett, MPH
Denise Simons-Morton, MD, PhD
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101:58B–62B.
104. Grundy SM, Vega GL, McGovern ME, et al. Efﬁcacy, safety, and
tolerability of once-daily niacin for the treatment of dyslipidemia
associated with type 2 diabetes: results of the assessment of diabetes
control and evaluation of the efﬁcacy of niaspan trial. Arch Intern
Med 2002;162:1568–76.
105. Crouse JR 3rd Hypertriglyceridemia: a contraindication to the use of
bile acid binding resins. Am J Med 1987;83:243–8.
106. Thompson GR, HEART-UK LDL Apheresis Working Group.
Recommendations for the use of LDL apheresis. Atherosclerosis
2008;198:247–55.
107. Schwertz DW, Badellino KO. High-dose statin therapy for sec-
ondary prevention of stroke: stroke prevention by aggressive
reduction in cholesterol levels study review. J Cardiovasc Nurs 2008;
23:8–13.
108. Rossebo AB, Pedersen TR, Allen C, et al. Design and baseline
characteristics of the Simvastatin and Ezetimibe in Aortic Stenosis
(SEAS) study. Am J Cardiol 2007;99:970–3.
109. Sharp Collaborative Group. Study of Heart and Renal Protection
(SHARP): randomized trial to assess the effects of lowering low-
density lipoprotein cholesterol among 9,438 patients with chronic
kidney disease. Am Heart J 2010;160:785–794. e10.
110. Yokoyama M, Origasa H, JELIS Investigators. Effects of eicosa-
pentaenoic acid on cardiovascular events in Japanese patients with
hypercholesterolemia: rationale, design, and baseline characteristics
of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J
2003;146:613–20.
111. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-
prevention trial with gemﬁbrozil in middle-aged men with dyslipi-
demia. Safety of treatment, changes in risk factors, and incidence of
coronary heart disease. N Engl J Med 1987;317:1237–45.
112. The Lipid Research Clinics Coronary Primary Prevention Trial
results. II. The relationship of reduction in incidence of coronary
heart disease to cholesterol lowering. JAMA 1984;251:365–74.
113. The Lipid Research Clinics Coronary Primary Prevention Trial
results. I. Reduction in incidence of coronary heart disease. JAMA
1984;251:351–64.
114. Rubins HB, Robins SJ, Collins D, et al. Gemﬁbrozil for the sec-
ondary prevention of coronary heart disease in men with low levels
of high-density lipoprotein cholesterol. Veterans Affairs High-
Density Lipoprotein Cholesterol Intervention Trial Study Group.
N Engl J Med 1999;341:410–8.
115. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenoﬁbrate
therapy on cardiovascular events in 9795 people with type 2 diabetes
mellitus (the FIELD study): randomised controlled trial. Lancet
2005;366:1849–61.
116. HPS2-THRIVE Collaborative Group. HPS2-THRIVE random-
ized placebo-controlled trial in 25 673 high-risk patients of ER
niacin/laropiprant: trial design, pre-speciﬁed muscle and liver out-
comes, and reasons for stopping study treatment. Eur Heart J 2013;
34:1279–91.
117. De Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a
delayed conservative simvastatin strategy in patients with acute
coronary syndromes: phase Z of the A to Z trial. JAMA 2004;292:
1307–16.
118. Koren MJ, Hunninghake DB, ALLIANCE Investigators. Clinical
outcomes in managed-care patients with coronary heart disease
treated aggressively in lipid-lowering disease management clinics:
the ALLIANCE study. J Am Coll Cardiol 2004;44:1772–9.
119. Knopp RH, d’ Emden M, Smilde JG, et al. Efﬁcacy and safety of
atorvastatin in the prevention of cardiovascular end points in subjects
with type 2 diabetes: the Atorvastatin Study for Prevention of
Coronary Heart Disease Endpoints in non–insulin-dependent dia-
betes mellitus (ASPEN). Diabetes Care 2006;29:1478–85.
JACC Vol. 63, No. 25, 2014
Stone et al.
July 1, 2014:2889–934
2013 ACC/AHA Blood Cholesterol Guideline
2917
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120. Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment
with atorvastatin to the National Cholesterol Educational Program
goal versus “usual” care in secondary coronary heart disease pre-
vention. The GREek Atorvastatin and Coronary-heart-disease
Evaluation (GREACE) study. Curr Med Res Opin 2002;18:220–8.
121. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin,
antioxidant vitamins, or the combination for the prevention of
coronary disease. N Engl J Med 2001;345:1583–92.
122. Serruys PWJC, de Feyter P, Macaya C, et al. Fluvastatin for pre-
vention of cardiac events following successful ﬁrst percutaneous
coronary intervention: a randomized controlled trial. JAMA 2002;
287:3215–22.
123. Sakamoto T, Kojima S, Ogawa H, et al. Effects of early statin
treatment on symptomatic heart failure and ischemic events after
acute myocardial infarction in Japanese. Am J Cardiol 2006;97:
1165–71.
124. Study of the Effectiveness of Additional Reductions in Cholesterol
and Homocysteine (SEARCH) Collaborative Group, Armitage J,
Bowman L, et al. Intensive lowering of LDL cholesterol with
80 mg versus 20 mg simvastatin daily in 12,064 survivors of
myocardial infarction: a double-blind randomised trial. Lancet 2010;
376:1658–69.
125. Ahmed S, Cannon CP, Murphy SA, et al. Acute coronary syn-
dromes and diabetes: is intensive lipid lowering beneﬁcial? Results of
the PROVE IT-TIMI 22 trial. Eur Heart J 2006;27:2323–9.
126. Wenger NK, Lewis SJ, Herrington DM, et al. Outcomes of
using high- or low-dose atorvastatin in patients 65 years of age or
older with stable coronary heart disease. Ann Int Med 2007;147:
1–9.
127. Chaturvedi S, Zivin J, Breazna A, et al. Effect of atorvastatin in
elderly patients with a recent stroke or transient ischemic attack.
Neurology 2009;72:688–94.
128. Shepherd J, Kastelein JJP, Bittner V, et al. Intensive lipid lowering
with atorvastatin in patients with coronary heart disease and chronic
kidney disease: The TNT (Treating to New Targets) study. J Am
Coll Cardiol 2008;51:1448–54.
129. Shepherd J, Kastelein JP, Bittner VA, et al. Intensive lipid lowering
with atorvastatin in patients with coronary artery disease, diabetes,
and chronic kidney disease. Mayo Clin Proc 2008;83:870–9.
130. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on
coronary events after myocardial infarction in patients with average
cholesterol levels. Cholesterol and Recurrent Events Trial In-
vestigators. N Engl J Med 1996;335:1001–9.
131. ALLHAT Ofﬁcers and Coordinators for the ALLHAT Collabo-
rative Research Group. Major outcomes in moderately hypercho-
lesterolemic, hypertensive patients randomized to pravastatin vs
usual care: The Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002;288:
2998–3007.
132. Sever PS, Poulter NR, Dahlof B, et al. Reduction in cardiovascular
events with atorvastatin in 2,532 patients with type 2 diabetes:
Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm
(ASCOT-LLA). Diabetes Care 2005;28:1151–7.
133. Holdaas H, Fellström B, Cole E, et al. Long-term cardiac outcomes
in renal transplant recipients receiving ﬂuvastatin: the ALERT
extension study. Am J Transplant 2005;5:2929–36.
134. Cholesterol
Treatment
Trialists
Collaboration,
Kearney
PM,
Blackwell L, et al. Efﬁcacy of cholesterol-lowering therapy in 18,686
people with diabetes in 14 randomised trials of statins: a meta-
analysis. Lancet 2008;371:117–25.
135. Messerli FH, Pinto L, Tang SSK, et al. Impact of systemic hy-
pertension on the cardiovascular beneﬁts of statin therapy–a meta-
analysis. Am J Cardiol 2008;101:319–25.
136. Kizer JR, Madias C, Wilner B, et al. Relation of different measures
of low-density lipoprotein cholesterol to risk of coronary artery
disease and death in a meta-regression analysis of large-scale trials of
statin therapy. Am J Cardiol 2010;105:1289–96.
137. Ray KK, Seshasai SRK, Erqou S, et al. Statins and all-cause mor-
tality in high-risk primary prevention: a meta-analysis of 11 ran-
domized controlled trials involving 65,229 participants. Arch Intern
Med 2010;170:1024–31.
138. Brugts JJ, Yetgin T, Hoeks SE, et al. The beneﬁts of statins in
people without established cardiovascular disease but with cardio-
vascular risk factors: meta-analysis of randomised controlled trials.
BMJ 2009;338:b2376.
139. Bukkapatnam RN, Gabler NB, Lewis WR. Statins for primary
prevention of cardiovascular mortality in women: a systematic review
and meta-analysis. Prev Cardiol 2010;13:84–90.
140. Mizuno K, Nakaya N, Ohashi Y, et al. Usefulness of pravastatin in
primary prevention of cardiovascular events in women: analysis of the
ManagementofElevatedCholesterol inthe Primary PreventionGroup
of Adult Japanese (MEGA study). Circulation 2008;117:494–502.
141. Bonovas S, Filioussi K, Tsantes A, et al. Use of statins and risk of
haematological malignancies: a meta-analysis of six randomized
clinical trials and eight observational studies. Br J Clin Pharmacol
2007;64:255–62.
142. Preiss D, Seshasai SRK, Welsh P, et al. Risk of incident diabetes
with intensive-dose compared with moderate-dose statin therapy: a
meta-analysis. JAMA 2011;305:2556–64.
143. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in
Coronary Drug Project patients: long-term beneﬁt with niacin.
J Am Coll Cardiol 1986;8:1245–55.
144. Parolari A, Tremoli E, Cavallotti L, et al. Do statins improve
outcomes and delay the progression of non-rheumatic calciﬁc aortic
stenosis? Heart 2011;97:523–9.
Key Words: ACC/AHA Practice Guideline - biomarkers,
pharmacological - cardiovascular disease - cholesterol - diabetes
mellitus - drug therapy - hydroxymethylglutaryl-CoA reductase
inhibitors/statins - hypercholesterolemia - lipids - patient
compliance - primary prevention - risk assessment - risk reduction
behavior - secondary prevention.
Stone et al.
JACC Vol. 63, No. 25, 2014
2013 ACC/AHA Blood Cholesterol Guideline
July 1, 2014:2889–934
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Appendix 1. Author Relationships With Industry and Other Entities (Relevant)d
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol in Adults to
Reduce Atherosclerotic Cardiovascular Risk
Panel Member
Employment
Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Expert Witness
Neil J. Stone
Chair
Northwestern Memorial
HospitaldBonow
Professor of Medicine,
Feinberg School of
Medicine, Northwestern
University
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
None
2013:
None
Jennifer G. Robinson
Co-Chair
University of Iowad
Professor of
Epidemiology and
Medicine; Prevention
Intervention
CenterdDirector
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
 Aegerion
 Amarin*
 Amgen*
 AstraZeneca*
 Esperion
 Genentech/
Hoffman LaRoche*
 GlaxoSmithKline*
 Merck*
 Sanoﬁ-aventis/
Regeneron *
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
 Amarin*
 Amgen*
 AstraZeneca*
 Genentech/
Hoffman LaRoche*
 GlaxoSmithKline*
 Merck*
 Sanoﬁ-aventis/
Regeneron*
2013:
None
Alice H. Lichtenstein
Co-Chair
Tufts University, USDA
Human Nutrition
Research Center
on AgingdGershoff
Professor of Nutrition
Science and Policy;
Professor of Public
Health and Family
Medicine
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
None
2013:
None
C. Noel Bairey Merz
Cedars-Sinai Medical
CenterdWomen’s
Guild Endowed Chair
in Women’s Health
Barbara Streisand
Women’s Heart
CenterdDirector;
Preventive Cardiac
CenterdProfessor
of Medicine
2008–2012:
 Abbott Vascular
 Bayer
 Bristol-Myers Squibb
 Gilead
 Novartis
 Pﬁzer
 Posen
2008–2012:
None
2008–2012:
 ATS Medical
 Boston Scientiﬁc
 Eli Lilly
 Johnson &
Johnson
 Medtronic
 Teva
Pharmaceuticals
2008–2012:
 RWISE
 Ranexa Microvascular
 Ranexa Angina
2008–2012:
None
2013:
 Amgen*
 Gilead
 Bristol-MyersSquibb
(DSMB)
2013:
None
2013:
None
2013:
 RWISE
2013:
None
Conrad Blum
Columbia University
Medical Center,
Columbia University
College of Physicians
and Surgeonsd
Professor of Medicine
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
None
2013:
None
Continued on the next page
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Stone et al.
July 1, 2014:2889–934
2013 ACC/AHA Blood Cholesterol Guideline
2919
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Appendix 1. Continued
Panel Member
Employment
Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Expert Witness
Robert H. Eckel
University of Colorado,
Denver School of
MedicinedProfessor of
Medicine; Professor of
Physiology and
Biophysics; and Charles
A. Boettcher II Chair in
Atherosclerosis
2008–2012:
 Foodminds
 Merck
 Pﬁzer
 Abbott
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2013:
 Amylin
 Eli Lilly
 Esperion
 Foodminds
 Johnson & Johnson
 Novo Nordisk
 Vivus
2013:
None
2013:
None
2013:
 GlaxoSmithKline*
 Sanoﬁ-aventis/
Regeneron
2013:
None
Anne Carol Goldberg
Washington University
School of Medicined
Associate Professor of
Medicine
2008–2012:
 Abbott
 Roche
 ISIS/Genzyme
 Sanoﬁ-aventis
 Unilever
 Merck
2008–2012:
None
2008–2012:
None
2008–2012:
 Abbott*
 Aegerion*
 Amarin*
 Amgen*
 Genentech/Roche*
 GlaxoSmithKline*
 ISIS/Genzyme*
 Merck*
 Novartis
 Reliant*
 Sanoﬁ-aventis/Regeneron*
 Sanoﬁ-aventis*
2008–2012:
None
2013:
 Merck
2013:
None
2013:
None
2013:
 Abbott*
 Amarin*
 Amgen*
 Genentech/Roche*
 GlaxoSmithKline*
 ISIS/Genzyme*
 Merck*
 Sanoﬁ-aventis/Regeneron*
2013:
None
David Gordon,
Ex-Ofﬁcio
NHLBIdSpecial Assistant
for Clinical Studies,
Division of
Cardiovascular
Diseases
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
None
2013:
None
Daniel Levy,
Ex-Ofﬁcio
NHLBIdDirector of the
Center for Population
Studies
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
None
2013:
None
Donald M. Lloyd-Jones
Northwestern University
Feinberg School of
MedicinedSenior
Associate Dean; Chair
and Professor of
Preventive Medicine;
Professor of Medicine
(Cardiology)
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
None
2013:
None
Patrick McBride
University of Wisconsin
School of Medicine and
Public Healthd
Professor of Medicine
and Family Medicine
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
None
2013:
None
Continued on the next page
Stone et al.
JACC Vol. 63, No. 25, 2014
2013 ACC/AHA Blood Cholesterol Guideline
July 1, 2014:2889–934
2920
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Appendix 1. Continued
Panel Member
Employment
Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Expert Witness
J. Sanford Schwartz
University of Pennsylvania
School of Medicined
Leon Hess Professor of
Internal Medicine,
Health Management
and Economics
2008–2012:
 Abbott
 Allergan
 Amgen
 Daiichi-Sankyo
 Genentech
 Johnson & Johnson
 Merck
 Pﬁzer
 Shire Pharmaceuticals
2008–2012:
None
2008–2012:
None
2008–2012:
 Pﬁzer
2008–2012:
None
2013:
 Abbott
 Allergan
 Amgen
 Daiichi-Sankyo
 Genentech
 Johnson & Johnson
 Merck
 Pﬁzer
 Shire Pharmaceuticals
2013:
None
2013:
None
2013:
 Pﬁzer
2013:
None
Susan T. Shero
Ex-Ofﬁcio
NHLBIdPublic Health
Advisor
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
None
2013:
None
Sidney C. Smith, Jr
University of North
CarolinadProfessor of
Medicine; Center for
Cardiovascular Science
and MedicinedDirector
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
None
2013:
None
Karol Watson
University of California,
Los Angeles School of
MedicinedCo-Director
2008–2012:
 Abbott
 AstraZeneca
 Genzyme
 GlaxoSmithKline
 Kos
 Medtronic
 Merck
 Novartis
 Pﬁzer
2008–2012:
None
2008–2012:
None
2008–2012:
 Merck
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
 Merck
2013:
None
Peter W.F. Wilson
Atlanta VA Medical Center
and Emory University
School of Medicined
Professor of Medicine
2008–2012:
 Merck
 XZK
2008–2012:
None
2008–2012:
None
2008–2012:
 Merck
 Liposcience
2008–2012:
None
2013:
None
2013:
None
2013:
None
2013:
 Merck
2013:
None
This table reﬂects the relevant healthcare-related relationships of authors with industry and other entities provided by the panels during the document development process (2008–2012). Both
compensated and uncompensated relationships are reported. These relationships were reviewed and updated in conjunction with all meetings and conference calls of the Expert Panel during the
document development process. Authors with relevant relationships during the document development process recused themselves from voting on recommendations relevant to their relationships. In
the spirit of full transparency, the ACC and AHA asked Expert Panel members to provide updates and approve the ﬁnal version of this table, which includes current relevant relationships (2013). To review
the NHLBI and ACC/AHA’s current comprehensive policies for managing relationships with industry and other entities, please refer to http://www.nhlbi.nih.gov/guidelines/cvd_adult/coi-rwi_policy.htm
and http://www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/Relationships-With-Industry-Policy.aspx. Per ACC/AHA policy: A person is deemed to have a signiﬁcant
interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $10,000 of the fair market value of the business entity; or if funds
received by the person from the business entity exceed 5% of the person’s gross income for the previous year. Relationships that exist with no ﬁnancial beneﬁt are also included for the purpose of
transparency. Relationships in this table are modest unless otherwise noted.
*Signiﬁcant relationship.
ACC indicates American College of Cardiology; AHA, American Heart Association; NHLBI, National Heart, Lung, and Blood Institute; and USDA, U.S. Department of Agriculture.
JACC Vol. 63, No. 25, 2014
Stone et al.
July 1, 2014:2889–934
2013 ACC/AHA Blood Cholesterol Guideline
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Appendix 2. Expert Reviewers Relationships With Industry and Other Entitiesd
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol in Adults to
Reduce Atherosclerotic Cardiovascular Risk
Reviewer
Employment
Representation
Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Expert
Witness
Roger Blumenthal
Johns Hopkins Hospital
Ciccarone Preventive
Cardiology Centerd
Professor of Medicine
ACC/AHA
None
None
None
None
None
William Virgil Brown
Emory University School
of Medicine
NLA
 Abbott
 Amgen
 Anthera
 Bristol-Myers Squibb
 Catabasis
 Cerenis
 GlaxoSmithKline
 Genzyme
 LipoScience
 Merck
 Pﬁzer
 Regeneron
None
None
None
None
Linda Hemphill
Massachusetts General
HospitaldDirector,
LDL Apheresis Program
NLA
 Regeneron
None
None
None
None
Matthew Ito
Oregon Health & Science
University, Department
of Pharmacy Practiced
Professor
NLA
 Aegeron
 Kowa
None
None
None
None
Terry Jacobson
Emory University
NLA
 Abbott
 Merck
None
None
 Amarin
 HealthCore
None
Andrew Kates
Washington University School
of Medicine in St. Louisd
Cardiovascular Fellowship
Program Director
ACC/AHA
None
None
None
None
None
James M. McKenney
Virginia Commonwealth
UniversitydProfessor
Emeritus
NLA
None
None
None
None
None
E. Magnus Ohman
Duke Clinical Research
InstitutedProfessor of
Medicine; Program for
Advanced Coronary
DiseasedDirector
ACC/AHA Task
Force on
Practice
Guidelines
None
None
None
None
None
Carl E. Orringer
Case Western Reserve University
School of MedicinedAssociate
Professor of Medicine
NLA
None
None
None
None
None
Robert S. Rosenson
Mount Sinai Hospitald
Director, Preventive
Cardiology; Professor
of Medicine, Cardiology
NLA
 Amgen
 LipoScience
 Novartis
 Pﬁzer
 Sanoﬁ-aventis/
Regeneron
None
 LipoScience
None
None
John Rumsfeld
Denver VA Medical Center,
University of Coloradod
National Director of
Cardiology, U.S. Veterans
Health Administration
ACC/AHA
None
None
None
None
None
Robert A. Wild
University of Oklahoma, College
of Medicine, Department of
Obstetrics and Gynecologyd
Professor
NLA
 Atherotec
None
None
None
None
This table represents the relationships of reviewers with industry and other entities that were self-disclosed at the time of peer review. It does not necessarily reﬂect relationships with industry at the time
of publication. To review the NHLBI and ACC/AHA’s current comprehensive policies for managing relationships with industry and other entities, please refer to http://www.nhlbi.nih.gov/guidelines/cvd_
adult/coi-rwi_policy.htm and http://www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/Relationships-With-Industry-Policy.aspx.
ACC indicates American College of Cardiology; AHA, American Heart Association; NLA, National Lipid Association; and VA, Veterans Affairs.
Stone et al.
JACC Vol. 63, No. 25, 2014
2013 ACC/AHA Blood Cholesterol Guideline
July 1, 2014:2889–934
2922
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Page 152 of 364


Appendix 3. Abbreviations
ALT ¼ alanine transaminase
ASCVD ¼ atherosclerotic cardiovascular disease
CHD ¼ coronary heart disease
COR ¼ Class of Recommendation
CQ ¼ critical question
HDL-C ¼ high-density lipoprotein cholesterol
LDL-C ¼ low-density lipoprotein cholesterol
LOE ¼ Level of Evidence
MI ¼ myocardial infarction
NHLBI ¼ National Heart, Lung, and Blood Institute
RCT ¼ randomized controlled trial
RWI ¼ relationships with industry and other entities
Appendix 4. Evidence Statements
ES No.
Evidence Statement
Level of
Evidence
Recommendation(s)/
Section
References
1
Data are not available regarding treatment or titration to a speciﬁc LDL-C
goal in adults with CHD/CVD. The Expert Panel found insufﬁcient
evidence to support setting LDL-C goals in CHD/CVD patients.
I
Secondary Prevention
Conclusion after reviewing 19 RCTs in CQ1 Evidence
Table:
4D (87), A–Z (117), ACCORD (14), ALLIANCE (118),
ASPEN (119), AURORA (84), CARE (73),
CORONA (85), GREACE (120), HATS (121), HPS
(16), IDEAL (47), LIPID (74), LIPS (122), MIRACL
(93), MUSHASHI-AMI (123), PROVE-IT (48),
SPARCL (78,107), TNT (46)
2
The Expert Panel did not identify any trials in adults with CHD/CVD
reporting mean or median on-treatment non–HDL-C levels in adults with
CHD/CVD.
Secondary Prevention
N/A
3
LDL-C goals <130 mg/dL or <100 mg/dL in patients without CHD/CVD.
Randomized trial data are not available regarding dose titration to
achieve a speciﬁc LDL-C goal.
I
Primary Prevention
Conclusion after reviewing 6 RCTs included in CQ2:
AFCAPS (17), ASPEN (119), AURORA (84), CARDS
(75), JUPITER (49), MEGA (18)
4
There was insufﬁcient evidence in women without CHD/CVD to evaluate
the reduction in CVD risk with achieved LDL-C levels <130 mg/dL
or <100 mg/dL.
I
Primary Prevention
N/A
5
The Expert Panel did not identify any trials in adults without CHD/CVD
reporting on-treatment non–HDL-C levels in adults with CHD/CVD.
Primary Prevention
N/A
6
In adults with CHD/CVD, ﬁxed high-intensity statin treatment (atorvastatin
40–80 mg) that achieved a mean LDL-C 67–79 mg/dL reduced the
RR for CHD/CVD events more than ﬁxed lower-dose statin treatment
that achieved a mean LDL-C 97–102 mg/dL. In these trials, the
mean LDL-C levels achieved differed by 23–30 mg/dL, or 22%–32%,
between the 2 groups. Simvastatin 80 mg did not decrease CVD
events compared with simvastatin 20–40 mg.
See Table 4 for deﬁnitions of high, moderate, and low intensity for statins.
Higher intensity ¼ atorvastatin 40–80 mg
Moderate intensity ¼ atorvastatin 10 mg, pravastatin 40 mg,
or simvastatin 20–40 mg
H
Secondary Prevention
Beneﬁt:
TNT (46), IDEAL (47), PROVE-IT (48)
Lower LDL-C reductions, no beneﬁt:
A–Z (117), ACCORD (14)
No difference in LDL-C between groups: (SEARCH
(124) not included in CQ1)
7
In adults with CHD/CVD who do not have Class II–IV heart failure, ﬁxed
high-intensity statin (atorvastatin 80 mg) or statin-niacin treatment that
achieved a mean LDL-C 72–79 mg/dL reduced the RR for CHD/CVD
events compared with placebo with a mean LDL-C 112–135 mg/dL.
In these trials, the mean LDL-C levels were reduced by 45–57 mg/dL
or by 45% (HATS [121]) to 53% (SPARCL [107]).
H
Secondary Prevention
SPARCL (107)
HATS (121)
MIRACL (93)
CORONA (85)–no beneﬁt
Continued on the next page
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Appendix 4. Continued
ES No.
Evidence Statement
Level of
Evidence
Recommendation(s)/
Section
References
8
In adults with CHD/CVD and diabetes, ﬁxed high-intensity statin treatment
(atorvastatin 80 mg) that achieved a mean LDL-C of 57–77 mg/dL
reduced the RR for CHD/CVD events more than ﬁxed lower-intensity
statin treatment that achieved a mean LDL-C of 81–99 mg/dL. In these
trials, the mean LDL-C levels achieved differed by 22–24 mg/dL,
or 22%–30%, between the 2 groups.
M to H
Secondary Prevention
(diabetes subgroup
included)
TNT (46,94), PROVE-IT (48,125)
No diabetes subgroup publications found for MIRACL
(93) or IDEAL (47)
9
In adults 65 years of age with CHD/CVD, ﬁxed high-intensity statin
treatment (atorvastatin 80 mg) that achieved a mean LDL-C of 72 mg/dL
reduced CHD/CVD events more than ﬁxed lower-intensity statin treatment
that achieved a mean LDL-C of 97 mg/dL. In this trial, the mean LDL-C
levels achieved differed by 25 mg/dL, or 26%, between the 2 groups. In
adults 65 years of age with a history of stroke or TIA, higher ﬁxed-dose
statin treatment that achieved a mean LDL-C of 72 mg/dL reduced CHD
events more than placebo, with a mean LDL-C of 129 mg/dL. In this trial,
the mean LDL-C level was reduced by 61 mg/dL, or 46%, from baseline in
those 65 years of age.
L
Secondary Prevention (age
subgroups included)
TNT (46,126), SPARCL (107,127)
No publications by age included for:
PROVE-IT (48)
IDEAL (47)
HATS (121)
10
In adults with CHD/CVD and CKD (excluding hemodialysis), ﬁxed high-
intensity statin treatment (atorvastatin 80 mg) that achieved a mean
LDL-C of 79 mg/dL reduced CHD/CVD events more than ﬁxed lower-
dose statin treatment that achieved a mean LDL-C of 99 mg/dL. In this
trial, the mean LDL-C levels achieved differed by 20 mg/dL, or 20%
between the 2 groups.
L
Secondary Prevention (CKD
subgroup included)
TNT (46,128)
TNT (46,129)
No publications included for CKD:
PROVE-IT (48)
IDEAL (47)
11
In adults with CHD or acute coronary syndromes, more intensive-dose
statin therapy reduced LDL-C to a greater degree (by 20 mg/dL or an
additional 20%) than less intensive-dose statin therapy or placebo and
produced a greater reduction in CVD events.
Each 1-mmol/L (38.7-mg/dL) reduction in LDL-C reduced the RR for CVD
events by approximately 28%.
See Table 4 for deﬁnitions of high-, moderate-, and low-intensity statin
therapy.
More intensive statin therapy ¼ atorvastatin 80 mg, simvastatin 80 mg.
Less intensive statin therapy ¼ atorvastatin 10 mg, pravastatin 40 mg,
or simvastatin 20–40 mg.
H
Secondary Prevention
CTT 2010 (20)ddata from 5 trials
TNT (46)
IDEAL (47)
PROVE-IT (48)
A–Z (117)
SEARCH (124) (not included in CQ1)
12
In trials of more intensive statin therapy (atorvastatin 80 mg, simvastatin
80 mg) compared with less intensive statin therapy (atorvastatin 10
mg, pravastatin 40 mg, or simvastatin 20–40 mg), women with CHD or
acute coronary syndromes experienced a similar (approximately 25%)
magnitude of relative CVD reduction as men (approximately 29%).
Women also experienced a similar magnitude of absolute risk
reduction as men.
H
Secondary Prevention
(women included)
CTT 2010 (20)d5 trials
TNT (46)
IDEAL (47)
PROVE-IT (48)
A–Z (117)
SEARCH (124) (not included in CQ1)
13
In adults with and without CVD, in trials comparing more intensive to less
intensive statin therapy or statin therapy with placebo/control, the
relative CVD risk reduction was similar for those <65 years, 65 to 75,
or >75 years of age. There is less information to estimate the
magnitude of beneﬁt in those under age 45 or over age 75 years,
because fewer participants in these age groups were enrolled in clinical
trials. More intensive statin therapy did not appear to reduce CVD risk,
compared with less intensive statin therapy, in those with ASCVD and
age >75 years. Statin therapy, compared with control (most RCTs
evaluated moderate-intensity statin therapy), had a similar magnitude
of RR reduction in those >75 as in those 75 years of age with and
without ASCVD.
Statin therapy vs. control trials ¼ atorvastatin (A) 10–20 mg, ﬂuvastatin (F)
80 mg, lovastatin (L) 40–80 mg, pravastatin (P) 40 mg, rosuvastatin (R)
10–20 mg, simvastatin (S) 40 mg.
See Table 4 for the Expert Panel’s deﬁnitions for high-, moderate-, and low-
intensity statin therapy.
The Panel uses moderate intensity to refer to statin drugs and doses that
lower LDL-C by 30% to approximately 50%.
This dose refers to atorvastatin 10 mg, ﬂuvastatin 80 mg, lovastatin 40
mg, pravastatin 40 mg, rosuvastatin 10 mg, and simvastatin 40 mg.
H
Primary Prevention,
Secondary Prevention
CTT 2010 (20)d26 trials
Included:
More vs. less statin
TNT (46)
IDEAL (47)
PROVE-IT (48)
A–Z (117)
SEARCH (124)
Statin vs. control (statin/dose, percent LDL-C
reduction)
4S (47) S20–40, –36%
WOSCOPS (72) P40, –22%
CARE (130) P40, –29%
AFCAPS/TexCAPS (17) L20-40, –24%
LIPID (74) P40, –27%
GISSI-P (86) P20, –9%
LIPS (122) F40 BID, –27%
HPS (16) S40, –38%
PROSPER (38) P40, –27%
ALLHAT-LLT (131) P40, –14%
ASCOT-LLA (132) A10, –31%
ALERT (133) F40, –20%
CARDS (75) A10, –38%
ALLIANCE (118)dNA
4D (87)dA20, –27%
ASPEN (119) A10, –34%
MEGA (18) P10–20, –17%
JUPITER (49) R20, –40%
GISSI-HF (86) R10, –30%
AURORA (84) R10, –38%
Continued on the next page
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Appendix 4. Continued
ES No.
Evidence Statement
Level of
Evidence
Recommendation(s)/
Section
References
14
In adults with CHD (including acute coronary syndromes, or a history of MI,
stable or unstable angina, coronary revascularization), statin therapy
reduced the RR for CVD events by approximately 21% per 1-mmol/L
(38.7-mg/dL) LDL-C reduction. This relationship was similar for more
intensive compared with less intensive statin therapy and for statin
therapy compared with placebo/control.
H
Secondary Prevention
CTT 2010 (20)d26 trialsdsee above
15
In adults with CVD other than CHD (including stroke, TIA presumed to be of
atherosclerotic origin, or peripheral arterial disease or
revascularization), statin therapy reduced the RR for CVD events by
approximately 19% per 1-mmol/L (38.7-mg/dL) LDL-C reduction.
This relationship was similar for more intensive compared with less
intensive statin therapy and for statin therapy compared with
placebo/control.
H
Secondary Prevention
CTT 2010 (20)d26 trials
16
In adults with diabetes and CHD or other CVD, moderate-dose statin
therapy reduced CVD events by approximately 20% per 1-mmol/L
(38.7-mg/dL) LDL-C reduction.
H
Secondary Prevention
(diabetes subgroup
included)
CTT 2008 (134)d14 trials
17
In adults with and without CVD, statin therapy reduced CVD events in both
men and women.
H
Primary Prevention,
Secondary Prevention
CTT 2010 (20)d26 trials
18
In adults with and without CVD, in trials comparing more* intensive with
less intensive statin therapy, or statin therapy with placebo/control,
there were no clinically important differences in the CVD risk reduction
between the subgroups listed below:
 Treated hypertension or all others
 Systolic blood pressure <140, 140 to <160, and 160 mm Hg
 Diastolic blood pressure <80, 80 to <90, and 90 mm Hg
 Body mass index <25, 25 to <30, and 30 kg/m2
 Current smoking and nonsmokers
GFR <60, 60 to <90, 90 mL/min per 1.73 m2)
 Post-MI
 Total cholesterol 5.2 (201 mg/dL), >5.2 to 6.5, >6.5
(251 mg/dL) mmol/L
 Triglycerides 1.4 (124 mg/dL), >1.4 to 2.0, >2.0 (177 mg/dL)
mmol/L
 HDL-C 1.0 (39 mg/dL), >1.0 to 1.3, >1.3 (50 mg/dL) mmol/L
H
Primary Prevention,
Secondary Prevention
CTT 2010 (20)d26 trials
19
In more vs. less statin and statin vs. control trials combined, each 1-mmol/L
(38.7-mg/dL) reduction in LDL-C resulted in approximately 22%
reductions in CVD risk across baseline LDL-C levels [<2 mmol/L (77
mg/dL), 2 to <2.5 mmol/L (97 mg/dL), 2.5 to <3.0 mmol/L (116
mg/dL), 3.0 to <3.5 mmol/L (135 mg/dL), and 3.5 mmol/L, either
untreated or on statin therapy]. In the statin vs. placebo/control trials,
those with LDL-C <2 mmol/L may have experienced less beneﬁt than
those with higher LDL-C level.
M
CTT 2010 (20)d26 trials
20
In adults, statins reduce the RR for CVD, CHD, and fatal CHD similarly in
those with or without hypertension. This beneﬁt applies across all levels
of baseline systolic and diastolic blood pressure and in those with
treated hypertension.
H
Primary Prevention,
Secondary Prevention
CTT 2010 (20), Messerli AJC 2008 (135)
21
In adults with and without CVD who received more intensive compared
with less intensive statin therapy, or statin therapy compared with
placebo/control, the RR for ﬁrst stroke was reduced by approximately
16% per 1-mmol/L (38.7-mg/dL) LDL-C reduction, primarily because of
an approximately 21% reduction in the RR for ischemic stroke.
M to H
Primary Prevention,
Secondary Prevention
CTT 2010 (20)d26 trials
22
In adults with and without CHD/CVD who received more intensive
compared with less intensive statin therapy, or statin therapy compared
with placebo/control:
 The RR for major coronary events was reduced by approximately
24% per 1-mmol/L (38.7-mg/dL) LDL-C reduction.
 The RR for nonfatal myocardial infarction was reduced by approxi-
mately 27% per 1-mmol/L LDL-C reduction.
 Total mortality was reduced by approximately 10% per 1-mmol/L
(38.7-mg/dL) LDL-C reduction, primarily because of a 16%
reduction in the risk for cardiac death.
 The risk for CVD mortality was reduced by approximately 14% per
1-mmol/L (38-mg/dL) LDL-C reduction, primarily because of a 16%
reduction in the risk for cardiac death.
H
Primary Prevention,
Secondary Prevention
CTT 2010 (20)d26 trials
Continued on the next page
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Appendix 4. Continued
ES No.
Evidence Statement
Level of
Evidence
Recommendation(s)/
Section
References
23
In adults with CHD or acute coronary syndromes who received more
intensive compared with less intensive statin therapy, the RR for
coronary revascularization was reduced by approximately 34% per
1-mmol/L (38.7-mg/dL) LDL-C reduction.
H
Secondary Prevention
CTT 2010 (20)d5 trials
24
In adults with and without CVD who received statin therapy compared with
placebo/control, the RR for coronary revascularization was reduced by
approximately 24% per 1-mmol/L (38.7-mg/dL) LDL-C reduction.
H
Primary Prevention,
Secondary Prevention
CTT 2010 (20)d21 trials
25
In adults with and without CVD who received statin therapy, a larger
absolute reduction in LDL-C (mmol/L or mg/dL) was associated with a
greater reduction in the risk for CVD.
M
Primary Prevention,
Secondary Prevention
CTT2010 (20), Kizer 2010 (136)
26
In adults with and without CVD who received statin therapy, there was no
variation in the relative reduction of CVD risk among the trials after
adjustment for LDL-C reduction. Thus, LDL-C reduction appeared to
account for the reduction in CVD risk.
M
Primary Prevention,
Secondary Prevention
CTT 2010 (20)
27
Consistent 23%–28% relative reductions in CVD risk per 39-mg/dL
(1-mmol/L) reduction in LDL-C were observed after 1 year to beyond
5 years of statin treatment.
H
Secondary Prevention,
Primary Prevention
CTT 2008 (134), 2005 (50) CTT 2010 (96)
28
Statins reduce the RR for CVD similarly in primary- and secondary-
prevention populations.
H
Primary Prevention;
Secondary Prevention
CTT 2010 (20) CTT 2010 Web appendix (50)
29
In adults with diabetes (some of whom had CHD), statin therapy reduced
the RR for CVD events by approximately 20% per 1-mmol/L (38.7-mg/dL)
LDL-C reduction. This 1-mmol (20%) risk-reduction relationship was
similar for more intensive compared with less intensive statin therapy
and for statin therapy compared with placebo/control.
H
Secondary Prevention
(includes diabetes
subgroup)
Primary Prevention in
Individuals With
Diabetes
CTT 2010 (20) CTT 2008 (134)
30
Adults with type 2, type 1, and no diabetes had similar RRRs in CVD per
1-mmol/L (38.7-mg/dL) LDL-C reduction.
H
Primary Prevention in
Individuals With
Diabetes
CTT 2010 (20)
31
In adults with diabetes without CVD, moderate-dose statin therapy,
compared with placebo/control, reduced the RR for CVD events by
approximately 27% per 1-mmol/L (38.7-mg/dL) LDL-C reduction.
H
Primary Prevention in
Individuals With
Diabetes
CTT 2008 (134)d14 trials
32
In adults with diabetes, statin therapy reduced the RR for CVD by a similar
magnitude for subgroups of diabetic men and women, <65 and 65
years of age; treated hypertension; body mass index <25, >25 to <30,
and 30; systolic blood pressure <160 and 160 mm Hg; diastolic
blood pressure <90 and 90 mm Hg; current smokers and
nonsmokers; estimated GFR <60, 60 to <90, and 90 mL/min/
1.73 m2; and predicted annual risk for CVD <4.5%, >4.5% to <8.0%,
and 8.0%. Whereas RRRs are similar across these subgroups,
absolute risk reductions may differ for various subgroups.
H
Primary Prevention in
Individuals With
Diabetes
CTT 2008 (134)d14 trials
33
In adults 40 to 75 years of age with diabetes and 1 risk factor, ﬁxed
moderate-dose statin therapy that achieved a mean LDL-C of 72 mg/dL
reduced the RR for CVD by 37% (in this trial, LDL-C was reduced by
46 mg/dL or 39%).
M
Primary Prevention in
Individuals With
Diabetes
CARDS (75)
34
In men and postmenopausal women 40 to 73 years of age without CHD/
CVD, the majority of whom did not have diabetes and had baseline LDL-
C levels <190 mg/dL, ﬁxed low- to moderate-dose statin therapy that
achieved a mean LDL-C of 115–127 mg/dL reduced the RR for CVD by
24%–25%, compared with placebo, with mean LDL-C levels of 153–
156 mg/dL. (In these trials, LDL-C was reduced by 29–35 mg/dL and
19%–25% from baseline with a low- to moderate-dose statin.)
H
Primary Prevention
AFCAPS (17); MEGA (18)
35
In men 50 years and women 60 years of age without CHD/CVD with
LDL <130 mg/dL and hs-CRP 2 mg/L, ﬁxed intensive-dose statin that
achieved a mean LDL-C of 53 mg/dL reduced the RR for CVD events by
44% compared with placebo, which had a mean LDL-C 110 mg/dL. In
this trial, LDL-C was reduced by 53 mg/dL, or 49%.
M
Primary Prevention
JUPITER (49)
36
In adults without CVD (some of whom had diabetes) who received more
intensive or less intensive statin therapy, or statin therapy compared
with placebo/control, the RR for CVD events was reduced by
approximately 25% per 1-mmol/L LDL-C reduction. This was similar to
the CVD RRR observed in those with CHD or CVD.
H
Primary Prevention
CTT 2010 (20)
37
Statin therapy reduces CHD and stroke events in adults 40 years of age
without CHD/CVD, and with a wide range of baseline LDL-C levels.
H
Primary Prevention
CTT 2010 (20)
JUPITER (49)
AFCAPS (17)
MEGA (18)
Continued on the next page
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Appendix 4. Continued
ES No.
Evidence Statement
Level of
Evidence
Recommendation(s)/
Section
References
38
Statin therapy, with a range of LDL-C lowering, reduces all-cause mortality,
compared with placebo, in primary-prevention clinical trials of adults
who were in general 40 years of age and had at least 1 risk factor,
and with a wide range of baseline LDL-C levels.
M
Primary Prevention
CTT 2010 (20)
39
There is insufﬁcient evidence to determine the beneﬁt of statins in primary
prevention on all-cause mortality separately for women and men or with
advancing age.
I
Primary Prevention
CTT 2010 (20)
40
In MEGA (18), AFCAPS (17), JUPITER (49), and CARDS (75), the 10-year
NNTs to prevent 1 hard CVD event were 82, 56, 30, and 15,
respectively. These reﬂect RRRs of 24%, 26%, 44%, and 37%,
respectively, and placebo event rates for major CVD calculated at 10
years of 5.1%, 6.9%, 7.6%, and 18%, respectively.
M
Primary Prevention
CTT 2010 (20) appendix individual trialsdprojected
calculation
41
In adults without CVD (some of whom had diabetes) overall, who received
statin therapy compared with placebo/control, the RR for CVD events
was reduced by approximately 25% per 1-mmol/L LDL-C reduction. This
was similar to the CVD RRR observed in those with CHD or CVD.
H
Primary Prevention,
Primary Prevention in
Individuals With
Diabetes
CTT 2010 (20)
42
Statin therapy, with a range of LDL-C lowering, reduces all-cause mortality
by about 10%, compared with placebo, in primary-prevention clinical
trials of adults who were 40 years of age and in general who had at
least 1 risk factor, and with a wide range of baseline LDL-C levels.
M
Primary Prevention,
efﬁcacy
Cochrane (15), Ray (137), Brugts (138),
Bukkapatnam (139), JUPITER (49)
MEGAdwomen (140)
43
In adults with and without CVD, intensive- and moderate-dose statins do
not increase the risk for death from noncardiovascular causes,
regardless of baseline LDL-C. Statins do not increase (or decrease) the
risk for incident cancer overall or cancer of any type, or the risk for
cancer death.
H
Primary Prevention,
Secondary Prevention,
Safety of Statins
CTT 2010 (20), Mills 2008 (97), Cochrane (15),
Bonovas (141)
44
In adults with or without CVD, statin therapy is associated with an excess
risk for incident diabetes.
 Statin therapy was associated with 1 excess case of incident
diabetes per 1,000 individuals treated for 1 year, compared with
placebo/control, with little heterogeneity among 13 trials (including
JUPITER [49]). Risk for diabetes was highest in older persons
(NNH¼1,002 per year).
 Statin therapy resulted in 5.4 fewer major CVD events per 1-mmol/L
LDL-C reduction per 1,000 individuals treated for 1 year compared
with placebo (NNT to beneﬁt, 185 per year).
 High-intensity statin therapy was associated with 2 excess cases of
incident diabetes per 1,000 individuals treated for 1 year, compared
with moderate-intensity statins (NNH¼498 per year). High-intensity
statin therapy resulted in 6.5 fewer major CVD events per 1,000
individuals treated for 1 year, compared with moderate-intensity
statin therapy (NNT¼155 per year). Rosuvastatin 20 mg was
associated with 3 excess cases of incident diabetes per 1,000
individuals treated for 1 year, compared with placebo (NNH¼332 per
year).
 Rosuvastatin 20 mg resulted in 5.9 fewer major CVD events per
1,000 individuals treated for 1 year, compared with placebo
(NNT¼169 per year).
M
Primary Prevention,
Secondary Prevention,
Safety of Statins
Sattar 2010 (81)
Preiss (142), PROVE-IT (48), A–Z (117),
TNT (46), IDEAL (47), SEARCH (124),
JUPITER (49)
Continued on the next page
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Appendix 4. Continued
ES No.
Evidence Statement
Level of
Evidence
Recommendation(s)/
Section
References
45
In trials of high-intensity compared with moderate-intensity statins (clinical
CVD), moderate-intensity statin compared with placebo
(diabetesdprimary prevention), high-intensity statin compared with
placebo (secondary and primary prevention), or statin-niacin versus
placebo, participants were:
 Seen at visits that occurred at 4–13 weeks after randomization, and
every 3–6 months thereafter.
 Counseled on diet (IDEAL [47], AFCAPS [17], MEGA [18], PROVE-IT
[48], SPARCL [107]) and lifestyle (JUPITER [49]) at baseline and
regularly thereafter or when LDL-C increased (JUPITER [49], CARDS
[75]).
 Assessed for adherence to study medication at every visit.
 Assessed for adverse effects by history and laboratory
measurements at every visit or every other visit.
 Able to reduce the statin dose for adverse events so that atorvastatin
80 mg could be reduced to 40 mg (IDEAL [47], PROVE-IT [48]) or
pravastatin 40 mg could be reduced to 20 mg (PROVE-IT [48]) or
simvastatin reduced by 10 mg/d (HATS [121]).
 Able to reduce the statin dose if LDL-C decreased to <39 mg/dL
(1.0 mmol/L) (per investigator discretion in IDEAL [47]) or reduce
the statin dose if total cholesterol was <100 mg/dL on 2
successive visits (AFCAPS [17]) or reduce by 10 mg simvastatin
per day if LDL-C was <40 mg/d (HATS [121]), although they
continued on study drug no matter how low the cholesterol in
CARDS (75).
 Allowed to have their statin doses uptitrated or switched to more
potent statin to further reduce
 LDL-C (IDEAL [47], CARDS [75], AFCAPS [17], MEGA [18], PROVE-IT
[48]dpravastatin to 80 mg) if LDL-C exceeded 125 mg/dL.
 Given counseling on diet and/or glycemic control when LDL-C or
triglyceride levels increased (CARDS [75]).
 Had study medication discontinued for CK 10  ULN with muscle
aches or weakness, or persistent ALT 3  ULN on 2 consecutive
tests (JUPITER [49], CARDS [75]); the dose of atorvastatin or
pravastatin could be halved for abnormal LFTs, CK elevations, or
myalgias (PROVE-IT [48]).
H
Statin Adherence
Reﬂects review of TNT (46), IDEAL (47), PROVE-IT
(48), CARDS (75), JUPITER (49), SPARCL (107),
MEGA (18), AFCAPS (17) baseline and main
papers; these were statin trials that
demonstrated signiﬁcant CVD risk reduction (and
were the basis of recommendations arising from
CQ1 and CQ2) HATS (121)
46
Most RCTs of moderate-intensity statin therapy and all RCTs of high-
intensity statin therapy excluded subjects with serious comorbidities
and other conditions or concomitant drug therapy predisposing to
adverse events from statin therapy (see Table 9).
H
Primary Prevention,
Secondary Prevention,
Safety of Statins,
Safety of Nonstatins
RCTs included in CQ1, 2, and 3:
A–Z (117), ACCORD (14), AIM-HIGH (9), ASPEN
(119), CARE (130), CDP (101), FIELD (115),
GREACE (120), HATS (121), HHS (111), HPS
(16), IDEAL (47), JUPITER (49), LIPID (74), LIPS
(122), LRC (113), MIRACL (93), MUSHASHI-AMI
(123), PROVE-IT (48), SEAS (108), SHARP (109),
SPARCL (107), TNT (46)
47
In adults with and without CVD who received more intensive compared
with less intensive statin therapy, or statin therapy compared with
placebo/control, overall the RR for ﬁrst hemorrhagic stroke was not
increased. Hemorrhagic stroke comprised 11% of total strokes in the
more intensive/statin group, compared with 8% in the less intensive/
control groups.
M
Primary Prevention,
Secondary Prevention,
Safety of Statins
CTT 2010 (20)
48
In adults with and without CVD, statin-treated individuals in clinical trials
are not more likely to discontinue treatment than placebo-treated
individuals.
H
Primary Prevention,
Secondary Prevention,
Safety of Statins
Cochraned14 trials (15), CTT 2010 (20)
49
In adults with and without CVD in clinical trials, low- to moderate-dose
statins do not increase the risk for myalgias or muscle pain.
H
Primary Prevention,
Secondary Prevention,
Safety of Statins
Cochraned14 trials (15), CTT 2010 (20)
50
In adults selected for participation in clinical trials of statin therapy,
rhabdomyolysis occurred rarely (<0.06% over a mean 4.8- to 5.1-year
treatment period).
H
Primary Prevention,
Secondary Prevention,
Safety of Statins
CTT 2010 (20)
51
In adults with CHD, the rate of creatine kinase elevation 3 times ULN
occurs infrequently and at a similar rate in those treated with intensive-
or moderate-dose statin therapy.
H
Primary Prevention,
Secondary Prevention,
Safety of Statins
Dale (98), CTT 2010 (20)
52
In adults with CHD, although uncommon (<1.5% over 5 years), intensive
statin therapy increases the risk for elevated hepatic transaminase (ALT
and/or AST) levels 2–3 times ULN more than moderate-dose statin
therapy. No cases of hepatic failure were reported.
H
Primary Prevention,
Safety of Statins
Dale (98), Cochrane (15), CTT 2010 (20), TNT (46),
IDEAL (47), PROVE-IT (48), JUPITER (49)
53
Low- to moderate-dose statin therapy has similar rates of elevated hepatic
transaminase levels as placebo/no statin treatment. In general, clinical
trials tend to underestimate those likely to have side effects, often
related to selection procedures.
H
Primary Prevention,
Safety of Statins
CTT 2010 (20)
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Appendix 4. Continued
ES No.
Evidence Statement
Level of
Evidence
Recommendation(s)/
Section
References
54
With the exception of simvastatin 80 mg, intensive- and moderate-dose
statins did not increase the risk for rhabdomyolysis.
L
Safety of Statins
CTT 2010 (20), Cochrane (15), Mills (97)
55
In adults with CHD, CK elevation 3 times ULN occurs infrequently
and at a similar rate in those treated with intensive- or moderate-dose
statin therapy (0.02% [moderate-dose statin] to 0.1% [higher-dose
statin]) over a 1- to 5-year treatment period (RR 2.63, 95% CI
0.88–7.85).
H
Secondary Prevention,
Safety
Dale 2007 (98)
56
The Expert Panel did not ﬁnd evidence that statins had an adverse effect
on cognitive changes or risk of dementia.
I
Safety of Statins
Reviewed RCTs in CQ1, CQ2; assessment of
cognitive function only reported in HPS (16)
57
In men with CHD who are 30 to 64 years of age, immediate-release
niacin (with an approximately 2-g dose):
 Decreased total cholesterol by 10% and triglycerides by 27%.
 Markedly increased the risk for adverse skin events (including
ﬂushing, pruritus, acanthosis nigricans, and other types of skin rash).
 Increased the risk for other adverse events:
 Atrial ﬁbrillation
 Gastrointestinal events (including nausea, stomach pain,
decreased appetite, and unexplained weight loss)
 Gout
 Elevated levels of uric acid, serum glutamic oxaloacetic
transaminase, alkaline phosphatase, and glucose
 Lipids, LFTs, uric acid, and glucose were monitored during up-titration
and every 4–12 months thereafter.
L
Secondary Prevention,
Safety,
Monotherapy,
Safety,
Efﬁcacy
CDP (101,143)
58
In a trial in 67 adults with CHD and low HDL-C, slow-release niacin (at a
mean 2.4-g dose) plus low-dose simvastatin resulted in the following:
 Low levels of LDL-C and raised levels of HDL-C.
 Although not powered to detect a reduction in CVD events, the rate of
major clinical events was 90% lower than that in the placebo group.
 Slow-release niacin did not cause ﬂushing in this trial.
 The simvastatin-niacin group had increased ALT, CK, uric acid,
and homocysteine.
 Antioxidant vitamins diminished the beneﬁcial effect of niacin
on HDL-C.
 Lipids, LFTs, uric acid, and glucose were monitored during up-titration
and every 2–4 months thereafter.
L
Secondary Prevention,
Combination Treatment
HATS Investigators (121)
59
In adults 45 years of age and older with established CVD and low HDL-C
(<40 mg/dL in men or <50 mg/dL in women), elevated triglycerides
(150–400 mg/dL), and LDL-C <180 mg/dL off statin, in whom the
dose of simvastatin was adjusted, or ezetimibe was added, to maintain
LDL-C in a range of 40–80 mg/dL, extended-release niacin 1,500–
2,000 mg/day plus simvastatin (9.5% also on ezetimibe 10 mg)
compared with placebo (with 50 mg immediate-release niacin) plus
simvastatin (21.5% also on ezetimibe 10 mg:
 Improved the lipid proﬁle without a further decrease in CVD events.
Speciﬁcally, it lowered LDL-C levels an additional 6%, increased HDL-
C by an additional 14%, reduced triglycerides by an additional 23%,
lowered apolipoprotein B by an additional 10%, and reduced
lipoprotein(a) by an additional 19%.
 There were similar rates of CVD events in subgroups by age, sex, or
diabetes, metabolic syndrome, or previous myocardial infarction
status, as well as similar rates of adverse events, including liver
function abnormalities, muscle symptoms, and rhabdomyolysis.
 Lipids, LFTs, uric acid, and glucose were monitored during up-titration
and every 3–12 months thereafter.
M
Secondary Prevention,
Combination Treatment
AIM-HIGH Investigators (9)
60
In men 35–59 years of age without CHD, hypertension, diabetes, or obesity
and with LDL-C 175 mg/dL and triglycerides <300 mg/dL,
cholestyramine:
 Reduced LDL-C by 13%, with minimal changes in triglycerides or
HDL-C levels.
 Reduced the RR for CHD events by 19%.
 Increased the risk for adverse gastrointestinal effects, including
constipation, heartburn, abdominal pain, belching, bloating, gas,
nausea.
 Adherence was only modest.
L
Primary Prevention,
Safety,
Efﬁcacy
LRC (113)
61
Insufﬁcient data to evaluate the efﬁcacy and safety of ezetimibe
monotherapy.
I
Efﬁcacy,
Safety,
Nonstatin
Continued on the next page
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Appendix 4. Continued
ES No.
Evidence Statement
Level of
Evidence
Recommendation(s)/
Section
References
62
Insufﬁcient data to evaluate the additional efﬁcacy and safety of ezetimibe
in combination with a statin compared with a statin alone.
I
Safety,
Efﬁcacy,
Combination Treatment
63
In adults 45–85 years of age with mild to moderate aortic stenosis and
without CVD or diabetes, simvastatin 40 mg coadministered with
ezetimibe 10 mg, compared with placebo:
 Decreased LDL-C by an average of 50%.
 Reduced the RR for CVD events by 22% over 4.35 years of treatment.
 Increased the risk for elevated hepatic transaminases.
L
Safety,
Efﬁcacy,
Combination Treatment
SEAS (108)
64
In adults 40 years of age with CKD, of whom 33% were receiving dialysis
(peritoneal or hemodialysis), ezetimibe 10 mg coadministered with
simvastatin 20 mg, compared with placebo:
 Lowered LDL-C by 37 mg/dL (33%) in those who were not
receiving dialysis and by 23% in those who were receiving dialysis.
 Reduced the risk for CVD events by 17% overall and 21% in
those without CVD.
 Reduced the risk for CVD events by 22% in those who were
not receiving dialysis.
 Did not reduce CVD events in those with CVD or in those receiving
hemodialysis.
 Modestly increased the risk for muscle symptoms requiring
discontinuation of treatment (1.1% vs. 0.6% with p¼0.02).
 Did not increase the risk for elevated hepatic transaminases, cancer,
hemorrhagic stroke, or noncardiovascular mortality.
L
Safety,
Efﬁcacy,
Combination Treatment,
CKD
SHARP (109)
65
Ezetimibe coadministered with simvastatin does not appear to increase
the risk for cancer compared with placebo.
L
Safety,
Combination Treatment
SHARP (109)
66
In adults 50–75 years of age with diabetesdwith total cholesterol <250
mg/dL, and total cholesterol/HDL ratio 4.0 or triglycerides <450
mg/dLdfenoﬁbrate, compared with placebo:
 Modestly reduced LDL-C, minimally increased HDL-C, and
substantially reduced triglycerides.
 In those without clinical CVD, reduced the risk for CHD/CVD events.
 In those with clinical CVD, did not reduce the risk for
CHD/CVD events.
 Was no different than placebo for myositis or rhabdomyolysis, CK or
ALT elevations, renal disease requiring hemodialysis, or cancer.
 Was associated with higher rates of pancreatitis and pulmonary
embolism, and increased creatinine levels on average by
0.113–0.136 mg/dL (10–12 mmol/L).
L
Safety,
Efﬁcacy,
Nonstatin Treatment
FIELD (115)
67
In adults 40–79 years of age with diabetes, CVD, and/or CVD risk factors,
with LDL-C 60–180 mg/dL, HDL-C <55 mg/dL in women and black
individuals, HDL-C <50 mg/dL for all others, and triglycerides
<750 mg/dL on no medication or <400 mg/dL on medication:
 Fenoﬁbrate added to simvastatin did not additionally reduce LDL-C,
minimally increased HDL-C (1 mg/dL or 2%), and moderately
reduced triglycerides (23 mg/dL or 14%), compared with simvastatin
therapy, which had on-treatment mean LDL-C of 80 mg/dL, HDL-C of
40.5 mg/dL, and triglycerides of 170 mg/dL.
 In the trial overall, and in those without and with clinical CVD,
fenoﬁbrate-simvastatin did not reduce the risk for CVD events
compared with simvastatin alone.
 Those with triglycerides 204 mg/dL and HDL-C 40 mg/dL may
have experienced a reduction in CVD events from fenoﬁbrate-
simvastatin, compared with simvastatin alone.
 Fenoﬁbrate-simvastatin had similar rates as simvastatin alone for
myopathy, myositis, or rhabdomyolysis; CK or ALT elevations,
renal disease requiring hemodialysis; cancer death; or pulmonary
embolism/thrombosis.
 Fenoﬁbrate-simvastatin was more likely to increase ALT >5 times
ULN and to increase creatinine level.
 CVD event rates were higher in women with well-controlled diabetes
who received fenoﬁbrate-simvastatin compared with simvastatin alone.
M
Safety,
Efﬁcacy,
Nonstatin Treatment
ACCORD (14)
68
In men 40–55 yearsof agewithout CHD or CHF and non–HDL-C 200 mg/dL,
gemﬁbrozil:
 Reduced LDL-C by 10% and triglycerides by 43%, and increased
HDL-C by 10%.
 Reduced the RR for CHD by 37%, compared with placebo.
 Increased skin cancer, increased gastrointestinal surgery, and
increased severe upper gastrointestinal symptoms, especially in ﬁrst
year. There was no difference in diarrhea, constipation, nausea, or
vomiting. Total mortality was not reported.
M
Safety,
Efﬁcacy,
Nonstatin Treatment
Helsinki Heart Study (111)
Continued on the next page
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Appendix 4. Continued
ES No.
Evidence Statement
Level of
Evidence
Recommendation(s)/
Section
References
69
In men with CHD who were <74 years of age with HDL-C 40 mg/dL and
LDL-C 140 mg/dL, and triglycerides 300 mg/dL, gemﬁbrozil,
compared with placebo:
 Did not reduce LDL-C, but did reduce triglycerides by 31% and
increase HDL-C by 6%.
 Reduced the RR for CVD by 24%.
M
Efﬁcacy,
Nonstatin Treatment
VA-HIT (114)
70
In Japanese men who were 40–75 years of age and postmenopausal
women 75 years of age with and without CHD and LDL-C 170 mg/dL,
EPA 1,800 mg added to statin therapy:
 Did not reduce LDL-C and modestly reduced triglycerides (5%),
compared with statin therapy alone.
 Reduced the risk for CHD events (including revascularization and
unstable angina) by 19%, compared with statin therapy alone.
 Caused a similar magnitude of risk reduction in primary- and
secondary-prevention populations, but the study was insufﬁciently
powered to evaluate these populations separately.
 Increased the risk for gastrointestinal disturbance, skin abnormal-
ities, hemorrhage, and abnormal serum glutamic oxaloacetic
transaminase.
M
Efﬁcacy,
Safety,
Combination Treatment
JELIS (110)
71
In individuals with NYHA Classes II–IV systolic or ischemic heart failure,
initiation of a statin did not change the absolute or RR for CVD
compared with placebo.
M
Efﬁcacy,
Selected Population
Subgroups
CORONA (85) from CQ1
72
In individuals receiving maintenance hemodialysis, initiation of a statin did
not change the relative or absolute risk for CVD compared with placebo.
M
Efﬁcacy,
Selected Population
Subgroups
4D (87) and AURORA (84) CQ1 & CQ2,
SHARP (109)dHD subgroup
73
In men and women of mean age 58 to 68 years with aortic stenosis,
treatment with statin or statin plus ezetimibe for a mean of 2.1–4.4
years resulted in a reduction in LDL-C of 50%–55% (67–73 mg/dL)
from a baseline LDL-C of 123–140 mg/dL and did not alter the
progression of aortic stenosis as assessed by change in valve area,
peak aortic valve jet velocity, peak or mean aortic valve gradient,
or need for aortic valve surgery.
H
Aortic Stenosis,
Combination Treatment
Parolari (144)
74
Women who were pregnant or nursing were excluded from statin,
fenoﬁbrate, niacin-statin, and ezetimibe-statin RCTs.
Only men were enrolled in RCTs of niacin, BAS, and gemﬁbrozil.
H
Primary Prevention,
Secondary Prevention
All RCTs CQ1, CQ2, and CQ3
75
Only individuals with primary hypercholesterolemia were included in RCTs.
H
Primary Prevention,
Secondary Prevention
AFCAPS (17)
JUPITER (49)
JELIS (110)
HATS (121)
FIELD (115)
ACCORD (14)
MEGA (18)
76
In the 3 exclusively primary-prevention RCTs, low-, moderate-, and high-
intensity statin therapy reduced the risk for ASCVD when LDL-C levels
were approximately 70–130 mg/dL, 130–190 mg/dL, and 160–200
mg/dL.
H
Primary Prevention
JUPITER (49)
MEGA (18)
AFCAPS (17)
77
Lipids, liver function, uric acid, and glucose tests were obtained at
baseline, during up-titration, and every 2–12 months thereafter.
H
Secondary Prevention
CDP (101) (fair) 4–12 months;
HATS (121) (good) 2–4 months;
AIM-HIGH (9) (good) 3–12 months
78
Immediate- and extended-release niacin increase cutaneous adverse
effects.
M
Secondary Prevention
CDP (101), AIM-HIGH (9) (not HATS [121]d
Slo-Niacin)
79
When used as monotherapy or with a statin, niacin increases:
 Hepatic function tests.
 Hyperglycemia.
 Gastrointestinal adverse effects.
 Gout or increased uric acid.
H
M
M
M
Secondary Prevention,
Safety
(CDP [101], HATS [121], AIM-HIGH [9])
(CDP [101], AIM-HIGH [9]dniacin dose reduced or
discontinued)
(CDP [101], AIM-HIGH [9]dniacin dose reduced or
discontinued)
Gout (CDP [101])
Increased uric acid (HATS [121])
80
Niacin increases the incidence of atrial ﬁbrillation and weight loss.
L
Secondary Prevention,
Safety
CDP (101) (atrial ﬁbrillation not reported in
AIM-HIGH [9] or HATS [121])
ALT indicates alanine transaminase; ASCVD, atherosclerotic cardiovascular disease; BAS, bile acid sequestrant; BID, twice daily; CHD, coronary heart disease; CHF, congestive heart failure; CK, creatine
kinase; CKD, chronic kidney disease; CVD, cardiovascular disease; EPA, eicosapentaenoic acid; GFR, glomerular ﬁltration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein
cholesterol; LFT, liver function test; MI, myocardial infarction; NNH, number needed to harm; NNT, number needed to treat; NYHA, New York Heart Association; RCT, randomized controlled trial; RR,
relative risk; RRR, relative risk reduction; TIA, transient ischemic attack; and ULN, upper limit of normal.
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Appendix 5. Expanded Discussion of What’s New in the Guideline
Focus on ASCVD Risk Reduction: 4 Statin Beneﬁt Groups
 The 2013 guideline focuses on treatment of blood cholesterol to reduce ASCVD risk. Each Expert Panel was limited in the number of CQs it could choose. When
the CQs from the Risk Assessment and Lifestyle Work Groups were combined with the 3 Cholesterol Panel CQs, there were 8 CQs in total that were systematically
reviewed. All 3 CQs of the Cholesterol Panel evaluated evidence from RCTs with ASCVD outcomes. CQ1 and CQ2 evaluated the evidence for LDL-C and non–HDL-C
goals in secondary and primary prevention. CQ3 was a comprehensive evaluation of the reduction in ASCVD events and safety for each of the cholesterol-lowering
drugs available in the United States.
 The systematic review of evidence from the highest-quality RCTs with ASCVD outcomes identiﬁed strong evidence to indicate who should get which therapy at what
intensity.
 The statin RCTs provided the most extensive evidence for the greatest magnitude of ASCVD event reduction, with the best margin of safety.
 Four statin beneﬁt groups were identiﬁed, in which the potential for an ASCVD risk-reduction beneﬁt clearly exceeds the potential for adverse effects in:
1. Individuals with clinical ASCVD
2. Individuals with primary elevations of LDL-C 190 mg/dL
3. Individuals 40–75 years of age with diabetes but without clinical ASCVD and LDL-C 70–189 mg/dL
4. Individuals 40–75 years of age without diabetes or clinical ASCVD with LDL-C 70–189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher.
This requires a clinician-patient discussion.
 Because few trials have been performed with nonstatin cholesterol-lowering drugs in the statin era, and those that have been performed were unable to
demonstrate signiﬁcant additional ASCVD event reductions in the RCT populations studied, there was less evidence to support the use of nonstatin drugs for
ASCVD prevention.
 It is difﬁcult to determine how observational data could override the conclusions from the extensive body of evidence from the statin RCTs and the paucity of
evidence from nonstatin RCTs. Inherent biases of observational data are well understood and include biases in the decisions on whom to treat and who is adherent
to therapy, as well as multiple measurement biases, including veriﬁcation of statin use, type and dose of statin used, consistency of use over time, and outcome
ascertainment. All of these problems are addressed in intent-to-treat analyses of RCTs, which is why the FDA requires well-designed RCTs to determine drug efﬁcacy
for ASCVD event reduction and common adverse effects.
 Other approaches to treatment of blood cholesterol have been advocated, including:
A. Treat to targetdThis strategy has been the most widely used in the past 15 years, but there are 3 problems with this approach. First, current clinical trial data do
not indicate what the target should be. Second, we do not know the magnitude of additional ASCVD risk reduction that would be achieved with one target lower
than another. Third, this strategy does not take into account potential adverse effects from statin monotherapy or from multidrug therapy that might be needed
to achieve a speciﬁc goal. Thus, in the absence of these data, this approach is less useful than it appears (Section 3). It is possible that future clinical trials may
provide information warranting reconsideration of this strategy.
B. Lowest is bestdThis approach was not taken because it does not consider the potential adverse effects of multidrug therapy with an unknown magnitude of
ASCVD event reduction. Ongoing RCTs of new LDL-C–lowering drugs in the setting of maximal statin therapy may address this question.
C. Treat level of ASCVD riskdA modiﬁed version of this approach was taken, which considers both the ASCVD risk-reduction beneﬁts and the adverse effects of
statin treatment on the basis of an extensive body of RCT evidence to determine the 4 statin beneﬁt groups. By focusing treatment on the 4 statin beneﬁt groups,
the approach is practical and simpler to implement than the past strategies. There are also important exceptions for routine initiation of statin treatment for
individuals requiring hemodialysis or with NYHA class II to IV heart failure.
D. Lifetime riskdTreatment strategies based on lifetime ASCVD risk are problematic because of the lack of data on the long-term follow-up of RCTs >15 years, the
safety and ASCVD event reduction when statins are used for periods >10 years, and treatment of individuals <40 years of age.
A New Perspective on LDL-C and/or Non–HDL-C Goals
 The difﬁculty of giving up the treat-to-goal paradigm was deliberated extensively over a 3-year period. Many clinicians use targets such as LDL-C <70 mg/dL and
LDL-C <100 mg/dL for secondary and primary ASCVD prevention (non–HDL-C targets are 30 mg/dL higher). However, the RCT evidence clearly shows that ASCVD
events are reduced by using the maximum-tolerated statin intensity in those groups shown to beneﬁt. After a comprehensive review, no RCTs were identiﬁed that
titrated drug therapy to speciﬁc LDL-C or non–HDL-C goals to improve ASCVD outcomes. However, one RCT was identiﬁed that showed no additional ASCVD event
reduction from the addition of nonstatin therapy to further treat non–HDL-C levels once an LDL-C goal was reached. In AIM-HIGH (9), the additional reduction in non–
HDL-C levels [as well as additional reductions in Apo B, Lp(a), and triglycerides in addition to HDL-C increases] with niacin therapy DID NOT further reduce ASCVD risk
in individuals treated to LDL-C levels of 40–80 mg/dL.
 Use of LDL-C targets may result in under treatment with evidence-based statin therapy or overtreatment with nonstatin drugs that have not been shown to reduce
ASCVD events in RCTs (even though the drug may additionally lower LDL-C and/or non–HDL-C). Implications of treating to an LDL-C goal may mean that a
suboptimal intensity of statin is used because the goal has been achieved, or that adding a nonstatin therapy to achieve a speciﬁc target results in down-titration of
the evidence-based intensity of statin for safety reasons. However, when RCT evidence is available that a nonstatin therapy further reduces ASCVD events when
added to statin therapy, the nonstatin therapy may be considered.
 Some examples comparing a strategy based on the 4 statin beneﬁt groups to a strategy using LDL-C/non–HDL-C targets:
A. Secondary preventiondEvidence supports high-intensity statin therapy for this group to maximally lower LDL-C. It does not support the use of an LDL-C target.
For example, if a secondary-prevention patient achieves an LDL-C of 78 mg/dL on a dose of 80 mg of atorvastatin, he/she is receiving evidence-based therapy.
As of yet, there are no data to show that adding nonstatin drug(s) to high-intensity statin therapy will provide incremental ASCVD risk-reduction beneﬁt with an
acceptable margin of safety. Indeed, AIM-HIGH (9) demonstrated the futility of adding niacin in individuals with low HDL-C and high triglycerides, and ACCORD
(14) demonstrated the futility of adding fenoﬁbrate in persons with diabetes. Although an ACCORD subgroup analysis of those with high triglycerides and low
HDL-C levels suggested that fenoﬁbrate may reduce ASCVD events in patients with diabetes, this is hypothesis generating and needs further testing in
comparison to the evidence-based use of a high-intensity statin. In addition, not having a goal of <70 mg/dL for LDL-C means that the patient who is adhering to
optimal lifestyle management and receiving a high-intensity statin avoids additional, non–evidence-based therapy just because his/her LDL-C is higher than an
arbitrary cutpoint. Indeed, the LDL-C goal approach can make this patient unnecessarily feel like a failure.
Continued on the next page
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Appendix 5. Continued
B. Familial hypercholesterolemia with LDL-C 190 mg/dLdIn many cases, individuals with familial hypercholesterolemia are unable to achieve an LDL-C
goal <100 mg/dL. For example, an individual with familial hypercholesterolemia may achieve an LDL-C of only 120 mg/dL despite use of 3 cholesterol-
lowering drugs. Although this patient may have fallen short of the 100-mg/dL goal, he/she has decreased his/her LDL-C by >50% (starting from an untreated
LDL-C level of w325–400 mg/dL). These patients are not treatment failures, as observational data has shown signiﬁcant reductions in ASCVD events without
achieving speciﬁc LDL-C targets. This is an area where observational data supports the recommended approach.
C. Type 2 diabetesdFor those 40–75 years of age with risk factors, the potential beneﬁts of LDL-C lowering with a high-intensity statin are substantial. Because
those with diabetes often have lower LDL-C levels than those without diabetes, “goal”-directed therapy often encourages use of a lower statin dose than is
supported by the RCTs, and nonstatin drugs may be added to address low HDL-C or high triglycerides, for which RCT evidence of an ASCVD event reduction is
lacking. Giving a maximally tolerated statin intensity should receive primary emphasis because it most accurately reﬂects the data that statins reduce the
relative risk of ASCVD events similarly in individuals with and without diabetes, and in primary and secondary prevention in those with diabetes, along with
evidence that high-intensity statins reduce ASCVD events more than moderate-intensity statins.
D. Estimated 10-year ASCVD risk ‡7.5%dData have shown that statins used for primary prevention have substantial ASCVD risk-reduction beneﬁts across the
range of LDL-C levels of 70–189 mg/dL. Moreover, the Cochrane meta-analysis (15), as well as a meta-analysis by the Cholesterol Treatment Trialists (13),
conﬁrms that primary prevention with statins reduces total mortality as well as nonfatal ASCVD events.
 RCTs are used to identify those who are unlikely to beneﬁt from initiation of statin therapy despite being at high ASCVD risk, such as those with higher NYHA classes
of heart failure or those on hemodialysis.
Global Risk Assessment for Primary Prevention
 Use of the new Pooled Cohort Equations is recommended to estimate 10-year ASCVD risk in both white and black men and women who do not have clinical ASCVD.
 By more accurately identifying higher-risk individuals for statin therapy, the guideline focuses statin therapy on those most likely to beneﬁt.
 It also indicates, on the basis of RCT data, those high-risk groups that might not beneﬁt. The Expert Panel emphasizes that the guideline is “patient centered” in
primary prevention. It is recommended that the potential for an ASCVD risk-reduction beneﬁts, adverse effects, and drug–drug interactions, along with patient
preferences, must be considered before statins are initiated for the primary prevention of ASCVD. Other factors such as LDL-C 160 mg/dL may also be considered.
This gives clinicians and patients the opportunity for input into treatment decisions rather than a simplistic “one-treatment-ﬁts-all” approach to drug therapy.
 These guidelines are not a replacement for clinical judgment; they are meant to guide and inform decision making.
 Some worry that a person 70 years of age without other risk factors will receive statin treatment on the basis of age alone. The estimated 10-year risk is still 7.5%,
a risk threshold for which a reduction in ASCVD risk events has been demonstrated in RCTs. Most ASCVD events occur after age 70 years, giving individuals 70
years of age the greatest potential for absolute risk reduction.
 Some have proposed using selected inclusion criteria from RCTs to determine the threshold for statin initiation. However, the Cholesterol Treatment Trialists
individual-level meta-analysis showed that statin therapy reduces ASCVD events regardless of categorical risk factors in both primary and secondary prevention.
Therefore, the rationale for using ﬁxed cutpoints to determine whether statin therapy should be initiated is refuted by a consideration of the total body of evidence
from RCTs.
 In addition, a trial-based strategy identiﬁes those at increased ASCVD risk less accurately than does a strategy based on an assessment of global ASCVD risk. This
selective use of inclusion criteria excludes well-established risk factors, such as smoking and advancing age (the strongest risk factor because it represents
cumulative risk factor exposure).
 The poor discrimination of RCT inclusion criteria for identifying those at increased 10-year ASCVD risk is shown by a calculation performed by the Risk Assessment
Work Group using nationally representative data from NHANES. Use of the RCT inclusion criteria (from RCTs that found a reduction in ASCVD events to guide
initiation of statin therapy) would result in the treatment of 16% of individuals with <2.5% estimated 10-year ASCVD risk and 45% of those with 2.5% to <5%
estimated 10-year ASCVD risk (many would say inappropriately), whereas 38% of those with 7.5% 10-year ASCVD risk would not have been identiﬁed as
candidates for statin therapy.
Safety
 RCTs are used to identify important safety considerations in individuals receiving treatment of blood cholesterol to reduce ASCVD risk and to determine statin
adverse effects to facilitate understanding of the net beneﬁt from statin therapy.
 Safety issues that are uncommon or unlikely to be seen in the populations studied in RCTs require more than analyses of single RCTs. This limitation was overcome,
in part, by considering high-quality systematic reviews and meta-analyses of statin RCTs.
 Expert guidance is provided on management of statin-associated adverse effects, including muscle symptoms.
 This guideline emphasizes the importance of using additional sources of information on safety, including FDA reports, manufacturers’ prescribing information, and
pharmacists, to aid in the safe use of cholesterol-lowering drug therapy.
Role of Biomarkers and Noninvasive Tests
 There is a concern about other factors that may indicate elevated ASCVD risk but were not included in the Pooled Cohort Equations for predicting 10-year ASCVD
risk.
 The Risk Assessment Work Group has performed an updated systematic review of nontraditional risk factors, such as CAC, and has included recommendations to
consider their use to the extent that the evidence allows.
 In selected individuals who are not in 1 of the 4 statin beneﬁt groups, and for whom a decision to initiate statin therapy is otherwise unclear, additional factors may
be considered to inform treatment decision making.
 These factors include primary LDL-C 160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset <55 years of age in a
ﬁrst-degree male relative or <65 years of age in a ﬁrst-degree female relative; high-sensitivity C-reactive protein 2 mg/L; CAC score 300 Agatston units or 75th
percentile for age, sex, and ethnicity; ankle-brachial index <0.9; and elevated lifetime risk of ASCVD. Additional factors may be identiﬁed in the future.
Continued on the next page
JACC Vol. 63, No. 25, 2014
Stone et al.
July 1, 2014:2889–934
2013 ACC/AHA Blood Cholesterol Guideline
2933
Page 161 of 356
Page 163 of 364


Appendix 5. Continued
Future Updates to the Blood Cholesterol Guideline
 This guideline focuses on treatments proven to reduce ASCVD events. It is not and was never intended to be a comprehensive approach to lipid management.
 Using RCT evidence assessed for quality provides a strong foundation for treatment of blood cholesterol to reduce ASCVD risk that can be used now. There are many
clinical questions for which there is an absence of RCT data available to develop high-quality, evidence-based recommendations. For these questions, expert opinion
may be helpful to clinicians and could be developed in the next iteration of the guideline.
 CQs for future guidelines could examine:
1. the treatment of hypertriglyceridemia;
2. the use of non–HDL-C in treatment decision making;
3. whether on-treatment markers such as Apo B, Lp(a), or LDL particles are useful for guiding treatment decisions;
4. the best approaches to using noninvasive imaging for reﬁning risk estimates to guide treatment decisions;
5. how lifetime ASCVD risk should be used to inform treatment decisions and the optimal age for initiating statin therapy to reduce lifetime risk of ASCVD;
6. subgroups of individuals with heart failure or undergoing hemodialysis who might beneﬁt from statin therapy;
7. long-term effects of statin-associated new-onset diabetes and management;
8. efﬁcacy and safety of statins in patient groups excluded from RCTs to date (e.g., those who are HIV positive or have received a solid organ transplant); and
9. role of pharmacogenetic testing.
*For additional information, see http://www.mesa-nhlbi.org/CACReference.aspx.
AIM-HIGH indicates Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes; ACCORD, Action to Control Cardiovascular Risk in
Diabetes; Apo B, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CQ, critical question; FDA, U.S. Food and Drug Administration; HDL-C, high-density
lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); NHANES, National Health and Nutrition Examination Survey; and RCTs, randomized controlled trials.
Stone et al.
JACC Vol. 63, No. 25, 2014
2013 ACC/AHA Blood Cholesterol Guideline
July 1, 2014:2889–934
2934
Page 162 of 356
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APPENDIX B. GUIDANCE FOR ELEVATED LIVER BIOCHEMISTRY 
VALUES  
For subjects who progress to cirrhosis and decompensation while participating in the study, 
elevation in liver biochemistry and development of other laboratory and clinical abnormalities 
may be expected.  Clinical adverse events (AEs) should be reported and recorded as described in 
Section 12.1.5 and appropriate action should be taken regarding investigational product use and 
study participation as described in Section 8.4. 
However, if these abnormalities are not consistent with the pattern of change attributable to 
disease progression (as assessed by the Investigator) and no other cause is readily apparent 
(eg, acute biliary obstruction caused by gallstones in the common bile duct), further actions are 
appropriate as outlined below.  The Sponsor should be contacted to discuss the case further. 
Per guidance from the FDA (FDA 2009), subjects with normal ALT/AST and bilirubin at 
baseline, an increase in ALT/AST to >3× ULN or total bilirubin >2× ULN should be followed by 
repeat testing within 48 to 72 hours of the serum chemistry to confirm the abnormalities and to 
determine if they are increasing or decreasing.  In conjunction with this, a physical exam should 
be performed and AE information should be collected.  If symptoms persist or repeat testing 
shows ALT/AST >3× ULN or total bilirubin >2× ULN, subjects should be closely monitored.  In 
subjects with abnormal ALT/AST or bilirubin at baseline, fold increase should be assessed 
against baseline levels instead of ULN as follows:  3× baseline ALT/AST, or total bilirubin 
>2× baseline (and >2 mg/dL).  In subjects with abnormal values at baseline who develop a nadir 
value during the study, the reference points noted above should be changed from baseline to the 
nadir value for subsequent assessments. 
In subjects who are far from their study site, it may be difficult for the subjects to return to the 
site promptly.  In this case, the subjects should be retested locally, but normal laboratory ranges 
should be recorded, results should be made available to the Investigator immediately, and the 
data should be included in the case reports.  If symptoms persist or repeat testing shows 
persistent abnormality as described above, it is appropriate to initiate close observation (defined 
below) to determine whether the abnormalities are improving or worsening.  
If close observation is not possible, investigational product should be interrupted until further 
investigation can be performed. 
Close observation may include:  
• Repeating liver enzyme and serum bilirubin tests 2 or 3 times weekly.  Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the 
investigational product has been discontinued and the subject is asymptomatic.  
• Obtaining a more detailed history of symptoms and prior or concurrent diseases.  
• Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets.  
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; hypoxic/ischemic hepatopathy; and other biliary tract disease.  
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• Obtaining a history of exposure to environmental chemical agents.  
• Obtaining additional tests to evaluate liver function, as appropriate (eg, INR, direct 
bilirubin).  
Discontinuation of treatment should be considered if the following abnormality or group of 
abnormalities occur (in subjects with baseline values within the normal range):  
• ALT or AST >8× ULN  
• ALT or AST >5× ULN for more than 2 weeks  
• ALT or AST >3× ULN and total bilirubin >2× ULN or INR >1.5)  
• ALT or AST >3× ULN with the appearance of new onset fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
In subjects with abnormal baseline values, the reference point should be changed from ULN to 
baseline.  In subjects with abnormal values at baseline who develop a nadir value during the 
study, the reference points noted above should be changed from ULN or baseline to the nadir 
value for subsequent assessments.  Baseline is defined as the average of all on-study, predose 
values (including Screening Visit and Day 1).  A nadir value is defined as the average of at least 
2 consecutive post-baseline assessments, including the lowest value, regardless of when it occurs 
(ie, on or off treatment).  Repeat and unscheduled visits will be included in the determination of 
the nadir value.  A new nadir value may develop over the course of the study if liver 
biochemistries improve over time. 
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APPENDIX C. COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS 
 
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1. CTCAE 4.03
 
 
Common Terminology Criteria for
Adverse Events (CTCAE)
Version 4.0
Published: May 28, 2009 (v4.03: June 14, 2010)
U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Cancer Institute
Page 168 of 364


__________ 
† CTCAE v4.0 incorporates certain elements of the MedDRA terminology. For further details on MedDRA refer to the MedDRA MSSO Web site (http://www.meddramsso.com). 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
Publish Date: May 28, 2009
Quick Reference 
The NCI Common Terminology Criteria for 
Adverse Events is a descriptive terminology which 
can be utilized for Adverse Event (AE) reporting.  
A grading (severity) scale is provided for each AE 
term. 
Components and Organization 
SOC 
System Organ Class, the highest level of the 
MedDRA hierarchy, is identified by anatomical or 
physiological system, etiology, or purpose (e.g., 
SOC Investigations for laboratory test results).  
CTCAE terms are grouped by MedDRA Primary 
SOCs. Within each SOC, AEs are listed and 
accompanied by descriptions of severity (Grade). 
CTCAE Terms  
An Adverse Event (AE) is any unfavorable and 
unintended 
sign 
(including 
an 
abnormal 
laboratory 
finding), 
symptom, 
or 
disease 
temporally associated with the use of a medical 
treatment or procedure that may or may not be 
considered related to the medical treatment or 
procedure.  An AE is a term that is a unique 
representation of a specific event used for 
medical documentation and scientific analyses.  
Each CTCAE v4.0 term is a MedDRA LLT (Lowest 
Level Term). 
 
Definitions 
A brief definition is provided to clarify the 
meaning of each AE term. 
Grades 
Grade refers to the severity of the AE.  The CTCAE 
displays Grades 1 through 5 with unique clinical 
descriptions of severity for each AE based on this 
general guideline: 
 
Grade 1 
Mild; 
asymptomatic 
or 
mild 
symptoms; clinical or diagnostic 
observations only; intervention not 
indicated. 
 
Grade 2 
Moderate; 
minimal, 
local 
or 
noninvasive intervention indicated; 
limiting 
age-appropriate 
instrumental ADL*. 
 
Grade 3 
Severe or medically significant but 
not immediately life-threatening; 
hospitalization or prolongation of 
hospitalization indicated; disabling; 
limiting self care ADL**. 
 
Grade 4 
Life-threatening 
consequences; 
urgent intervention indicated. 
 
Grade 5 
Death related to AE. 
A Semi-colon indicates ‘or’ within the description 
of the grade. 
A single dash (-) indicates a grade is not available. 
Not all Grades are appropriate for all AEs. 
Therefore, some AEs are listed with fewer than 
five options for Grade selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs 
and therefore is not an option. 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, 
shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self care ADL refer to bathing, dressing and 
undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Page 169 of 364


CONTENTS
SOC
Page
Blood and lymphatic system disorders
3
Cardiac disorders
4
Congenital, familial and genetic disorders
7
Ear and labyrinth disorders
8
Endocrine disorders
9
Eye disorders
10
Gastrointestinal disorders
12
General disorders and administration site conditions
22
Hepatobiliary disorders
24
Immune system disorders
26
Infections and infestations
27
Injury, poisoning and procedural complications
34
Investigations
41
Metabolism and nutrition disorders
44
Musculoskeletal and connective tissue disorders
46
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
50
Nervous system disorders
51
Pregnancy, puerperium and perinatal conditions
56
Psychiatric disorders
57
Renal and urinary disorders
59
Reproductive system and breast disorders
61
Respiratory, thoracic and mediastinal disorders
65
Skin and subcutaneous tissue disorders
71
Social circumstances
75
Surgical and medical procedures
76
Vascular disorders
77
Page 170 of 364


CTCAE 4.03 - June 14, 2010 : Blood and lymphatic system disorders 
3
2. Blood and lymphatic system disorders
Blood and lymphatic system disorders
Grade
Adverse Event
1
2
3
4
5
Anemia
Hemoglobin (Hgb) <LLN - 10.0
g/dL; <LLN - 6.2 mmol/L; <LLN -
100 g/L
Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9
mmol/L;  <100 - 80g/L
Hgb <8.0 g/dL; <4.9 mmol/L;
<80 g/L; transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an reduction in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of anemia may include pallor of the skin and mucous
membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.
Bone marrow hypocellular
Mildly hypocellular or <=25%
reduction from normal cellularity
for age
Moderately hypocellular or >25 -
<50% reduction from normal
cellularity for age
Severely hypocellular or >50 -
<=75% reduction cellularity from
normal for age
Aplastic persistent for longer
than 2 weeks
Death
Definition: A disorder characterized by the inability of the bone marrow to produce hematopoietic elements.
Disseminated intravascular
coagulation
 -
Laboratory findings with no
bleeding
Laboratory findings and
bleeding
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by systemic pathological activation of blood clotting mechanisms which results in clot formation throughout the body. There is an increase in the
risk of hemorrhage as the body is depleted of platelets and coagulation factors.
Febrile neutropenia
 -
 -
ANC <1000/mm3 with a single
temperature of >38.3 degrees C
(101 degrees F) or a sustained
temperature of >=38 degrees C
(100.4 degrees F) for more than
one hour.
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an ANC <1000/mm3 and a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >=38 degrees C (100.4
degrees F) for more than one hour.
Hemolysis
Laboratory evidence of
hemolysis only (e.g., direct
antiglobulin test; DAT; Coombs';
schistocytes; decreased
haptoglobin)
Evidence of hemolysis and >=2
gm decrease in hemoglobin.
Transfusion or medical
intervention indicated (e.g.,
steroids)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate widespread erythrocyte cell membrane destruction.
Hemolytic uremic syndrome
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic anemia, and severe thrombocytopenia.
Leukocytosis
 -
 -
>100,000/mm3
Clinical manifestations of
leucostasis; urgent intervention
indicated
Death
Definition: A disorder characterized by laboratory test results that indicate an increased number of white blood cells in the blood.
Lymph node pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a lymph node.
Spleen disorder
Incidental findings (e.g., Howell-
Jolly bodies); mild degree of
thrombocytosis and
leukocytosis
Prophylactic antibiotics
indicated
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder of the spleen.
Thrombotic thrombocytopenic
purpura
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, renal abnormalities and neurological abnormalities such
as seizures, hemiplegia, and visual disturbances. It is an acute or subacute condition.
Blood and lymphatic system
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
4
3. Cardiac disorders
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Acute coronary syndrome
 -
Symptomatic, progressive
angina; cardiac enzymes
normal; hemodynamically stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
unstable
Death
Definition: A disorder characterized by signs and symptoms related to acute ischemia of the myocardium secondary to coronary artery disease. The clinical presentation covers a
spectrum of heart diseases from unstable angina to myocardial infarction.
Aortic valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in aortic valve function or structure.
Asystole
Periods of asystole; non-urgent
medical management indicated
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without cardiac electrical activity. Typically, this is accompanied by cessation of the pumping function of the heart.
Atrial fibrillation
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible P waves and an irregular ventricular response due to multiple reentry circuits. The rhythm disturbance
originates above the ventricles.
Atrial flutter
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with organized rhythmic atrial contractions with a rate of 200-300 beats per minute. The rhythm disturbance originates in the
atria.
Atrioventricular block complete
 -
Non-urgent intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with complete failure of atrial electrical impulse conduction through the AV node to the ventricles.
Atrioventricular block first
degree
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
 -
 -
 -
Definition: A disorder characterized by a dysrhythmia with a delay in the time required for the conduction of an electrical impulse through the atrioventricular (AV) node beyond 0.2
seconds; prolongation of the PR interval greater than 200 milliseconds.
Cardiac arrest
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by cessation of the pumping function of the heart.
Chest pain - cardiac
Mild pain
Moderate pain; limiting
instrumental ADL
Pain at rest; limiting self care
ADL
 -
 -
Definition: A disorder characterized by substernal discomfort due to insufficient myocardial oxygenation.
Conduction disorder
Mild symptoms; intervention not
indicated
Moderate symptoms
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by pathological irregularities in the cardiac conduction system.
Constrictive pericarditis
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by a thickened and fibrotic pericardial sac; these fibrotic changes impede normal myocardial function by restricting myocardial muscle action.
Heart failure
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by the inability of the heart to pump blood at an adequate volume to meet tissue metabolic requirements, or, the ability to do so only at an elevation
in the filling pressure.
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CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
5
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Left ventricular systolic
dysfunction
 -
 -
Symptomatic due to drop in
ejection fraction responsive to
intervention
Refractory or poorly controlled
heart failure due to drop in
ejection fraction; intervention
such as ventricular assist
device, intravenous vasopressor
support, or heart transplant
indicated
Death
Definition: A disorder characterized by failure of the left ventricle to produce adequate output despite an increase in distending pressure and in end-diastolic volume. Clinical
manifestations mayinclude dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema.
Mitral valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in mitral valve function or structure.
Mobitz (type) II atrioventricular
block
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with relatively constant PR interval prior to the block of an atrial impulse. This is the result of intermittent failure of atrial electrical
impulse conduction through the atrioventricular (AV) node to the ventricles.
Mobitz type I
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a progressively lengthening PR interval prior to the blocking of an atrial impulse. This is the result of intermittent failure of
atrial electrical impulse conduction through the atrioventricular (AV) node to the ventricles.
Myocardial infarction
 -
Asymptomatic and cardiac
enzymes minimally abnormal
and no evidence of ischemic
ECG changes
Severe symptoms; cardiac
enzymes abnormal;
hemodynamically stable; ECG
changes consistent with
infarction
Life-threatening consequences;
hemodynamically unstable
Death
Definition: A disorder characterized by gross necrosis of the myocardium; this is due to an interruption of blood supply to the area.
Myocarditis
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by inflammation of the muscle tissue of the heart.
Palpitations
Mild symptoms; intervention not
indicated
Intervention indicated
 -
 -
 -
Definition: A disorder characterized by an unpleasant sensation of irregular and/or forceful beating of the heart.
Paroxysmal atrial tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; medical
management indicated
IV medication indicated
Life-threatening consequences;
incompletely controlled
medically; cardioversion
indicated
Death
Definition: A disorder characterized by a dysrhythmia with abrupt onset and sudden termination of atrial contractions with a rate of 150-250 beats per minute. The rhythm disturbance
originates in the atria.
Pericardial effusion
 -
Asymptomatic effusion size
small to moderate
Effusion with physiologic
consequences
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by fluid collection within the pericardial sac, usually due to inflammation.
Pericardial tamponade
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in intrapericardial pressure due to the collection of blood or fluid in the pericardium.
Pericarditis
Asymptomatic, ECG or physical
findings (e.g., rub) consistent
with pericarditis
Symptomatic pericarditis (e.g.,
chest pain)
Pericarditis with physiologic
consequences (e.g., pericardial
constriction)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irritation to the layers of the pericardium (the protective sac around the heart).
Page 173 of 364


CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
6
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Pulmonary valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in pulmonary valve function or structure.
Restrictive cardiomyopathy
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by an inability of the ventricles to fill with blood because the myocardium (heart muscle) stiffens and loses its flexibility.
Right ventricular dysfunction
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., ventricular assist device);
heart transplant indicated
Death
Definition: A disorder characterized by impairment of right ventricular function associated with low ejection fraction and a decrease in motility of the right ventricular wall.
Sick sinus syndrome
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with alternating periods of bradycardia and atrial tachycardia accompanied by syncope, fatigue and dizziness.
Sinus bradycardia
Asymptomatic, intervention not
indicated
Symptomatic, medical
intervention indicated
Severe, medically significant,
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate less than 60 beats per minute that originates in the sinus node.
Sinus tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; non-urgent
medical intervention indicated
Urgent medical intervention
indicated
 -
 -
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates in the sinus node.
Supraventricular tachycardia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates above the ventricles.
Tricuspid valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis;
symptoms controlled with
medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in tricuspid valve function or structure.
Ventricular arrhythmia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia that originates in the ventricles.
Ventricular fibrillation
 -
 -
 -
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible QRS complexes due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the
ventricles.
Ventricular tachycardia
 -
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates distal to the bundle of His.
Wolff-Parkinson-White
syndrome
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically or
controlled with procedure
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of an accessory conductive pathway between the atria and the ventricles that causes premature ventricular activation.
Cardiac disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 174 of 364


CTCAE 4.03 - June 14, 2010 : Congenital, familial and genetic disorders 
7
4. Congenital, familial and genetic disorders
Congenital, familial and genetic disorders
Grade
Adverse Event
1
2
3
4
5
Congenital, familial and genetic
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 175 of 364


CTCAE 4.03 - June 14, 2010 : Ear and labyrinth disorders 
8
5. Ear and labyrinth disorders
Ear and labyrinth disorders
Grade
Adverse Event
1
2
3
4
5
Ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the ear.
External ear inflammation
External otitis with erythema or
dry desquamation
External otitis with moist
desquamation, edema,
enhanced cerumen or
discharge; tympanic membrane
perforation; tympanostomy
External otitis with mastoiditis;
stenosis or osteomyelitis;
necrosis of soft tissue or bone
Urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation, swelling and redness to the outer ear and ear canal.
External ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the external ear region.
Hearing impaired
Adults enrolled on a Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of 15 - 25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: subjective change in
hearing in the absence of
documented hearing loss.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 8 kHz in at least
one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz  audiogram):  Threshold
shift of >25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: hearing loss but
hearing aid or intervention not
indicated; limiting instrumental
ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 4 kHz and above
in at least one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of >25 dB averaged at 3
contiguous test frequencies in at
least one ear; therapeutic
intervention indicated.
Adults not enrolled in Monitoring
Program:  hearing loss with
hearing aid or intervention
indicated; limiting self care ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): hearing loss
sufficient to indicate therapeutic
intervention, including hearing
aids; threshold shift >20 dB at 3
kHz and above in at least one
ear; additional speech-language
related services indicated.
Adults: Decrease in hearing to
profound bilateral loss (absolute
threshold >80 dB HL  at 2 kHz
and above); non-servicable
hearing.
Pediatric: Audiologic indication
for cochlear implant and
additional speech-language
related services indicated.
 -
Definition: A disorder characterized by partial or complete loss of the ability to detect or understand sounds resulting from damage to ear structures.
Middle ear inflammation
Serous otitis
Serous otitis, medical
intervention indicated
Mastoiditis; necrosis of canal
soft tissue or bone
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation (physiologic response to irritation), swelling and redness to the middle ear.
Tinnitus
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by noise in the ears, such as ringing, buzzing, roaring or clicking.
Vertigo
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective
vertigo).
Vestibular disorder
 -
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by dizziness, imbalance, nausea, and vision problems.
Ear and labyrinth disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 176 of 364


CTCAE 4.03 - June 14, 2010 : Endocrine disorders 
9
6. Endocrine disorders
Endocrine disorders
Grade
Adverse Event
1
2
3
4
5
Adrenal insufficiency
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder that occurs when the adrenal cortex does not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. It may be due to a disorder
of the adrenal cortex as in Addison's disease or primary adrenal insufficiency.
Cushingoid
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms, medical
intervention or hospitalization
indicated
 -
 -
Definition: A disorder characterized by signs and symptoms that resemble Cushing's disease or syndrome: buffalo hump obesity, striations, adiposity, hypertension, diabetes, and
osteoporosis, usually due to exogenous corticosteroids.
Delayed puberty
 -
No breast development by age
13 yrs for females; testes
volume of <3 cc or no Tanner
Stage 2 development by age
14.5 yrs for males
No breast development by age
14 yrs for females; no increase
in testes volume or no Tanner
Stage 2 by age 16 yrs for
males; hormone replacement
indicated
 -
 -
Definition: A disorder characterized by unusually late sexual maturity.
Growth accelerated
 -
>= +2 SD (standard deviation)
above mid parental height or
target height
 -
 -
 -
Definition: A disorder characterized by greater growth than expected for age.
Hyperparathyroidism
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an increase in production of parathyroid hormone by the parathyroid glands. This results in hypercalcemia (abnormally high levels of calcium in
the blood).
Hyperthyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
suppression therapy indicated;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive levels of thyroid hormone in the body. Common causes include an overactive thyroid gland or thyroid hormone overdose.
Hypoparathyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; medical
intervention or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of parathyroid hormone by the parathyroid glands.
Hypothyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
replacement indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of thyroid hormone by the thyroid gland.
Precocious puberty
Physical signs of puberty with
no biochemical markers for
females <8 years and males <9
years
Physical signs and biochemical
markers of puberty for females
<8 years and males <9 years
 -
 -
 -
Definition: A disorder characterized by unusually early development of secondary sexual features; the onset of sexual maturation begins usually before age 8 for girls and before age
9 for boys.
Virilization
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by inappropriate masculinization occurring in a female or prepubertal male.
Endocrine disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 177 of 364


CTCAE 4.03 - June 14, 2010 : Eye disorders 
10
7. Eye disorders
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Blurred vision
Intervention not indicated
Symptomatic; limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by visual perception of unclear or fuzzy images.
Cataract
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic with marked
decrease in visual acuity
(worse than 20/40 but better
than 20/200); operative
intervention indicated (e.g.,
cataract surgery)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by partial or complete opacity of the crystalline lens of one or both eyes. This results in a decrease in visual acuity and eventual blindness if
untreated.
Conjunctivitis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; topical
intervention indicated (e.g.,
antibiotics); limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation, swelling and redness to the conjunctiva of the eye.
Corneal ulcer
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Limiting self care ADL;
declining vision (worse than
20/40 but better than 20/200)
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by an area of epithelial tissue loss on the surface of the cornea. It is associated with inflammatory cells in the cornea and anterior chamber.
Dry eye
Asymptomatic; clinical or
diagnostic observations only;
mild symptoms relieved by
lubricants
Symptomatic; multiple
agents indicated; limiting
instrumental ADL
Decrease in visual acuity
(<20/40); limiting self care
ADL
 -
 -
Definition: A disorder characterized by dryness of the cornea and conjunctiva.
Extraocular muscle paresis
Asymptomatic; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
disabling
 -
 -
Definition: A disorder characterized by incomplete paralysis of an extraocular muscle.
Eye pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the eye.
Eyelid function disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; nonoperative
intervention indicated;
limiting instrumental ADL
Limiting self care ADL;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by impaired eyelid function.
Flashing lights
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by a sudden or brief burst of light.
Floaters
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by an individual seeing spots before their eyes. The spots are shadows of opaque cell fragments in the vitreous humor or lens.
Glaucoma
Elevated intraocular
pressure (EIOP) with single
topical agent for intervention;
no visual field deficit
EIOP causing early visual
field deficits; multiple topical
or oral agents indicated;
limiting instrumental ADL
EIOP causing marked visual
field deficits (e.g., involving
both superior and inferior
visual fields); operative
intervention indicated;
limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an increase in pressure in the eyeball due to obstruction of the aqueous humor outflow.
Keratitis
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Decline in vision (worse than
20/40 but better than
20/200); limiting self care
ADL
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by inflammation to the cornea of the eye.
Night blindness
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an inability to see clearly in dim light.
Page 178 of 364


CTCAE 4.03 - June 14, 2010 : Eye disorders 
11
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Optic nerve disorder
Asymptomatic; clinical or
diagnostic observations only
Limiting vision of the affected
eye (20/40 or better)
Limiting vision in the affected
eye (worse than 20/40 but
better than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the optic nerve (second cranial nerve).
Papilledema
Asymptomatic; no visual field
defects
Symptomatic decline in
vision; visual field defect
present sparing the central
20 degrees
Marked visual field defect
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by swelling around the optic disc.
Photophobia
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by fear and avoidance of light.
Retinal detachment
Asymptomatic
Exudative and visual acuity
20/40 or better
Rhegmatogenous or
exudative detachment;
operative intervention
indicated; decline in vision
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by the separation of the inner retina layers from the underlying pigment epithelium.
Retinal tear
 -
Laser therapy or
pneumopexy indicated
Vitroretinal surgical repair
indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by a small laceration of the retina, this occurs when the vitreous separates from the retina. Symptoms include flashes and floaters.
Retinal vascular disorder
 -
Topical medication indicated
Intravitreal medication;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by pathological retinal blood vessels that adversely affects vision.
Retinopathy
Asymptomatic; clinical or
diagnostic observations only
Symptomatic with moderate
decrease in visual acuity
(20/40 or better); limiting
instrumental ADL
Symptomatic with marked
decrease in visual acuity
(worse than 20/40);
disabling; limiting self care
ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder involving the retina.
Scleral disorder
Asymptomatic; clinical or
diagnostic observations only
Symptomatic, limiting
instrumental ADL; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic, limiting self
care ADL; marked decrease
in visual acuity (worse than
20/40)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the sclera of the eye.
Uveitis
Asymptomatic; clinical or
diagnostic observations only
Anterior uveitis; medical
intervention indicated
Posterior or pan-uveitis
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by inflammation to the uvea of the eye.
Vitreous hemorrhage
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
vitrectomy indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by blood extravasation into the vitreous humor.
Watering eyes
Intervention not indicated
Intervention indicated
Operative intervention
indicated
 -
 -
Definition: A disorder of excessive tearing in the eyes; it can be caused by overproduction of tears or impaired drainage of the tear duct.
Eye disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only;
intervention not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental
ADL
Severe or medically
significant but not
immediately sight-
threatening; hospitalization
or prolongation of existing
hospitalization indicated;
disabling;  limiting self care
ADL
Sight-threatening
consequences; urgent
intervention indicated;
blindness (20/200 or worse)
in the affected eye
 -
Page 179 of 364


CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
12
8. Gastrointestinal disorders
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal distension
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe discomfort; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling of the abdomen.
Abdominal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the abdominal region.
Anal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the opening in the anal canal to the perianal skin.
Anal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the anal region.
Anal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the anus.
Anal necrosis
 -
 -
TPN or hospitalization indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the anal region.
Anal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the anal region.
Anal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; non-
emergent operative intervention
indicated; TPN or hospitalization
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the anal canal.
Anal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the anal canal.
Ascites
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; invasive
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by accumulation of serous or hemorrhagic fluid in the peritoneal cavity.
Bloating
No change in bowel function or
oral intake
Symptomatic, decreased oral
intake; change in bowel function
 -
 -
 -
Definition: A disorder characterized by subject-reported feeling of uncomfortable fullness of the abdomen.
Cecal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cecum.
Cheilitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; intervention indicated
 -
 -
Definition: A disorder characterized by inflammation of the lip.
Page 180 of 364


CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
13
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Colitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe abdominal pain; change
in bowel habits; medical
intervention indicated;
peritoneal signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the colon.
Colonic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the large intestine and another organ or anatomic site.
Colonic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the colon.
Colonic obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization indicated;
elective operative intervention
indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the colon.
Colonic perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the colonic wall.
Colonic stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the colon.
Colonic ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the colon.
Constipation
Occasional or intermittent
symptoms; occasional use of
stool softeners, laxatives,
dietary modification, or enema
Persistent symptoms with
regular use of laxatives or
enemas; limiting instrumental
ADL
Obstipation with manual
evacuation indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irregular and infrequent or difficult evacuation of the bowels.
Dental caries
One or more dental caries, not
involving the root
Dental caries involving the root
Dental caries resulting in pulpitis
or periapical abscess or
resulting in tooth loss
 -
 -
Definition: A disorder characterized by the decay of a tooth, in which it becomes softened, discolored and/or porous.
Diarrhea
Increase of <4 stools per day
over baseline; mild increase in
ostomy output compared to
baseline
Increase of 4 - 6 stools per day
over baseline; moderate
increase in ostomy output
compared to baseline
Increase of >=7 stools per day
over baseline; incontinence;
hospitalization indicated; severe
increase in ostomy output
compared to baseline; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by frequent and watery bowel movements.
Dry mouth
Symptomatic (e.g., dry or thick
saliva) without significant dietary
alteration; unstimulated saliva
flow >0.2 ml/min
Moderate symptoms; oral intake
alterations (e.g., copious water,
other lubricants, diet limited to
purees and/or soft, moist foods);
unstimulated saliva 0.1 to 0.2
ml/min
Inability to adequately aliment
orally; tube feeding or TPN
indicated; unstimulated saliva
<0.1 ml/min
 -
 -
Definition: A disorder characterized by reduced salivary flow in the oral cavity.
Page 181 of 364


CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
14
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Duodenal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the duodenum and another organ or anatomic site.
Duodenal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the duodenum.
Duodenal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization or elective
operative intervention indicated;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of stomach contents through the duodenum.
Duodenal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the duodenal wall.
Duodenal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the duodenum.
Duodenal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the duodenal wall.
Dyspepsia
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by an uncomfortable, often painful feeling in the stomach, resulting from impaired digestion. Symptoms include burning stomach, bloating,
heartburn, nausea and vomiting.
Dysphagia
Symptomatic, able to eat
regular diet
Symptomatic and altered
eating/swallowing
Severely altered
eating/swallowing; tube feeding
or TPN or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by difficulty in swallowing.
Enterocolitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe or persistent abdominal
pain; fever; ileus; peritoneal
signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the small and large intestines.
Enterovesical fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the urinary bladder and the intestine.
Esophageal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the esophagus and another organ or anatomic site.
Esophageal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the esophagus.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
15
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Esophageal necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the esophageal wall.
Esophageal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the esophagus.
Esophageal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the esophageal region.
Esophageal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the esophagus.
Esophageal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the esophagus.
Esophageal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the esophageal wall.
Esophageal varices
hemorrhage
 -
Self-limited; intervention not
indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from esophageal varices.
Esophagitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered
eating/swallowing;  oral
supplements indicated
Severely altered
eating/swallowing; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the esophageal wall.
Fecal incontinence
Occasional use of pads required Daily use of pads required
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by inability to control the escape of stool from the rectum.
Flatulence
Mild symptoms; intervention not
indicated
Moderate; persistent;
psychosocial sequelae
 -
 -
 -
Definition: A disorder characterized by a state of excessive gas in the alimentary canal.
Gastric fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest; tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the stomach and another organ or anatomic site.
Gastric hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the gastric wall.
Gastric necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gastric wall.
Page 183 of 364


CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
16
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Gastric perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the stomach wall.
Gastric stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the stomach.
Gastric ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the stomach.
Gastritis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated
Severely altered eating or
gastric function; TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the stomach.
Gastroesophageal reflux
disease
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by reflux of the gastric and/or duodenal contents into the distal esophagus. It is chronic in nature and usually caused by incompetence of the lower
esophageal sphincter, and may result in injury to the esophageal mucosal. Symptoms include heartburn and acid indigestion.
Gastrointestinal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the gastrointestinal system and another organ or anatomic site.
Gastrointestinal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gastrointestinal region.
Gastroparesis
Mild nausea, early satiety and
bloating, able to maintain caloric
intake on regular diet
Moderate symptoms; able to
maintain nutrition with dietary
and lifestyle modifications; may
need pharmacologic
intervention
Weight loss; refractory to
medical intervention; unable to
maintain nutrition orally
 -
 -
Definition: A disorder characterized by an incomplete paralysis of the muscles of the stomach wall resulting in delayed emptying of the gastric contents into the small intestine.
Gingival pain
Mild pain
Moderate pain interfering with
oral intake
Severe pain; inability to aliment
orally
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gingival region.
Hemorrhoidal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the hemorrhoids.
Hemorrhoids
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; banding or
medical intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by the presence of dilated veins in the rectum and surrounding area.
Ileal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the ileum and another organ or anatomic site.
Ileal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the ileal wall.
Page 184 of 364


CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
17
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Ileal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the ileum.
Ileal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the ileal wall.
Ileal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the ileum.
Ileal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the ileum.
Ileus
 -
Symptomatic; altered GI
function; bowel rest indicated
Severely altered GI function;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by failure of the ileum to transport intestinal contents.
Intra-abdominal hemorrhage
 -
Medical intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding in the abdominal cavity.
Jejunal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the jejunum and another organ or anatomic site.
Jejunal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the jejunal wall.
Jejunal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the jejunum.
Jejunal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the jejunal wall.
Jejunal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the jejunum.
Jejunal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the jejunum.
Lip pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort of the lip.
Page 185 of 364


CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
18
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Lower gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the lower gastrointestinal tract (small intestine, large intestine, and anus).
Malabsorption
 -
Altered diet; oral intervention
indicated
Inability to aliment adequately;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inadequate absorption of nutrients in the small intestine. Symptoms include abdominal marked discomfort, bloating and diarrhea.
Mucositis oral
Asymptomatic or mild
symptoms; intervention not
indicated
Moderate pain; not interfering
with oral intake; modified diet
indicated
Severe pain; interfering with oral
intake
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the oral mucosal.
Nausea
Loss of appetite without
alteration in eating habits
Oral intake decreased without
significant weight loss,
dehydration or malnutrition
Inadequate oral caloric or fluid
intake; tube feeding, TPN, or
hospitalization indicated
 -
 -
Definition: A disorder characterized by a queasy sensation and/or the urge to vomit.
Obstruction gastric
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the stomach.
Oral cavity fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the oral cavity and another organ or anatomic site.
Oral dysesthesia
Mild discomfort; not interfering
with oral intake
Moderate pain; interfering with
oral intake
Disabling pain; tube feeding or
TPN indicated
 -
 -
Definition: A disorder characterized by a burning or tingling sensation on the lips, tongue or entire mouth.
Oral hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mouth.
Oral pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the mouth, tongue or lips.
Pancreatic duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the pancreatic duct.
Pancreatic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the pancreas and another organ or anatomic site.
Pancreatic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the pancreas.
Pancreatic necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the pancreas.
Pancreatitis
 -
Enzyme elevation or radiologic
findings only
Severe pain; vomiting; medical
intervention indicated (e.g.,
analgesia, nutritional support)
Life-threatening consequences;
urgent intervention indicated
Death
Page 186 of 364


CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
19
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by inflammation of the pancreas.
Periodontal disease
Gingival recession or gingivitis;
limited bleeding on probing; mild
local bone loss
Moderate gingival recession or
gingivitis; multiple sites of
bleeding on probing; moderate
bone loss
Spontaneous bleeding; severe
bone loss with or without tooth
loss; osteonecrosis of maxilla or
mandible
 -
 -
Definition: A disorder in the gingival tissue around the teeth.
Peritoneal necrosis
 -
 -
Tube feeding or TPN  indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the peritoneum.
Proctitis
Rectal discomfort, intervention
not indicated
Symptoms (e.g., rectal
discomfort, passing blood or
mucus); medical intervention
indicated; limiting instrumental
ADL
Severe symptoms; fecal
urgency or stool incontinence;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the rectum.
Rectal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the rectum and another organ or anatomic site.
Rectal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the rectal wall and discharged from the anus.
Rectal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the rectum.
Rectal necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the rectal wall.
Rectal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the rectum.
Rectal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the rectal region.
Rectal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the rectal wall.
Rectal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the rectum.
Rectal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function (e.g. altered dietary
habits, vomiting, diarrhea)
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the rectum.
Page 187 of 364


CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
20
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Retroperitoneal hemorrhage
 -
Self-limited; intervention
indicated
Transfusion, medical, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the retroperitoneal area.
Salivary duct inflammation
Slightly thickened saliva; slightly
altered taste (e.g., metallic)
Thick, ropy, sticky saliva;
markedly altered taste;
alteration in diet indicated;
secretion-induced symptoms;
limiting instrumental ADL
Acute salivary gland necrosis;
severe secretion-induced
symptoms (e.g., thick saliva/oral
secretions or gagging);  tube
feeding or TPN indicated;
limiting self care ADL; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the salivary duct.
Salivary gland fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; tube feeding indicated
Severely altered GI function;
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between a salivary gland and another organ or anatomic site.
Small intestinal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe pain; interfering with oral
intake; tube feeding, TPN or
hospitalization indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the small intestine.
Small intestinal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents.
Small intestinal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the small intestine wall.
Small intestinal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the small intestine.
Small intestine ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the small intestine.
Stomach pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the stomach.
Tooth development disorder
Asymptomatic; hypoplasia of
tooth or enamel
Impairment correctable with oral
surgery
Maldevelopment with
impairment not surgically
correctable; disabling
 -
 -
Definition: A disorder characterized by a pathological process of the teeth occurring during tooth development.
Tooth discoloration
Surface stains
 -
 -
 -
 -
Definition: A disorder characterized by a change in tooth hue or tint.
Toothache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the tooth.
Page 188 of 364


CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
21
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Typhlitis
 -
 -
Symptomatic (e.g., abdominal
pain, fever, change in bowel
habits with ileus); peritoneal
signs
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the cecum.
Upper gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the upper gastrointestinal tract (oral cavity, pharynx, esophagus, and stomach).
Vomiting
1 - 2 episodes (separated by 5
minutes) in 24 hrs
3 - 5 episodes (separated by 5
minutes) in 24 hrs
>=6 episodes (separated by 5
minutes) in 24 hrs; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
Gastrointestinal disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 189 of 364


CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions 
22
9. General disorders and administration site conditions
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Chills
Mild sensation of cold;
shivering; chattering of teeth
Moderate tremor of the entire
body; narcotics indicated
Severe or prolonged, not
responsive to narcotics
 -
 -
Definition: A disorder characterized by a sensation of cold that often marks a physiologic response to sweating after a fever.
Death neonatal
 -
 -
 -
 -
Death
Definition: A disorder characterized by cessation of life occurring during the first 28 days of life.
Death NOS
 -
 -
 -
 -
Death
Definition: A cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
Edema face
Localized facial edema
Moderate localized facial
edema; limiting instrumental
ADL
Severe swelling; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in facial tissues.
Edema limbs
5 - 10% inter-limb discrepancy
in volume or circumference at
point of greatest visible
difference; swelling or
obscuration of anatomic
architecture on close inspection
>10 - 30% inter-limb
discrepancy in volume or
circumference at point of
greatest visible difference;
readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
>30% inter-limb discrepancy in
volume; gross deviation from
normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the upper or lower extremities.
Edema trunk
Swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
Gross deviation from normal
anatomic contour; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the trunk area.
Facial pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the face.
Fatigue
Fatigue relieved by rest
Fatigue not relieved by rest;
limiting instrumental ADL
Fatigue not relieved by rest,
limiting self care ADL
 -
 -
Definition: A disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities.
Fever
38.0 - 39.0 degrees C  (100.4 -
102.2 degrees F)
>39.0 - 40.0 degrees C (102.3 -
104.0 degrees F)
>40.0 degrees C (>104.0
degrees F) for <=24 hrs
>40.0 degrees C (>104.0
degrees F) for >24 hrs
Death
Definition: A disorder characterized by elevation of the body's temperature above the upper limit of normal.
Flu like symptoms
Mild flu-like symptoms present
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a group of symptoms similar to those observed in patients with the flu. It includes fever, chills, body aches, malaise, loss of appetite and dry
cough.
Gait disturbance
Mild change in gait (e.g., wide-
based, limping or hobbling)
Moderate change in gait (e.g.,
wide-based, limping or
hobbling); assistive device
indicated; limiting instrumental
ADL
Disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by walking difficulties.
Hypothermia
 -
35 - >32 degrees C;  95 - >89.6
degrees F
32 - >28 degrees C;  89.6 -
>82.4 degrees F
<=28 degrees C; 82.4 degrees
F; life-threatening
consequences (e.g., coma,
hypotension, pulmonary edema,
acidemia, ventricular fibrillation)
Death
Definition: A disorder characterized by an abnormally low body temperature. Treatment is required when the body temperature is 35C (95F) or below.
Page 190 of 364


CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions 
23
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Infusion related reaction
Mild transient reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances.
Infusion site extravasation
 -
Erythema with associated
symptoms (e.g., edema, pain,
induration, phlebitis)
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of a pharmacologic or a biologic substance from the infusion site into the surrounding tissue. Signs and symptoms include induration,
erythema, swelling, burning sensation and marked discomfort at the infusion site.
Injection site reaction
Tenderness with or without
associated symptoms (e.g.,
warmth, erythema, itching)
Pain; lipodystrophy; edema;
phlebitis
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an intense adverse reaction (usually immunologic) developing at the site of an injection.
Irritability
Mild; easily consolable
Moderate; limiting instrumental
ADL; increased attention
indicated
Severe abnormal or excessive
response; limiting self care ADL;
inconsolable
 -
 -
Definition: A disorder characterized by an abnormal responsiveness to stimuli or physiological arousal; may be in response to pain, fright, a drug, an emotional situation or a medical
condition.
Localized edema
Localized to dependent areas,
no disability or functional
impairment
Moderate localized edema and
intervention indicated; limiting
instrumental ADL
Severe localized edema and
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation at a specific anatomic site.
Malaise
Uneasiness or lack of well being Uneasiness or lack of well
being; limiting instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a feeling of general discomfort or uneasiness, an out-of-sorts feeling.
Multi-organ failure
 -
 -
Shock with azotemia and acid-
base disturbances; significant
coagulation abnormalities
Life-threatening consequences
(e.g., vasopressor dependent
and oliguric or anuric or
ischemic colitis or lactic
acidosis)
Death
Definition: A disorder characterized by progressive deterioration of the lungs, liver, kidney and clotting mechanisms.
Neck edema
Asymptomatic localized neck
edema
Moderate neck edema; slight
obliteration of anatomic
landmarks; limiting instrumental
ADL
Generalized neck edema (e.g.,
difficulty in turning neck);
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an accumulation of excessive fluid in the neck.
Non-cardiac chest pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by discomfort in the chest unrelated to a heart disorder.
Pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by the sensation of marked discomfort, distress or agony.
Sudden death NOS
 -
 -
 -
 -
Death
Definition: An unexpected cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
General disorders and
administration site conditions -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 191 of 364


CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders 
24
10. Hepatobiliary disorders
Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Bile duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated <24
hrs
Severely altered GI function;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the bile duct.
Biliary fistula
 -
Symptomatic and intervention
not indicated
Severely altered GI function;
TPN indicated; endoscopic
intervention indicated; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the bile ducts and another organ or anatomic site.
Cholecystitis
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation involving the gallbladder. It may be associated with the presence of gallstones.
Gallbladder fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Symptomatic or severely altered
GI function; TPN indicated;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the gallbladder and another organ or anatomic site.
Gallbladder necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gallbladder.
Gallbladder obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated  <24
hrs
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents of the gallbladder.
Gallbladder pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gallbladder region.
Gallbladder perforation
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the gallbladder wall.
Hepatic failure
 -
 -
Asterixis; mild encephalopathy;
limiting self care ADL
Moderate to severe
encephalopathy; coma; life-
threatening consequences
Death
Definition: A disorder characterized by the inability of the liver to metabolize chemicals in the body. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic
dehydrogenase, and alkaline phosphatase.
Hepatic hemorrhage
Mild; intervention not indicated
Symptomatic; medical
intervention indicated
Transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the liver.
Hepatic necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the hepatic parenchyma.
Hepatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the liver region.
Perforation bile duct
 -
 -
Radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the extrahepatic or intrahepatic bile duct.
Page 192 of 364


CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders 
25
Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Portal hypertension
 -
Decreased portal vein flow
Reversal/retrograde portal vein
flow; associated with varices
and/or ascites
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in blood pressure in the portal venous system.
Portal vein thrombosis
 -
Intervention not indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the formation of a thrombus (blood clot) in the portal vein.
Hepatobiliary disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 193 of 364


CTCAE 4.03 - June 14, 2010 : Immune system disorders 
26
11. Immune system disorders
Immune system disorders
Grade
Adverse Event
1
2
3
4
5
Allergic reaction
Transient flushing or rash, drug
fever <38 degrees C (<100.4
degrees F); intervention not
indicated
Intervention or infusion
interruption indicated; responds
promptly to symptomatic
treatment (e.g., antihistamines,
NSAIDS, narcotics);
prophylactic medications
indicated for <=24 hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
 -
 -
Symptomatic bronchospasm,
with or without urticaria;
parenteral intervention
indicated; allergy-related
edema/angioedema;
hypotension
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity
immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death.
Autoimmune disorder
Asymptomatic; serologic or
other evidence of autoimmune
reaction, with normal organ
function;  intervention not
indicated
Evidence of autoimmune
reaction involving a non-
essential organ or function (e.g.,
hypothyroidism)
Autoimmune reactions involving
major organ (e.g., colitis,
anemia, myocarditis, kidney)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder resulting from loss of function or tissue destruction of an organ or multiple organs, arising from humoral or cellular immune responses of the individual to his own
tissue constituents.
Cytokine release syndrome
Mild reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by the release of cytokines from the cells.
Serum sickness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate arthralgia; fever, rash,
urticaria, antihistamines
indicated
Severe arthralgia or arthritis;
extensive rash; steroids or IV
fluids indicated
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by a delayed-type hypersensitivity reaction to foreign proteins derived from an animal serum. It occurs approximately six to twenty-one days
following the administration of the foreign antigen. Symptoms include fever, arthralgias, myalgias, skin eruptions, lymphadenopathy, chest marked discomfort and dyspnea.
Immune system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 194 of 364


CTCAE 4.03 - June 14, 2010 : Infections and infestations 
27
12. Infections and infestations
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Abdominal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the abdominal cavity.
Anorectal infection
Localized; local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the anal area and the rectum.
Appendicitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent.
Appendicitis perforated
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent with gangrenous changes resulting in the rupture of the
appendiceal wall. The appendiceal wall rupture causes the release of inflammatory and bacterial contents from the appendiceal lumen into the abdominal cavity.
Arteritis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving an artery.
Biliary tract infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the biliary tract.
Bladder infection
 -
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bladder.
Bone infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bones.
Breast infection
 -
Local infection with moderate
symptoms; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
Severe infection; axillary
adenitis;  IV antibacterial,
antifungal, or antiviral
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the breast.
Bronchial infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bronchi.
Catheter related infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process that arises secondary to catheter use.
Cecal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Page 195 of 364


CTCAE 4.03 - June 14, 2010 : Infections and infestations 
28
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the cecum.
Cervicitis infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the uterine cervix.
Conjunctivitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the conjunctiva. Clinical manifestations include pink or red color in the eyes.
Corneal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the cornea.
Cranial nerve infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a cranial nerve.
Device related infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the use of a medical device.
Duodenal infection
 -
Moderate symptoms; medical
intervention indicated (e.g., oral
antibiotics)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the duodenum.
Encephalitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
severe changes in mental
status; self-limited seizure
activity; focal neurologic
abnormalities
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain tissue.
Encephalomyelitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain and spinal cord tissues.
Endocarditis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endocardial layer of the heart.
Endophthalmitis
 -
Local intervention indicated
Systemic intervention or
hospitalization indicated
Blindness (20/200 or worse)
 -
Definition: A disorder characterized by an infectious process involving the internal structures of the eye.
Page 196 of 364


CTCAE 4.03 - June 14, 2010 : Infections and infestations 
29
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Enterocolitis infectious
 -
Passage of >3 unformed stools
per 24 hrs or duration of illness
>48 hrs; moderate abdominal
pain
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated;
profuse watery diarrhea with
signs of hypovolemia;  bloody
diarrhea; fever; severe
abdominal pain; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small and large intestines.
Esophageal infection
 -
Local intervention indicated
(e.g., oral antibiotic, antifungal,
antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the esophagus.
Eye infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated;
enucleation
Death
Definition: A disorder characterized by an infectious process involving the eye.
Gallbladder infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gallbladder.
Gum infection
Local therapy indicated (swish
and swallow)
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gums.
Hepatic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the liver.
Hepatitis viral
Asymptomatic, treatment not
indicated
 -
Symptomatic liver dysfunction;
fibrosis by biopsy; compensated
cirrhosis; reactivation of chronic
hepatitis
Decompensated liver function
(e.g., ascites, coagulopathy,
encephalopathy, coma)
Death
Definition: A disorder characterized by a viral pathologic process involving the liver parenchyma.
Infective myositis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skeletal muscles.
Joint infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral); needle
aspiration indicated (single or
multiple)
Arthroscopic intervention
indicated (e.g., drainage) or
arthrotomy (e.g., open surgical
drainage)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a joint.
Kidney infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the kidney.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
30
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Laryngitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammatory process involving the larynx.
Lip infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the lips.
Lung infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lungs.
Lymph gland infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lymph nodes.
Mediastinal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mediastinum.
Meningitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated; focal
neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation of the meninges of the brain and/or spinal cord.
Mucosal infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a mucosal surface.
Nail infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the nail.
Otitis externa
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the outer ear and ear canal. Contributory factors include excessive water exposure (swimmer's ear infection)
and cuts in the ear canal. Symptoms include fullness, itching, swelling and marked discomfort in the ear and ear drainage.
Otitis media
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the middle ear.
Ovarian infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the ovary.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
31
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Pancreas infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pancreas.
Papulopustular rash
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10-30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self-care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering  any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption consisting of papules (a small, raised pimple) and pustules (a small pus filled blister), typically appearing in face, scalp, and upper
chest and back Unlike acne, this rash does not present with whiteheads or blackheads, and can be symptomatic, with itchy or tender lesions.
Paronychia
Nail fold edema or erythema;
disruption of the cuticle
Localized intervention indicated;
oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral);
nail fold edema or erythema
with pain; associated with
discharge or nail plate
separation; limiting instrumental
ADL
Surgical intervention or IV
antibiotics indicated; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an infectious process involving the soft tissues around the nail.
Pelvic infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pelvic cavity.
Penile infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the penis.
Periorbital infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the orbit of the eye.
Peripheral nerve infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peripheral nerves.
Peritoneal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peritoneum.
Pharyngitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the throat.
Phlebitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
32
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the vein. Clinical manifestations include erythema, marked discomfort, swelling, and induration along the course
of the infected vein.
Pleural infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pleura.
Prostate infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the prostate gland.
Rash pustular
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed and elevated skin lesion filled with pus.
Rhinitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
 -
 -
 -
Definition: A disorder characterized by an infectious process involving the nasal mucosal.
Salivary gland infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the salivary gland.
Scrotal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the scrotum.
Sepsis
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of pathogenic microorganisms in the blood stream that cause a rapidly progressing systemic reaction that may lead to shock.
Sinusitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mucous membranes of the paranasal sinuses.
Skin infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skin.
Small intestine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small intestine.
Soft tissue infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving soft tissues.
Splenic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
33
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the spleen.
Stoma site infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a stoma (surgically created opening on the surface of the body).
Tooth infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a tooth.
Tracheitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the trachea.
Upper respiratory infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the upper respiratory tract (nose, paranasal sinuses, pharynx, larynx, or trachea).
Urethral infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urethra.
Urinary tract infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urinary tract, most commonly the bladder and the urethra.
Uterine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endometrium. It may extend to the myometrium and parametrial tissues.
Vaginal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vagina.
Vulval infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vulva.
Wound infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the wound.
Infections and infestations -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
34
13. Injury, poisoning and procedural complications
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Ankle fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of damage to the ankle joint characterized by a break in the continuity of the ankle bone. Symptoms include marked discomfort, swelling and difficulty moving the
affected leg and foot.
Aortic injury
 -
 -
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the aorta.
Arterial injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to an artery.
Biliary anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of bile due to breakdown of a biliary anastomosis (surgical connection of two separate anatomic structures).
Bladder anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a bladder anastomosis (surgical connection of two separate anatomic structures).
Bruising
Localized or in a dependent
area
Generalized
 -
 -
 -
Definition: A finding of injury of the soft tissues or bone characterized by leakage of blood into surrounding tissues.
Burn
Minimal symptoms; intervention
not indicated
Medical intervention; minimal
debridement indicated
Moderate to major debridement
or reconstruction indicated
Life-threatening consequences
Death
Definition: A finding of impaired integrity to the anatomic site of an adverse thermal reaction. Burns can be caused by exposure to chemicals, direct heat, electricity, flames and
radiation. The extent of damage depends on the length and intensity of exposure and time until provision of treatment.
Dermatitis radiation
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of cutaneous inflammatory reaction occurring as a result of exposure to biologically effective levels of ionizing radiation.
Esophageal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an esophageal anastomosis (surgical connection of two separate anatomic structures).
Fall
Minor with no resultant injuries;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding of sudden movement downward, usually resulting in injury.
Fallopian tube anastomotic leak
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a fallopian tube anastomosis (surgical connection of two separate anatomic structures).
Fallopian tube perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A finding of rupture of the fallopian tube wall.
Fracture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but non-displaced;
immobilization indicated
Severe symptoms; displaced or
open wound with bone
exposure; disabling; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of traumatic injury to the bone in which the continuity of the bone is broken.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
35
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Gastric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastric anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastrointestinal anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal stoma necrosis
 -
Superficial necrosis;
intervention not indicated
Severe symptoms;
hospitalization or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of a necrotic process occurring in the gastrointestinal tract stoma.
Hip fracture
 -
Hairline fracture; mild pain;
limiting instrumental ADL; non-
surgical intervention indicated
Severe pain; hospitalization or
intervention indicated for pain
control (e.g., traction); operative
intervention indicated
Life-threatening consequences;
symptoms associated with
neurovascular compromise
 -
Definition: A finding of traumatic injury to the hip in which the continuity of either the femoral head, femoral neck, intertrochanteric or subtrochanteric regions is broken.
Injury to carotid artery
 -
 -
Severe symptoms; limiting self
care ADL (e.g., transient
cerebral ischemia); repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the carotid artery.
Injury to inferior vena cava
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the inferior vena cava.
Injury to jugular vein
 -
 -
Symptomatic limiting self care
ADL; disabling; repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the jugular vein.
Injury to superior vena cava
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic; repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the superior vena cava.
Intestinal stoma leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from an intestinal stoma (surgically created opening on the surface of the body).
Intestinal stoma obstruction
 -
Self-limited; intervention not
indicated
Severe symptoms; IV fluids,
tube feeding, or TPN indicated
>=24 hrs; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of blockage of the normal flow of the contents of the intestinal stoma.
Intestinal stoma site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the intestinal stoma.
Intraoperative arterial injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to an artery during a surgical procedure.
Intraoperative breast injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
36
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the breast parenchyma during a surgical procedure.
Intraoperative cardiac injury
 -
 -
Primary repair of injured
organ/structure indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the heart during a surgical procedure.
Intraoperative ear injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection of injured
organ/structure indicated;
disabling (e.g., impaired
hearing; impaired balance)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the ear during a surgical procedure.
Intraoperative endocrine injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the endocrine gland during a surgical procedure.
Intraoperative gastrointestinal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the gastrointestinal system during a surgical procedure.
Intraoperative head and neck
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the head and neck during a surgical procedure.
Intraoperative hemorrhage
 -
 -
Postoperative radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of uncontrolled bleeding during a surgical procedure.
Intraoperative hepatobiliary
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the hepatic parenchyma and/or biliary tract during a surgical procedure.
Intraoperative musculoskeletal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the musculoskeletal system during a surgical procedure.
Intraoperative neurological
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the nervous system during a surgical procedure.
Intraoperative ocular injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the eye during a surgical procedure.
Intraoperative renal injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the kidney during a surgical procedure.
Intraoperative reproductive tract
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
37
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the reproductive organs during a surgical procedure.
Intraoperative respiratory injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the respiratory system during a surgical procedure.
Intraoperative skin injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the skin during a surgical procedure.
Intraoperative splenic injury
 -
Primary repair of injured
organ/structure indicated
Resection or reconstruction of
injured organ/structure
indicated; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the spleen during a surgical procedure.
Intraoperative urinary injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the urinary system during a surgical procedure.
Intraoperative venous injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to a vein during a surgical procedure.
Kidney anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a kidney anastomosis (surgical connection of two separate anatomic structures).
Large intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the large intestine.
Pancreatic anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pancreatic anastomosis (surgical connection of two separate anatomic structures).
Pharyngeal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pharyngeal anastomosis (surgical connection of two separate anatomic structures).
Postoperative hemorrhage
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; radiologic,
endoscopic, or operative
intervention indicated
Transfusion indicated of >=2
units (10 cc/kg for pediatrics)
pRBCs beyond protocol
specification; urgent radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding occurring after a surgical procedure.
Postoperative thoracic
procedure complication
 -
Extubated within 24 - 72 hrs
postoperatively
Extubated >72 hrs
postoperatively, but before
tracheostomy indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of a previously undocumented problem that occurs after a thoracic procedure.
Prolapse of intestinal stoma
Asymptomatic; reducible
Recurrent after manual
reduction; local irritation or stool
leakage; difficulty to fit
appliance; limiting instrumental
ADL
Severe symptoms; elective
operative intervention indicated;
limiting self care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
38
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of protrusion of the intestinal stoma (surgically created opening on the surface of the body) above the abdominal surface.
Prolapse of urostomy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Local care or maintenance;
minor revision indicated
Dysfunctional stoma; elective
operative intervention or major
stomal revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of displacement of the urostomy.
Radiation recall reaction
(dermatologic)
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of acute skin inflammatory reaction caused by drugs, especially chemotherapeutic agents, for weeks or months following radiotherapy. The inflammatory reaction
is confined to the previously irradiated skin and the symptoms disappear after the removal of the pharmaceutical agent.
Rectal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a rectal anastomosis (surgical connection of two separate anatomic structures).
Seroma
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; simple aspiration
indicated
Symptomatic, elective radiologic
or operative intervention
indicated
 -
 -
Definition: A finding of tumor-like collection of serum in the tissues.
Small intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the small bowel.
Spermatic cord anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a spermatic cord anastomosis (surgical connection of two separate anatomic structures).
Spinal fracture
Mild back pain; nonprescription
analgesics indicated
Moderate back pain;
prescription analgesics
indicated; limiting instrumental
ADL
Severe back pain;
hospitalization or intervention
indicated for pain control (e.g.,
vertebroplasty); limiting self care
ADL; disability
Life-threatening consequences;
symptoms associated with
neurovascular compromise
Death
Definition: A finding of traumatic injury to the spine in which the continuity of a vertebral bone is broken.
Stenosis of gastrointestinal
stoma
 -
Symptomatic; IV fluids indicated
<24 hrs; manual dilation at
bedside
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the gastrointestinal stoma (surgically created opening on the surface of the body).
Stomal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the jejunal mucosal surface close to the anastomosis site following a
gastroenterostomy procedure.
Tracheal hemorrhage
Minimal bleeding identified on
clinical or diagnostic exam;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the trachea.
Tracheal obstruction
Partial asymptomatic
obstruction on examination
(e.g., visual, radiologic or
endoscopic)
Symptomatic (e.g., noisy airway
breathing), no respiratory
distress; medical intervention
indicated (e.g., steroids); limiting
instrumental ADL
Stridor; radiologic or endoscopic
intervention indicated (e.g.,
stent, laser); limiting self care
ADL
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of blockage of the lumen of the trachea.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
39
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Tracheostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the tracheostomy site.
Ureteric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a ureteral anastomosis (surgical connection of two separate anatomic structures).
Urethral anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a urethral anastomosis (surgical connection of two separate anatomic structures).
Urostomy leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from a urostomy.
Urostomy obstruction
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; dilation or
endoscopic repair or stent
placement indicated
Altered organ function (e.g.,
sepsis or hydronephrosis, or
renal dysfunction); elective
operative intervention indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A finding of blockage of the urostomy.
Urostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the urostomy site.
Urostomy stenosis
 -
Symptomatic but no
hydronephrosis, no sepsis or no
renal dysfunction; dilation or
endoscopic repair or stent
placement indicated
Symptomatic (e.g.,
hydronephrosis, or renal
dysfunction); elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the opening of a urostomy.
Uterine anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a uterine anastomosis (surgical connection of two separate anatomic structures).
Uterine perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the uterine wall.
Vaginal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vaginal anastomosis (surgical connection of two separate anatomic structures).
Vas deferens anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vas deferens anastomosis (surgical connection of two separate anatomic structures).
Vascular access complication
 -
Device dislodgement, blockage,
leak, or malposition; device
replacement indicated
Deep vein or cardiac
thrombosis; intervention
indicated (e.g., anticoagulation,
lysis, filter, invasive procedure)
Embolic event including
pulmonary embolism or life-
threatening thrombus
Death
Definition: A finding of a previously undocumented problem related to the vascular access site.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
40
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Venous injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; repair or revision
indicated; disabling
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to a vein.
Wound complication
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound; local care indicated
Hernia without evidence of
strangulation; fascial
disruption/dehiscence; primary
wound closure or revision by
operative intervention indicated
Hernia with evidence of
strangulation; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of development of a new problem at the site of an existing wound.
Wound dehiscence
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound with local care;
asymptomatic hernia or
symptomatic hernia without
evidence of strangulation
Fascial disruption or dehiscence
without evisceration; primary
wound closure or revision by
operative intervention indicated
Life-threatening consequences;
symptomatic hernia with
evidence of strangulation;
fascial disruption with
evisceration; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of separation of the approximated margins of a surgical wound.
Wrist fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of traumatic injury to the wrist joint in which the continuity of a wrist bone is broken.
Injury, poisoning and procedural
complications - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Investigations 
41
14. Investigations
Investigations
Grade
Adverse Event
1
2
3
4
5
Activated partial thromboplastin
time prolonged
>ULN - 1.5 x ULN
>1.5 - 2.5 x ULN
>2.5 x ULN; hemorrhage
 -
 -
Definition: An abnormal laboratory test result in which the partial thromboplastin time is found to be greater than the control value. As a possible indicator of coagulopathy, a prolonged
partial thromboplastin time (PTT) may occur in a variety of diseases and disorders, both primary and related to treatment.
Alanine aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or SGPT) in the blood specimen.
Alkaline phosphatase increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alkaline phosphatase in a blood specimen.
Aspartate aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST or SGOT) in a blood specimen.
Blood antidiuretic hormone
abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of antidiuretic hormone in the blood specimen.
Blood bilirubin increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an abnormally high level of bilirubin in the blood. Excess bilirubin is associated with jaundice.
Blood corticotrophin decreased
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of corticotrophin in a blood specimen.
Blood gonadotrophin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of gonadotrophin hormone in a blood specimen.
Blood prolactin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of prolactin hormone in a blood specimen.
Carbon monoxide diffusing
capacity decreased
3 - 5 units below LLN; for follow-
up, a decrease of 3 - 5 units
(ml/min/mm Hg) below the
baseline value
6 - 8 units below LLN; for follow-
up, an asymptomatic decrease
of >5 - 8 units (ml/min/mm Hg)
below the baseline value
Asymptomatic decrease  of >8
units drop;  >5 units drop along
with the presence of pulmonary
symptoms (e.g. , >Grade 2
hypoxia or >Grade 2 or higher
dyspnea)
 -
 -
Definition: A finding based on lung function test results that indicate  a decrease in the lung capacity to absorb carbon monoxide.
Cardiac troponin I increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin I in a biological specimen.
Cardiac troponin T increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin T in a biological specimen.
CD4 lymphocytes decreased
<LLN - 500/mm3;  <LLN - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200 - 50/mm3; <0.2 x 0.05 -
10e9 /L
<50/mm3; <0.05 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of CD4 lymphocytes in a blood specimen.
Cholesterol high
>ULN - 300 mg/dL; >ULN - 7.75
mmol/L
>300 - 400 mg/dL; >7.75 - 10.34
mmol/L
>400 - 500 mg/dL; >10.34 -
12.92 mmol/L
>500 mg/dL; >12.92 mmol/L
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of cholesterol in a blood specimen.
CPK increased
>ULN - 2.5 x ULN
>2.5 x ULN - 5 x ULN
>5 x ULN - 10 x ULN
>10 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in levels of creatine phosphokinase in a blood specimen.
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CTCAE 4.03 - June 14, 2010 : Investigations 
42
Investigations
Grade
Adverse Event
1
2
3
4
5
Creatinine increased
>1 - 1.5 x baseline; >ULN - 1.5
x ULN
>1.5 - 3.0 x baseline; >1.5 - 3.0
x ULN
>3.0 baseline; >3.0 - 6.0 x ULN
>6.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate increased levels of creatinine in a biological specimen.
Ejection fraction decreased
 -
Resting ejection fraction (EF) 50
- 40%; 10 - 19% drop from
baseline
Resting ejection fraction (EF) 39
- 20%; >20% drop from baseline
Resting ejection fraction (EF)
<20%
 -
Definition: The percentage computed when the amount of blood ejected during a ventricular contraction of the heart is compared to the amount that was present prior to the
contraction.
Electrocardiogram QT corrected
interval prolonged
QTc 450 - 480 ms
QTc 481 - 500 ms
QTc >= 501 ms on at least two
separate ECGs
QTc >= 501 or >60 ms change
from baseline and Torsade de
pointes or polymorphic
ventricular tachycardia or
signs/symptoms of serious
arrhythmia
 -
Definition: A finding of a cardiac dysrhythmia characterized by an abnormally long corrected QT interval.
Fibrinogen decreased
<1.0 - 0.75 x LLN  or <25%
decrease from baseline
<0.75 - 0.5 x LLN or 25 - <50%
decrease from baseline
<0.5 - 0.25 x LLN or 50 - <75%
decrease from baseline
<0.25 x LLN  or 75% decrease
from baseline or absolute value
<50 mg/dL
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of fibrinogen in a blood specimen.
Forced expiratory volume
decreased
FEV1% (percentages of
observed FEV1 and FVC
related to their respective
predicted values)  99 - 70%
predicted
FEV1 60 - 69%
50 - 59%
<= 49%
 -
Definition: A finding based on test results that indicate a relative decrease in the fraction of the forced vital capacity that is exhaled in a specific number of seconds.
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of the enzyme gamma-glutamyltransferase in the blood specimen. GGT (gamma-
glutamyltransferase ) catalyzes the transfer of a gamma glutamyl group from a gamma glutamyl peptide to another peptide, amino acids or water.
Growth hormone abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of growth hormone in a biological specimen.
Haptoglobin decreased
<LLN
 -
 -
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of haptoglobin in a blood specimen.
Hemoglobin increased
Increase in >0 - 2 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >2 - 4 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >4 gm/dL above
ULN or above baseline if
baseline is above ULN
 -
 -
Definition: A finding based on laboratory test results that indicate increased levels of hemoglobin in a biological specimen.
INR increased
>1 - 1.5 x ULN; >1 - 1.5 times
above baseline if on
anticoagulation
>1.5 - 2.5 x ULN; >1.5 - 2.5
times above baseline if on
anticoagulation
>2.5 x ULN; >2.5 times above
baseline if on anticoagulation
 -
 -
Definition: A finding based on laboratory test results that indicate an increase in the ratio of the patient's prothrombin time to a control sample in the blood.
Lipase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of lipase in a biological specimen.
Lymphocyte count decreased
 <LLN - 800/mm3; <LLN - 0.8 x
10e9 /L
<800 - 500/mm3; <0.8 - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200/mm3; <0.2 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of lymphocytes in a blood specimen.
Lymphocyte count increased
 -
>4000/mm3 - 20,000/mm3
>20,000/mm3
 -
 -
Definition: A finding based on laboratory test results that indicate an abnormal increase in the number of lymphocytes in the blood, effusions or bone marrow.
Neutrophil count decreased
<LLN - 1500/mm3; <LLN - 1.5 x
10e9 /L
<1500 - 1000/mm3; <1.5 - 1.0 x
10e9 /L
<1000 - 500/mm3; <1.0 - 0.5 x
10e9 /L
<500/mm3; <0.5 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of neutrophils in a blood specimen.
Pancreatic enzymes decreased
<LLN and asymptomatic
Increase in stool frequency,
bulk, or odor; steatorrhea
Sequelae of absorption
deficiency
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of pancreatic enzymes in a biological specimen.
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CTCAE 4.03 - June 14, 2010 : Investigations 
43
Investigations
Grade
Adverse Event
1
2
3
4
5
Platelet count decreased
<LLN - 75,000/mm3; <LLN -
75.0 x 10e9 /L
<75,000 - 50,000/mm3; <75.0 -
50.0 x 10e9 /L
<50,000 - 25,000/mm3; <50.0 -
25.0 x 10e9 /L
<25,000/mm3; <25.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.
Serum amylase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the levels of amylase in a serum specimen.
Urine output decreased
 -
 -
Oliguria (<80 ml in 8 hr)
Anuria (<240 ml in 24 hr)
 -
Definition: A finding based on test results that indicate urine production is less relative to previous output.
Vital capacity abnormal
90 - 75% of predicted value
<75 - 50% of predicted value;
limiting instrumental ADL
<50% of predicted value;
limiting self care ADL
 -
 -
Definition: A finding based on pulmonary function test results that indicate an abnormal vital capacity (amount of exhaled after a maximum inhalation) when compared to the predicted
value.
Weight gain
5 - <10% from baseline
10 - <20% from baseline
>=20% from baseline
 -
 -
Definition: A finding characterized by an increase in overall body weight; for pediatrics, greater than the baseline growth curve.
Weight loss
5 to <10% from baseline;
intervention not indicated
10 - <20% from baseline;
nutritional support indicated
>=20% from baseline; tube
feeding or TPN indicated
 -
 -
Definition: A finding characterized by a decrease in overall body weight; for pediatrics, less than the baseline growth curve.
White blood cell decreased
<LLN - 3000/mm3; <LLN - 3.0 x
10e9 /L
<3000 - 2000/mm3; <3.0 - 2.0 x
10e9 /L
<2000 - 1000/mm3; <2.0 - 1.0 x
10e9 /L
<1000/mm3; <1.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in number of white blood cells in a blood specimen.
Investigations - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders 
44
15. Metabolism and nutrition disorders
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Acidosis
pH <normal, but >=7.3
 -
pH <7.3
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high acidity (high hydrogen-ion concentration) of the blood and other body tissues.
Alcohol intolerance
 -
Present
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity to the adverse effects of alcohol, which can include nasal congestion, skin flushes, heart dysrhythmias, nausea,
vomiting, indigestion and headaches.
Alkalosis
pH >normal, but <=7.5
 -
pH >7.5
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high alkalinity (low hydrogen-ion concentration) of the blood and other body tissues.
Anorexia
Loss of appetite without
alteration in eating habits
Oral intake altered without
significant weight loss or
malnutrition; oral nutritional
supplements indicated
Associated with significant
weight loss or malnutrition (e.g.,
inadequate oral caloric and/or
fluid intake); tube feeding or
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a loss of appetite.
Dehydration
Increased oral fluids indicated;
dry mucous membranes;
diminished skin turgor
IV fluids indicated <24 hrs
IV fluids or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Glucose intolerance
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; dietary
modification or oral agent
indicated
Severe symptoms; insulin
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inability to properly metabolize glucose.
Hypercalcemia
Corrected serum calcium of
>ULN - 11.5 mg/dL; >ULN - 2.9
mmol/L;  Ionized calcium  >ULN
- 1.5 mmol/L
Corrected serum calcium of
>11.5 - 12.5 mg/dL; >2.9 - 3.1
mmol/L;  Ionized calcium >1.5 -
1.6 mmol/L; symptomatic
Corrected serum calcium of
>12.5 - 13.5 mg/dL; >3.1 - 3.4
mmol/L;  Ionized calcium  >1.6 -
1.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
>13.5 mg/dL; >3.4 mmol/L;
Ionized calcium  >1.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of calcium (corrected for albumin) in blood.
Hyperglycemia
Fasting glucose value >ULN -
160 mg/dL; Fasting glucose
value >ULN - 8.9 mmol/L
Fasting glucose value >160 -
250 mg/dL; Fasting glucose
value >8.9 - 13.9 mmol/L
>250 - 500 mg/dL; >13.9 - 27.8
mmol/L; hospitalization
indicated
>500 mg/dL; >27.8 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of blood sugar. It is usually an indication of diabetes mellitus or glucose
intolerance.
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L;
hospitalization indicated
>7.0 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of potassium in the blood; associated with kidney failure or sometimes with
the use of diuretic drugs.
Hypermagnesemia
>ULN - 3.0 mg/dL; >ULN - 1.23
mmol/L
 -
>3.0 - 8.0 mg/dL; >1.23 - 3.30
mmol/L
>8.0 mg/dL; >3.30 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of magnesium in the  blood.
Hypernatremia
>ULN - 150 mmol/L
>150 - 155 mmol/L
>155 - 160 mmol/L;
hospitalization indicated
>160 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of sodium in the  blood.
Hypertriglyceridemia
150 mg/dL - 300 mg/dL; 1.71
mmol/L - 3.42 mmol/L
>300 mg/dL - 500 mg/dL;  >3.42
mmol/L - 5.7 mmol/L
>500 mg/dL - 1000 mg/dL;  >5.7
mmol/L - 11.4 mmol/L
>1000 mg/dL; >11.4 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of triglyceride concentration in the blood.
Hyperuricemia
>ULN - 10 mg/dL (0.59 mmol/L)
without physiologic
consequences
 -
>ULN - 10 mg/dL (0.59 mmol/L)
with physiologic consequences
>10 mg/dL; >0.59 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of uric acid.
Hypoalbuminemia
<LLN - 3 g/dL; <LLN - 30 g/L
<3 - 2 g/dL; <30 - 20 g/L
<2 g/dL; <20 g/L
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of albumin in the blood.
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CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders 
45
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Hypocalcemia
Corrected serum calcium of
<LLN - 8.0 mg/dL; <LLN - 2.0
mmol/L; Ionized calcium  <LLN -
1.0 mmol/L
Corrected serum calcium of
<8.0 - 7.0 mg/dL; <2.0 - 1.75
mmol/L; Ionized calcium  <1.0 -
0.9 mmol/L; symptomatic
Corrected serum calcium of
<7.0 - 6.0 mg/dL; <1.75 - 1.5
mmol/L;  Ionized calcium  <0.9 -
0.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
<6.0 mg/dL; <1.5 mmol/L;
Ionized calcium  <0.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of calcium (corrected for albumin) in the  blood.
Hypoglycemia
<LLN - 55 mg/dL; <LLN - 3.0
mmol/L
<55 - 40 mg/dL; <3.0 - 2.2
mmol/L
<40 - 30 mg/dL; <2.2 - 1.7
mmol/L
<30 mg/dL; <1.7 mmol/L; life-
threatening consequences;
seizures
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of glucose in the blood.
Hypokalemia
<LLN - 3.0 mmol/L
<LLN - 3.0 mmol/L;
symptomatic; intervention
indicated
<3.0 - 2.5 mmol/L;
hospitalization indicated
<2.5 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of potassium in the  blood.
Hypomagnesemia
<LLN - 1.2 mg/dL; <LLN - 0.5
mmol/L
<1.2 - 0.9 mg/dL; <0.5 - 0.4
mmol/L
<0.9 - 0.7 mg/dL; <0.4 - 0.3
mmol/L
<0.7 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of magnesium in the  blood.
Hyponatremia
<LLN - 130 mmol/L
 -
<130 - 120 mmol/L
<120 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of sodium in the blood.
Hypophosphatemia
<LLN - 2.5 mg/dL; <LLN - 0.8
mmol/L
<2.5 - 2.0 mg/dL; <0.8 - 0.6
mmol/L
<2.0 - 1.0 mg/dL; <0.6 - 0.3
mmol/L
<1.0 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of phosphates in the  blood.
Iron overload
 -
Moderate symptoms;
intervention not indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by accumulation of iron in the tissues.
Obesity
 -
BMI 25 - 29.9 kg/m2
BMI 30 - 39.9 kg/m2
BMI >=40 kg/m2
 -
Definition: A disorder characterized by having a high amount of body fat.
Tumor lysis syndrome
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by metabolic abnormalities that result from a spontaneous or therapy-related cytolysis of tumor cells.
Metabolism and nutrition
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
46
16. Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g. tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the abdominal wall.
Arthralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a joint.
Arthritis
Mild pain with inflammation,
erythema, or joint swelling
Moderate pain associated with
signs of inflammation,
erythema, or joint swelling;
limiting instrumental ADL
Severe pain associated with
signs of inflammation,
erythema, or joint swelling;
irreversible joint damage;
disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation involving a joint.
Avascular necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by necrotic changes in the bone tissue due to interruption of blood supply. Most often affecting the epiphysis of the long bones, the necrotic
changes result in the collapse and the destruction of the bone structure.
Back pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the back region.
Bone pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the bones.
Buttock pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the buttocks.
Chest wall pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the chest wall region.
Exostosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by non-neoplastic overgrowth of bone.
Fibrosis deep connective tissue
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the deep connective tissues.
Flank pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation on the lateral side of the body in the region below the ribs and above the hip.
Generalized muscle weakness
Symptomatic; weakness
perceived by patient but not
evident on physical exam
Symptomatic; weakness evident
on physical exam; weakness
limiting instrumental ADL
Weakness limiting self care
ADL; disabling
 -
 -
Definition: A disorder characterized by a reduction in the strength of muscles in multiple anatomic sites.
Growth suppression
Reduction in growth velocity by
10 - 29% ideally measured over
the period of a year
Reduction in growth velocity by
30 - 49% ideally measured over
the period of a year or 0 - 49%
reduction in growth from the
baseline growth curve
Reduction in growth velocity of
>=50% ideally measured over
the period of a year
 -
 -
Definition: A disorder characterized by of stature that is smaller than normal as expected for age.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
47
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Head soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the head.
Joint effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated; disabling
 -
 -
Definition: A disorder characterized by excessive fluid in a joint, usually as a result of joint inflammation.
Joint range of motion decreased <=25% loss of ROM (range of
motion); decreased ROM
limiting athletic activity
>25 - 50% decrease in ROM;
limiting instrumental ADL
>50% decrease in ROM; limiting
self care ADL; disabling
 -
 -
Definition: A disorder characterized by a decrease in joint flexibility of any joint.
Joint range of motion decreased
cervical spine
Mild restriction of rotation or
flexion between 60 - 70 degrees
Rotation <60 degrees to right or
left; <60 degrees of flexion
Ankylosed/fused over multiple
segments with no C-spine
rotation
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a cervical spine joint.
Joint range of motion decreased
lumbar spine
Stiffness; difficulty bending to
the floor to pick up a very light
object but able to do athletic
activity
Pain with range of motion
(ROM) in lumbar spine; requires
a reaching aid to pick up a very
light object from the floor
<50% lumbar spine flexion;
associated with symptoms of
ankylosis or fused over multiple
segments with no L-spine
flexion (e.g., unable to reach to
floor to pick up a very light
object)
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a lumbar spine joint.
Kyphosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the thoracic portion of the spine.
Lordosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the lumbar portion of the spine.
Muscle weakness left-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the left side of the body.
Muscle weakness lower limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the lower limb muscles.
Muscle weakness right-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the right side of the body.
Muscle weakness trunk
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the trunk muscles.
Muscle weakness upper limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the upper limb muscles.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
48
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Musculoskeletal deformity
Cosmetically and functionally
insignificant hypoplasia
Deformity, hypoplasia, or
asymmetry able to be
remediated by prosthesis (e.g.,
shoe insert) or covered by
clothing
Significant deformity,
hypoplasia, or asymmetry,
unable to be remediated by
prosthesis or covered by
clothing; disabling
 -
 -
Definition: A disorder characterized by of a malformation of the musculoskeletal system.
Myalgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation originating from a muscle or group of muscles.
Myositis
Mild pain
Moderate pain associated with
weakness; pain limiting
instrumental ADL
Pain associated with severe
weakness; limiting self care
ADL
 -
 -
Definition: A disorder characterized by inflammation involving the skeletal muscles.
Neck pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the neck area.
Neck soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the neck.
Osteonecrosis of jaw
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the bone of the mandible.
Osteoporosis
Radiologic evidence of
osteoporosis or Bone Mineral
Density (BMD) t-score -1 to -2.5
(osteopenia); no loss of height
or intervention indicated
BMD t-score <-2.5; loss of
height <2 cm; anti-osteoporotic
therapy indicated; limiting
instrumental ADL
Loss of height >=2 cm;
hospitalization indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by reduced bone mass, with a decrease in cortical thickness and in the number and size of the trabeculae of cancellous bone (but normal chemical
composition), resulting in increased fracture incidence.
Pain in extremity
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the upper or lower extremities.
Pelvic soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the pelvis.
Scoliosis
<20 degrees; clinically
undetectable
>20 - 45 degrees; visible by
forward flexion; limiting
instrumental ADL
>45 degrees; scapular
prominence in forward flexion;
operative intervention indicated;
limiting self care ADL; disabling
 -
 -
Definition: A disorder characterized by a malformed, lateral curvature of the spine.
Soft tissue necrosis lower limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the lower extremity.
Soft tissue necrosis upper limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the upper extremity.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
49
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Superficial soft tissue fibrosis
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the superficial soft tissues.
Trismus
Decreased ROM (range of
motion) without impaired eating
Decreased ROM requiring small
bites, soft foods or purees
Decreased ROM with inability to
adequately aliment or hydrate
orally
 -
 -
Definition: A disorder characterized by lack of ability to open the mouth fully due to a decrease in the range of motion of the muscles of mastication.
Unequal limb length
Mild length discrepancy <2 cm
Moderate length discrepancy 2 -
5 cm; shoe lift indicated; limiting
instrumental ADL
Severe length discrepancy >5
cm; limiting self care ADL;
disabling; operative intervention
indicated
 -
 -
Definition: A disorder characterized by of a discrepancy between the lengths of the lower or upper extremities.
Musculoskeletal and connective
tissue disorder -  Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 217 of 364


CTCAE 4.03 - June 14, 2010 : Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
50
17. Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Grade
Adverse Event
1
2
3
4
5
Leukemia secondary to
oncology chemotherapy
 -
 -
 -
Present
Death
Definition: A disorder characterized by leukemia arising as a result of the mutagenic effect of chemotherapy agents.
Myelodysplastic syndrome
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by insufficiently healthy hematapoietic cell production by the bone marrow.
Treatment related secondary
malignancy
 -
 -
Non life-threatening secondary
malignancy
Acute life-threatening secondary
malignancy; blast crisis in
leukemia
Death
Definition: A disorder characterized by development of a malignancy most probably as a result of treatment for a previously existing malignancy.
Tumor pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort from a neoplasm that may be pressing on a nerve, blocking blood vessels, inflamed or fractured from metastasis.
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps) - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
51
18. Nervous system disorders
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Abducens nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the abducens nerve (sixth cranial nerve).
Accessory nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the accessory nerve (eleventh cranial nerve).
Acoustic nerve disorder NOS
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the acoustic nerve (eighth cranial nerve).
Akathisia
Mild restlessness or increased
motor activity
Moderate restlessness or
increased motor activity; limiting
instrumental ADL
Severe restlessness or
increased motor activity; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of inner restlessness and inability to stay still; this is a side effect of some psychotropic drugs.
Amnesia
Mild; transient memory loss
Moderate; short term memory
loss; limiting instrumental ADL
Severe; long term memory loss;
limiting self care ADL
 -
 -
Definition: A disorder characterized by systematic and extensive loss of memory.
Aphonia
 -
 -
Voicelessness; unable to speak
 -
 -
Definition: A disorder characterized by the inability to speak. It may result from injuries to the vocal cords or may be functional (psychogenic).
Arachnoiditis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the arachnoid membrane and adjacent subarachnoid space.
Ataxia
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; mechanical
assistance indicated
 -
 -
Definition: A disorder characterized by lack of coordination of muscle movements resulting in the impairment or inability to perform voluntary activities.
Brachial plexopathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by regional paresthesia of the brachial plexus, marked discomfort and muscle weakness, and limited movement in the arm or hand.
Central nervous system
necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
corticosteroids indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the brain and/or spinal cord.
Cerebrospinal fluid leakage
Post-craniotomy: asymptomatic;
Post-lumbar puncture: transient
headache; postural care
indicated
Post-craniotomy: moderate
symptoms; medical intervention
indicated; Post-lumbar
puncture: persistent moderate
symptoms; blood patch
indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by loss of cerebrospinal fluid into the surrounding tissues.
Cognitive disturbance
Mild cognitive disability; not
interfering with work/school/life
performance; specialized
educational services/devices
not indicated
Moderate cognitive disability;
interfering with work/school/life
performance but capable of
independent living; specialized
resources on part time basis
indicated
Severe cognitive disability;
significant impairment of
work/school/life performance
 -
 -
Definition: A disorder characterized by a conspicuous change in cognitive function.
Concentration impairment
Mild inattention or decreased
level of concentration
Moderate impairment in
attention or decreased level of
concentration; limiting
instrumental ADL
Severe impairment in attention
or decreased level of
concentration; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a deterioration in the ability to concentrate.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
52
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Depressed level of
consciousness
Decreased level of alertness
Sedation; slow response to
stimuli; limiting instrumental
ADL
Difficult to arouse
Life-threatening consequences
Death
Definition: A disorder characterized by a decrease in ability to perceive and respond.
Dizziness
Mild unsteadiness or sensation
of movement
Moderate unsteadiness or
sensation of movement; limiting
instrumental ADL
Severe unsteadiness or
sensation of movement; limiting
self care ADL
 -
 -
Definition: A disorder characterized by a disturbing sensation of lightheadedness, unsteadiness, giddiness, spinning or rocking.
Dysarthria
Mild slurred speech
Moderate impairment of
articulation or slurred speech
Severe impairment of
articulation or slurred speech
 -
 -
Definition: A disorder characterized by slow and slurred speech resulting from an inability to coordinate the muscles used in speech.
Dysesthesia
Mild sensory alteration
Moderate sensory alteration;
limiting instrumental ADL
Severe sensory alteration;
limiting self care ADL
 -
 -
Definition: A disorder characterized by distortion of sensory perception, resulting in an abnormal and unpleasant sensation.
Dysgeusia
Altered taste but no change in
diet
Altered taste with change in diet
(e.g., oral supplements);
noxious or unpleasant taste;
loss of taste
 -
 -
 -
Definition: A disorder characterized by abnormal sensual experience with the taste of foodstuffs; it can be related to a decrease in the sense of smell.
Dysphasia
Awareness of receptive or
expressive characteristics; not
impairing ability to communicate
Moderate receptive or
expressive characteristics;
impairing ability to communicate
spontaneously
Severe receptive or expressive
characteristics; impairing ability
to read, write or communicate
intelligibly
 -
 -
Definition: A disorder characterized by impairment of verbal communication skills, often resulting from brain damage.
Edema cerebral
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the brain.
Encephalopathy
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a pathologic process involving the brain.
Extrapyramidal disorder
Mild involuntary movements
Moderate involuntary
movements; limiting
instrumental ADL
Severe involuntary movements
or torticollis; limiting self care
ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal, repetitive, involuntary muscle movements, frenzied speech and extreme restlessness.
Facial muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a reduction in the strength of the facial muscles.
Facial nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the facial nerve (seventh cranial nerve).
Glossopharyngeal nerve
disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the glossopharyngeal nerve (ninth cranial nerve).
Headache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in various parts of the head, not confined to the area of distribution of any nerve.
Hydrocephalus
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
intervention not indicated
Severe symptoms or
neurological deficit; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal increase of cerebrospinal fluid in the ventricles of the brain.
Hypersomnia
Mild increased need for sleep
Moderate increased need for
sleep
Severe increased need for
sleep
 -
 -
Definition: A disorder characterized by characterized by excessive sleepiness during the daytime.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
53
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Hypoglossal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the hypoglossal nerve (twelfth cranial nerve).
Intracranial hemorrhage
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Ventriculostomy, ICP
monitoring, intraventricular
thrombolysis, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cranium.
Ischemia cerebrovascular
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
 -
 -
 -
Definition: A disorder characterized by a decrease or absence of blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurological
damage.
IVth nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trochlear nerve (fourth cranial nerve).
Lethargy
Mild symptoms; reduced
alertness and awareness
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a decrease in consciousness characterized by mental and physical inertness.
Leukoencephalopathy
Asymptomatic; small focal
T2/FLAIR hyperintensities;
involving periventricular white
matter or <1/3 of susceptible
areas of cerebrum +/- mild
increase in subarachnoid space
(SAS) and/or mild
ventriculomegaly
Moderate symptoms; focal
T2/FLAIR hyperintensities,
involving periventricular white
matter extending into centrum
semiovale or involving 1/3 to 2/3
of susceptible areas of
cerebrum +/- moderate increase
in SAS and/or moderate
ventriculomegaly
Severe symptoms; extensive
T2/FLAIR hyperintensities,
involving periventricular white
matter involving 2/3 or more of
susceptible areas of cerebrum
+/- moderate to severe increase
in SAS and/or moderate to
severe ventriculomegaly
Life-threatening consequences;
extensive T2/FLAIR
hyperintensities, involving
periventricular white matter
involving most of susceptible
areas of cerebrum +/- moderate
to severe increase in SAS
and/or moderate to severe
ventriculomegaly
Death
Definition: A disorder characterized by diffuse reactive astrocytosis with multiple areas of necrotic foci without inflammation.
Memory impairment
Mild memory impairment
Moderate memory impairment;
limiting instrumental ADL
Severe memory impairment;
limiting self care ADL
 -
 -
Definition: A disorder characterized by a deterioration in memory function.
Meningismus
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by neck stiffness, headache, and photophobia resulting from irritation of the cerebral meninges.
Movements involuntary
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by uncontrolled and purposeless movements.
Myelitis
Asymptomatic; mild signs (e.g.,
Babinski's reflex or Lhermitte's
sign)
Moderate weakness or sensory
loss; limiting instrumental ADL
Severe weakness or sensory
loss; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the spinal cord. Symptoms include weakness, paresthesia, sensory loss, marked discomfort and incontinence.
Neuralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by intense painful sensation along a nerve or group of nerves.
Nystagmus
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involuntary movements of the eyeballs.
Oculomotor nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the oculomotor nerve (third cranial nerve).
Olfactory nerve disorder
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the olfactory nerve (first cranial nerve).
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
54
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Paresthesia
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by functional disturbances of sensory neurons resulting in abnormal cutaneous sensations of tingling, numbness, pressure, cold, and warmth that
are experienced in the absence of a stimulus.
Peripheral motor neuropathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; assistive device
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral motor nerves.
Peripheral sensory neuropathy
Asymptomatic; loss of deep
tendon reflexes or paresthesia
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral sensory nerves.
Phantom pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort related to a limb or an organ that is removed from or is not physically part of the body.
Presyncope
 -
Present (e.g., near fainting)
 -
 -
 -
Definition: A disorder characterized by an episode of lightheadedness and dizziness which may precede an episode of syncope.
Pyramidal tract syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by dysfunction of the corticospinal (pyramidal) tracts of the spinal cord. Symptoms include  an increase in the muscle tone in the lower extremities,
hyperreflexia, positive Babinski and a decrease in fine motor coordination.
Radiculitis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL; medical
intervention indicated
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving a nerve root. Patients experience marked discomfort radiating along a nerve path because of spinal pressure on the
connecting nerve root.
Recurrent laryngeal nerve palsy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
Severe symptoms; medical
intervention indicated (e.g.,
thyroplasty, vocal cord injection)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by paralysis of the recurrent laryngeal nerve.
Reversible posterior
leukoencephalopathy syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; abnormal
imaging studies; limiting
instrumental ADL
Severe symptoms; very
abnormal imaging studies;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by headaches, mental status changes, visual disturbances, and seizures associated with imaging findings of posterior leukoencephalopathy. It has
been observed in association with hypertensive encephalopathy, eclampsia, and immunosuppressive and cytotoxic drug treatment. It is an acute or subacute reversible condition.
Seizure
Brief partial seizure; no loss of
consciousness
Brief generalized seizure
Multiple seizures despite
medical intervention
Life-threatening; prolonged
repetitive seizures
Death
Definition: A disorder characterized by a sudden, involuntary skeletal muscular contractions of cerebral or brain stem origin.
Sinus pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort in the face, between the eyes, or upper teeth originating from the sinuses.
Somnolence
Mild but more than usual
drowsiness or sleepiness
Moderate sedation; limiting
instrumental ADL
Obtundation or stupor
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by characterized by excessive sleepiness and drowsiness.
Spasticity
Mild or slight increase in muscle
tone
Moderate increase in muscle
tone and increase in resistance
through range of motion
Severe increase in muscle tone
and increase in resistance
through range of motion
Life-threatening; unable to move
active or passive range of
motion
Death
Definition: A disorder characterized by increased involuntary muscle tone that affects the regions interfering with voluntary movement. It results in gait, movement, and speech
disturbances.
Stroke
Asymptomatic or mild
neurologic deficit; radiographic
findings only
Moderate neurologic deficit
Severe neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden loss of sensory function due to an intracranial vascular event.
Syncope
 -
 -
Fainting; orthostatic collapse
 -
 -
Definition: A disorder characterized by spontaneous loss of consciousness caused by insufficient blood supply to the brain.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
55
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Transient ischemic attacks
Mild neurologic deficit with or
without imaging confirmation
Moderate neurologic deficit with
or without imaging confirmation
 -
 -
 -
Definition: A disorder characterized by a brief attack (less than 24 hours) of cerebral dysfunction of vascular origin, with no persistent neurological deficit.
Tremor
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by the uncontrolled shaking movement of the whole body or individual parts.
Trigeminal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trigeminal nerve (fifth cranial nerve).
Vagus nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the vagus nerve (tenth cranial nerve).
Vasovagal reaction
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden drop of the blood pressure, bradycardia, and peripheral vasodilation that may lead to loss of consciousness. It results from an
increase in the stimulation of the vagus nerve.
Nervous system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 223 of 364


CTCAE 4.03 - June 14, 2010 : Pregnancy, puerperium and perinatal conditions 
56
19. Pregnancy, puerperium and perinatal conditions
Pregnancy, puerperium and perinatal conditions
Grade
Adverse Event
1
2
3
4
5
Fetal death
 -
 -
 -
 -
Fetal loss at
any
gestational
age
Definition: A disorder characterized by death in utero; failure of the product of conception to show evidence of respiration, heartbeat, or definite movement of a voluntary muscle after
expulsion from the uterus, without possibility of resuscitation.
Fetal growth retardation
 -
<10% percentile of weight for
gestational age
<5% percentile of weight for
gestational age
<1% percentile of weight for
gestational age
 -
Definition: A disorder characterized by inhibition of fetal growth resulting in the inability of the fetus to achieve its potential weight.
Premature delivery
Delivery of a liveborn infant at
>34 to 37 weeks gestation
Delivery of a liveborn infant at
>28 to 34 weeks gestation
Delivery of a liveborn infant at
24 to 28 weeks gestation
Delivery of a liveborn infant at
24 weeks of gestation or less
 -
Definition: A disorder characterized by delivery of a viable infant before the normal end of gestation. Typically, viability is achievable between the twentieth and thirty-seventh week of
gestation.
Unintended pregnancy
 -
 -
Unintended pregnancy
 -
 -
Definition: A disorder characterized by an unexpected pregnancy at the time of conception.
Pregnancy, puerperium and
perinatal conditions - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 224 of 364


CTCAE 4.03 - June 14, 2010 : Psychiatric disorders 
57
20. Psychiatric disorders
Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Agitation
Mild mood alteration
Moderate mood alteration
Severe agitation; hospitalization
not indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a state of restlessness associated with unpleasant feelings of irritability and tension.
Anorgasmia
Inability to achieve orgasm not
adversely affecting relationship
Inability to achieve orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by an inability to achieve orgasm.
Anxiety
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization not
indicated
Life-threatening; hospitalization
indicated
Death
Definition: A disorder characterized by apprehension of danger and dread accompanied by restlessness, tension, tachycardia, and dyspnea unattached to a clearly identifiable
stimulus.
Confusion
Mild disorientation
Moderate disorientation; limiting
instrumental ADL
Severe disorientation; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a lack of clear and orderly thought and behavior.
Delayed orgasm
Delay in achieving orgasm not
adversely affecting relationship
Delay in achieving orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by sexual dysfunction characterized by a delay in climax.
Delirium
Mild acute confusional state
Moderate and acute confusional
state; limiting instrumental ADL
Severe and acute confusional
state; limiting self care ADL;
hospitalization indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by the acute and sudden development of confusion, illusions, movement changes, inattentiveness, agitation, and hallucinations. Usually, it is a
reversible condition.
Delusions
 -
Moderate delusional symptoms
Severe delusional symptoms;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by false personal beliefs held contrary to reality, despite contradictory evidence and common sense.
Depression
Mild depressive symptoms
Moderate depressive
symptoms; limiting instrumental
ADL
Severe depressive symptoms;
limiting self care ADL;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by melancholic feelings of grief or unhappiness.
Euphoria
Mild mood elevation
Moderate mood elevation
Severe mood elevation (e.g.,
hypomania)
 -
 -
Definition: A disorder characterized by an exaggerated feeling of well-being which is disproportionate to events and stimuli.
Hallucinations
Mild hallucinations (e.g.,
perceptual distortions)
Moderate hallucinations
Severe hallucinations;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by a false sensory perception in the absence of an external stimulus.
Insomnia
Mild difficulty falling asleep,
staying asleep or waking up
early
Moderate difficulty falling
asleep, staying asleep or
waking up early
Severe difficulty in falling
asleep, staying asleep or
waking up early
 -
 -
Definition: A disorder characterized by difficulty in falling asleep and/or remaining asleep.
Libido decreased
Decrease in sexual interest not
adversely affecting relationship
Decrease in sexual interest
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by a decrease in sexual desire.
Libido increased
Mild increase in sexual interest
not adversely affecting
relationship
Moderate increase in sexual
interest adversely affecting
relationship
Severe increase in sexual
interest leading to dangerous
behavior
 -
 -
Definition: A disorder characterized by an increase in sexual desire.
Mania
Mild manic symptoms (e.g.,
elevated mood, rapid thoughts,
rapid speech, decreased need
for sleep)
Moderate manic symptoms
(e.g., relationship and work
difficulties; poor hygiene)
Severe manic symptoms (e.g.,
hypomania; major sexual or
financial indiscretions);
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behavior and elevation of mood.
Personality change
Mild personality change
Moderate personality change
Severe personality change;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
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CTCAE 4.03 - June 14, 2010 : Psychiatric disorders 
58
Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a conspicuous change in a person's behavior and thinking.
Psychosis
Mild psychotic symptoms
Moderate psychotic symptoms
(e.g., disorganized speech;
impaired reality testing)
Severe psychotic symptoms
(e.g., paranoid; extreme
disorganization); hospitalization
not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by personality change, impaired functioning, and loss of touch with reality. It may be a manifestation of schizophrenia, bipolar disorder or brain
tumor.
Restlessness
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an inability to rest, relax or be still.
Suicidal ideation
Increased thoughts of death but
no wish to kill oneself
Suicidal ideation with no specific
plan or intent
Specific plan to commit suicide
without serious intent to die
which may not require
hospitalization
Specific plan to commit suicide
with serious intent to die which
requires hospitalization
 -
Definition: A disorder characterized by thoughts of taking one's own life.
Suicide attempt
 -
 -
Suicide attempt or gesture
without intent to die which may
not require hospitalization
Suicide attempt with intent to
die which requires
hospitalization
Death
Definition: A disorder characterized by self-inflicted harm in an attempt to end one's own life.
Psychiatric disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; disabling;  limiting
self care ADL
Life-threatening consequences;
hospitalization or urgent
intervention indicated
Death
Page 226 of 364


CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders 
59
21. Renal and urinary disorders
Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Acute kidney injury
Creatinine level increase of >0.3
mg/dL; creatinine 1.5 - 2.0 x
above baseline
Creatinine 2 - 3 x above
baseline
Creatinine >3 x baseline or >4.0
mg/dL; hospitalization indicated
Life-threatening consequences;
dialysis indicated
Death
Definition: A disorder characterized by the acute loss of renal function and is traditionally classified as pre-renal (low blood flow into kidney), renal (kidney damage) and post-renal
causes (ureteral or bladder outflow obstruction).
Bladder perforation
 -
Extraperitoneal perforation,
indwelling catheter indicated
Intraperitoneal perforation;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by a rupture in the bladder wall.
Bladder spasm
Intervention not indicated
Antispasmodics indicated
Hospitalization indicated
 -
 -
Definition: A disorder characterized by a sudden and involuntary contraction of the bladder wall.
Chronic kidney disease
eGFR (estimated Glomerular
Filtration Rate) or CrCl
(creatinine clearance) <LLN - 60
ml/min/1.73 m2 or proteinuria
2+ present; urine
protein/creatinine >0.5
eGFR or CrCl 59 - 30
ml/min/1.73 m2
eGFR or CrCl 29 - 15
ml/min/1.73 m2
eGFR or CrCl <15 ml/min/1.73
m2; dialysis or renal transplant
indicated
Death
Definition: A disorder characterized by gradual and usually permanent loss of kidney function resulting in renal failure.
Cystitis noninfective
Microscopic hematuria; minimal
increase in frequency, urgency,
dysuria, or nocturia; new onset
of incontinence
Moderate hematuria; moderate
increase in frequency, urgency,
dysuria, nocturia or
incontinence; urinary catheter
placement or bladder irrigation
indicated; limiting instrumental
ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by inflammation of the bladder which is not caused by an infection of the urinary tract.
Hematuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; urinary catheter
or bladder irrigation indicated;
limiting instrumental ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated; limiting
self care ADL
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate blood in the urine.
Hemoglobinuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of free hemoglobin in the urine.
Proteinuria
1+ proteinuria; urinary protein
<1.0 g/24 hrs
Adults: 2+ proteinuria; urinary
protein 1.0 - 3.4 g/24 hrs;
Pediatric: urine P/C
(Protein/Creatinine) ratio 0.5 -
1.9
Adults: urinary protein >=3.5
g/24 hrs;
Pediatric: urine P/C >1.9
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of excessive protein in the urine. It is predominantly albumin, but also globulin.
Renal calculi
Asymptomatic or mild
symptoms; occasional use of
nonprescription analgesics
indicated
Symptomatic; oral antiemetics
indicated; around the clock
nonprescription analgesics or
any oral narcotic analgesics
indicated
Hospitalization indicated; IV
intervention (e.g., analgesics,
antiemetics); elective
endoscopic or radiologic
intervention indicated
Life-threatening consequences;
urgent radiologic, endoscopic or
operative intervention indicated
Death
Definition: A disorder characterized by the formation of crystals in the pelvis of the kidney.
Renal colic
Mild pain not interfering with
activity; nonprescription
medication indicated
Moderate pain; limiting
instrumental ADL; prescription
medication indicated
Hospitalization indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by paroxysmal and severe flank marked discomfort radiating to the inguinal area. Often, the cause is the passage of kidney stones.
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CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders 
60
Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Renal hemorrhage
Mild symptoms; intervention not
indicated
Analgesics and hematocrit
monitoring indicated
Transfusion, radiation, or
hospitalization indicated;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by bleeding from the kidney.
Urinary fistula
 -
Noninvasive intervention
indicated; urinary or suprapubic
catheter placement indicated
Limiting self care ADL; elective
radiologic, endoscopic or
operative intervention indicated;
permanent urinary diversion
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the urinary system and another organ or anatomic site.
Urinary frequency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by urination at short intervals.
Urinary incontinence
Occasional (e.g., with coughing,
sneezing, etc.), pads not
indicated
Spontaneous; pads indicated;
limiting instrumental ADL
Intervention indicated (e.g.,
clamp, collagen injections);
operative intervention indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by inability to control the flow of urine from the bladder.
Urinary retention
Urinary, suprapubic or
intermittent catheter placement
not indicated; able to void with
some residual
Placement of urinary,
suprapubic or intermittent
catheter placement indicated;
medication indicated
Elective operative or radiologic
intervention indicated;
substantial loss of affected
kidney function or mass
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by accumulation of urine within the bladder because of the inability to urinate.
Urinary tract obstruction
Asymptomatic; clinical or
diagnostic observations only
Symptomatic but no
hydronephrosis, sepsis or renal
dysfunction; urethral dilation,
urinary or suprapubic catheter
indicated
Symptomatic and altered organ
function (e.g., hydronephrosis,
or renal dysfunction); elective
radiologic, endoscopic or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of contents of the urinary tract.
Urinary tract pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the urinary tract.
Urinary urgency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by a sudden compelling urge to urinate.
Urine discoloration
Present
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the urine.
Renal and urinary disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Page 228 of 364


CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
61
22. Reproductive system and breast disorders
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Azoospermia
 -
 -
Absence of sperm in ejaculate
 -
 -
Definition: A disorder characterized by laboratory test results that indicate complete absence of spermatozoa in the semen.
Breast atrophy
Minimal asymmetry; minimal
atrophy
Moderate asymmetry; moderate
atrophy
Asymmetry >1/3 of breast
volume; severe atrophy
 -
 -
Definition: A disorder characterized by underdevelopment of the breast.
Breast pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the breast region.
Dysmenorrhea
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by abnormally painful abdominal cramps during menses.
Dyspareunia
Mild discomfort or pain
associated with vaginal
penetration; discomfort relieved
with use of vaginal lubricants or
estrogen
Moderate discomfort or pain
associated with vaginal
penetration; discomfort or pain
partially relieved with use of
vaginal lubricants or estrogen
Severe discomfort or pain
associated with vaginal
penetration; discomfort or pain
unrelieved by vaginal lubricants
or estrogen
 -
 -
Definition: A disorder characterized by painful or difficult coitus.
Ejaculation disorder
Diminished ejaculation
Anejaculation or retrograde
ejaculation
 -
 -
 -
Definition: A disorder characterized by problems related to ejaculation. This category includes premature, delayed, retrograde and painful ejaculation.
Erectile dysfunction
Decrease in erectile function
(frequency or rigidity of
erections) but intervention not
indicated (e.g., medication or
use of mechanical device,
penile pump)
Decrease in erectile function
(frequency/rigidity of erections),
erectile intervention indicated,
(e.g., medication or mechanical
devices such as penile pump)
Decrease in erectile function
(frequency/rigidity of erections)
but erectile intervention not
helpful (e.g., medication or
mechanical devices such as
penile pump); placement of a
permanent penile prosthesis
indicated (not previously
present)
 -
 -
Definition: A disorder characterized by the persistent or recurrent inability to achieve or to maintain an erection during sexual activity.
Fallopian tube obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents in the fallopian tube.
Fallopian tube stenosis
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A disorder characterized by a narrowing of the fallopian tube lumen.
Female genital tract fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between a female reproductive system organ and another organ or anatomic site.
Feminization acquired
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the development of secondary female sex characteristics in males due to extrinsic factors.
Genital edema
Mild swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour
Lymphorrhea; gross deviation
from normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the genitals.
Gynecomastia
Asymptomatic breast
enlargement
Symptomatic (e.g., pain or
psychosocial impact)
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by excessive development of the breasts in males.
Hematosalpinx
Minimal bleeding identified on
imaging study or laparoscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
62
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by the presence of blood in a fallopian tube.
Irregular menstruation
Intermittent menses with
skipped menses for no more
than 1 to 3 months
Intermittent menses with
skipped menses for more than 4
to 6 months
Persistent amenorrhea for more
than 6 months
 -
 -
Definition: A disorder characterized by irregular cycle or duration of menses.
Lactation disorder
Mild changes in lactation, not
significantly affecting production
or expression of breast milk
Changes in lactation,
significantly affecting breast
production or expression of
breast milk
 -
 -
 -
Definition: A disorder characterized by disturbances of milk secretion. It is not necessarily related to pregnancy that is observed in females and can be observed in males.
Menorrhagia
Mild; iron supplements indicated Moderate symptoms; medical
intervention indicated (e.g.,
hormones)
Severe; transfusion indicated;
surgical intervention indicated
(e.g., hysterectomy)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormally heavy vaginal bleeding during menses.
Nipple deformity
Asymptomatic; asymmetry with
slight retraction and/or
thickening of the nipple areolar
complex
Symptomatic; asymmetry of
nipple areolar complex with
moderate retraction and/or
thickening of the nipple areolar
complex
 -
 -
 -
Definition: A disorder characterized by a malformation of the nipple.
Oligospermia
Sperm concentration >48
million/mL or motility >68%
Sperm concentration 13 - 48
million/mL or motility 32 - 68%
Sperm concentration <13
million/mL or motility <32%
 -
 -
Definition: A disorder characterized by a decrease in the number of spermatozoa in the semen.
Ovarian hemorrhage
Minimal bleeding identified on
imaging study or laproscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic  intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the ovary.
Ovarian rupture
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by tearing or disruption of the ovarian tissue.
Ovulation pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in one side of the abdomen between menstrual cycles, around the time of the discharge of the ovum from the
ovarian follicle.
Pelvic floor muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic, not interfering
with bladder, bowel, or vaginal
function; limiting instrumental
ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a reduction in the strength of the muscles of the pelvic floor.
Pelvic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pelvis.
Penile pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the penis.
Perineal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the area between the genital organs and the anus.
Premature menopause
 -
 -
Present
 -
 -
Definition: A disorder characterized by ovarian failure before the age of 40. Symptoms include hot flashes, night sweats, mood swings and a decrease in sex drive.
Prostatic hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
63
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by bleeding from the prostate gland.
Prostatic obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by compression of the urethra secondary to enlargement of the prostate gland. This results in voiding difficulties (straining to void, slow urine
stream, and incomplete emptying of the bladder).
Prostatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the prostate gland.
Scrotal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the scrotal area.
Spermatic cord hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the spermatic cord.
Spermatic cord obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents of the spermatic cord.
Testicular disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but not interfering
with urination or sexual
activities; intervention not
indicated; limiting instrumental
ADL
Severe symptoms; interfering
with urination or sexual function;
limiting self care ADL;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the testis.
Testicular hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the testis.
Testicular pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the testis.
Uterine fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the uterus and another organ or anatomic site.
Uterine hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the uterus.
Uterine obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the uterine outlet.
Uterine pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the uterus.
Vaginal discharge
Mild vaginal discharge (greater
than baseline for patient)
Moderate to heavy vaginal
discharge; use of perineal pad
or tampon indicated
 -
 -
 -
Definition: A disorder characterized by vaginal secretions. Mucus produced by the cervical glands is discharged from the vagina naturally, especially during the childbearing years.
Vaginal dryness
Mild vaginal dryness not
interfering with sexual function
Moderate vaginal dryness
interfering with sexual function
or causing frequent discomfort
Severe vaginal dryness
resulting in dyspareunia or
severe discomfort
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of itching and burning in the vagina.
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
64
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Vaginal fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the vagina and another organ or anatomic site.
Vaginal hemorrhage
Minimal bleeding identified on
clinical exam or imaging study;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the vagina.
Vaginal inflammation
Mild discomfort or pain, edema,
or redness
Moderate discomfort or pain,
edema, or redness; limiting
instrumental ADL
Severe discomfort or pain,
edema, or redness; limiting self
care ADL; small areas of
mucosal ulceration
Widespread areas of mucosal
ulceration; life-threatening
consequences; urgent
intervention indicated
Death
Definition: A disorder characterized by inflammation involving the vagina. Symptoms may include redness, edema, marked discomfort and an increase in vaginal discharge.
Vaginal obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of vaginal canal.
Vaginal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the vagina.
Vaginal perforation
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the vaginal wall.
Vaginal stricture
Asymptomatic; mild vaginal
shortening or narrowing
Vaginal narrowing and/or
shortening not interfering with
physical examination
Vaginal narrowing and/or
shortening interfering with the
use of tampons, sexual activity
or physical examination
 -
Death
Definition: A disorder characterized by a narrowing of the vaginal canal.
Vaginismus
Mild discomfort or pain
associated with vaginal
spasm/tightening; no impact
upon sexual function or physical
examination
Moderate discomfort or pain
associated with vaginal
spasm/tightening; disruption in
sexual function and physical
examination
Severe discomfort or pain
associated with vaginal
spasm/tightening; unable to
tolerate vaginal penetration or
physical examination
 -
 -
Definition: A disorder characterized by involuntary spasms of the pelvic floor muscles, resulting in pathologic tightness of the vaginal wall during penetration such as during sexual
intercourse.
Reproductive system and breast
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
65
23. Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Adult respiratory distress
syndrome
 -
 -
Present with radiologic findings;
intubation not indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by progressive and life-threatening pulmonary distress in the absence of an underlying pulmonary condition, usually following major trauma or
surgery.
Allergic rhinitis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an inflammation of the nasal mucous membranes caused by an IgE-mediated response to external allergens. The inflammation may also
involve the mucous membranes of the sinuses, eyes, middle ear, and pharynx. Symptoms include sneezing, nasal congestion, rhinorrhea and itching.
Apnea
 -
 -
Present; medical intervention
indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing.
Aspiration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Altered eating habits; coughing
or choking episodes after eating
or swallowing; medical
intervention indicated (e.g.,
suction or oxygen)
Dyspnea and pneumonia
symptoms (e.g., aspiration
pneumonia); hospitalization
indicated; unable to aliment
orally
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by inhalation of solids or liquids into the lungs.
Atelectasis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., dyspnea,
cough); medical intervention
indicated (e.g., chest
physiotherapy, suctioning);
bronchoscopic suctioning
Oxygen indicated;
hospitalization or elective
operative intervention indicated
(e.g., stent, laser)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by the collapse of part or the entire lung.
Bronchial fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between the bronchus and another organ or anatomic site.
Bronchial obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., mild
wheezing); endoscopic
evaluation indicated;
radiographic evidence of
atelectasis/lobar collapse;
medical management indicated
(e.g., steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by blockage of a bronchus passage, most often by bronchial secretions and exudates.
Bronchial stricture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., rhonchi or
wheezing) but without
respiratory distress; medical
intervention indicated (e.g.,
steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the bronchial tube.
Bronchopleural fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between a bronchus and the pleural cavity.
Bronchopulmonary hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the bronchial wall and/or lung parenchyma.
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
66
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Bronchospasm
Mild symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Limiting self care ADL; oxygen
saturation decreased
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a sudden contraction of the smooth muscles of the bronchial wall.
Chylothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thoracentesis or
tube drainage indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by milky pleural effusion (abnormal collection of fluid) resulting from accumulation of lymph fluid in the pleural cavity.
Cough
Mild symptoms; nonprescription
intervention indicated
Moderate symptoms, medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by sudden, often repetitive, spasmodic contraction of the thoracic cavity, resulting in violent release of air from the lungs and usually accompanied
by a distinctive sound.
Dyspnea
Shortness of breath with
moderate exertion
Shortness of breath with
minimal exertion; limiting
instrumental ADL
Shortness of breath at rest;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an uncomfortable sensation of difficulty breathing.
Epistaxis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated (e.g.,
nasal packing, cauterization;
topical vasoconstrictors)
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the nose.
Hiccups
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; interfering
with sleep; limiting self care
ADL
 -
 -
Definition: A disorder characterized by repeated gulp sounds that result from an involuntary opening and closing of the glottis. This is attributed to a spasm of the diaphragm.
Hoarseness
Mild or intermittent voice
change; fully understandable;
self-resolves
Moderate or persistent voice
changes; may require
occasional repetition but
understandable on telephone;
medical evaluation indicated
Severe voice changes including
predominantly whispered
speech
 -
 -
Definition: A disorder characterized by harsh and raspy voice arising from or spreading to the larynx.
Hypoxia
 -
Decreased oxygen saturation
with exercise (e.g., pulse
oximeter <88%); intermittent
supplemental oxygen
Decreased oxygen saturation at
rest (e.g., pulse oximeter <88%
or PaO2 <=55 mm Hg)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a decrease in the level of oxygen in the body.
Laryngeal edema
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
dexamethasone, epinephrine,
antihistamines)
Stridor; respiratory distress;
hospitalization indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the larynx.
Laryngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the larynx and another organ or anatomic site.
Laryngeal hemorrhage
Mild cough or trace hemoptysis;
laryngoscopic findings
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by bleeding from the larynx.
Laryngeal inflammation
Mild sore throat; raspy voice
Moderate sore throat;
analgesics indicated
Severe throat pain; endoscopic
intervention indicated
 -
 -
Definition: A disorder characterized by an inflammation involving the larynx.
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
67
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Laryngeal mucositis
Endoscopic findings only; mild
discomfort with normal intake
Moderate discomfort; altered
oral intake
Severe pain; severely altered
eating/swallowing; medical
intervention indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the larynx.
Laryngeal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the laryngeal airway.
Laryngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a narrowing of the laryngeal airway.
Laryngopharyngeal dysesthesia
Mild symptoms; no anxiety;
intervention not indicated
Moderate symptoms; mild
anxiety, but no dyspnea; short
duration of observation and or
anxiolytic indicated; limiting
instrumental ADL
Severe symptoms; dyspnea and
swallowing difficulty; limiting self
care ADL
Life-threatening consequences
Death
Definition: A disorder characterized by an uncomfortable persistent sensation in the area of the laryngopharynx.
Laryngospasm
 -
Transient episode; intervention
not indicated
Recurrent episodes;
noninvasive intervention
indicated (e.g., breathing
technique, pressure point
massage)
Persistent or severe episodes
associated with syncope; urgent
intervention indicated (e.g.,
fiberoptic laryngoscopy,
intubation, botox injection)
Death
Definition: A disorder characterized by paroxysmal spasmodic muscular contraction of the vocal cords.
Mediastinal hemorrhage
Radiologic evidence only;
minimal symptoms; intervention
not indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
(e.g., hemostasis of bleeding
site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mediastinum.
Nasal congestion
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Associated with bloody nasal
discharge or epistaxis
 -
 -
Definition: A disorder characterized by obstruction of the nasal passage due to mucosal edema.
Pharyngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the pharynx and another organ or anatomic site.
Pharyngeal hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pharynx.
Pharyngeal mucositis
Endoscopic findings only;
minimal symptoms with normal
oral intake; mild pain but
analgesics not indicated
Moderate pain and analgesics
indicated; altered oral intake;
limiting instrumental ADL
Severe pain; unable to
adequately aliment or hydrate
orally; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the pharynx.
Pharyngeal necrosis
 -
 -
Inability to aliment adequately
by GI tract; tube feeding or TPN
indicated; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
68
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a necrotic process occurring in the pharynx.
Pharyngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the pharyngeal airway.
Pharyngolaryngeal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pharyngolaryngeal region.
Pleural effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., diuretics or
limited therapeutic
thoracentesis)
Symptomatic with respiratory
distress and hypoxia; surgical
intervention including chest tube
or pleurodesis indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by an increase in amounts of fluid within the pleural cavity. Symptoms include shortness of breath, cough and marked chest discomfort.
Pleural hemorrhage
Asymptomatic; mild hemorrhage
confirmed by thoracentesis
Symptomatic or associated with
pneumothorax; chest tube
drainage indicated
>1000 ml of blood evacuated;
persistent bleeding (150-200
ml/hr for 2 - 4 hr); persistent
transfusion indicated; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pleural cavity.
Pleuritic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pleura.
Pneumonitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; oxygen indicated
Life-threatening respiratory
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma.
Pneumothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., tube placement
without sclerosis)
Sclerosis and/or operative
intervention indicated;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal presence of air in the pleural cavity resulting in the collapse of the lung.
Postnasal drip
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by excessive mucous secretion in the back of the nasal cavity or throat, causing sore throat and/or coughing.
Productive cough
Occasional/minimal production
of sputum with cough
Moderate sputum production;
limiting instrumental ADL
Persistent or copious production
of sputum; limiting self care ADL
 -
 -
Definition: A disorder characterized by expectorated secretions upon coughing.
Pulmonary edema
Radiologic findings only;
minimal dyspnea on exertion
Moderate dyspnea on exertion;
medical intervention indicated;
limiting instrumental ADL
Severe dyspnea or dyspnea at
rest; oxygen indicated; limiting
self care ADL
Life-threatening respiratory
compromise; urgent intervention
or intubation with ventilatory
support indicated
Death
Definition: A disorder characterized by accumulation of fluid in the lung tissues that causes a disturbance of the gas exchange that may lead to respiratory failure.
Pulmonary fibrosis
Mild hypoxemia; radiologic
pulmonary fibrosis <25% of lung
volume
Moderate hypoxemia; evidence
of pulmonary hypertension;
radiographic pulmonary fibrosis
25 - 50%
Severe hypoxemia; evidence of
right-sided heart failure;
radiographic pulmonary fibrosis
>50 - 75%
Life-threatening consequences
(e.g., hemodynamic/pulmonary
complications); intubation with
ventilatory support indicated;
radiographic pulmonary fibrosis
>75% with severe
honeycombing
Death
Definition: A disorder characterized by the replacement of the lung tissue by connective tissue, leading to progressive dyspnea, respiratory failure or right heart failure.
Pulmonary fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Limiting self care ADL;
endoscopic stenting or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
69
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an abnormal communication between the lung and another organ or anatomic site.
Pulmonary hypertension
Minimal dyspnea; findings on
physical exam or other
evaluation
Moderate dyspnea, cough;
requiring evaluation by cardiac
catheterization and medical
intervention
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening airway
consequences; urgent
intervention indicated (e.g.,
tracheotomy or intubation)
Death
Definition: A disorder characterized by an increase in pressure within the pulmonary circulation due to lung or heart disorder.
Respiratory failure
 -
 -
 -
Life-threatening consequences;
urgent intervention, intubation,
or ventilatory support indicated
Death
Definition: A disorder characterized by impaired gas exchange by the respiratory system resulting in hypoxemia and a decrease in oxygenation of the tissues that may be associated
with an increase in arterial levels of carbon dioxide.
Retinoic acid syndrome
Fluid retention; <3 kg of weight
gain; intervention with fluid
restriction and/or diuretics
indicated
Moderate signs or symptoms;
steroids indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
ventilatory support indicated
Death
Definition: A disorder characterized by weight gain, dyspnea, pleural and pericardial effusions, leukocytosis and/or renal failure originally described in patients treated with all-trans
retinoic acid.
Sinus disorder
Asymptomatic mucosal crusting;
blood-tinged secretions
Symptomatic stenosis or
edema/narrowing interfering
with airflow; limiting instrumental
ADL
Stenosis with significant nasal
obstruction; limiting self care
ADL
Necrosis of soft tissue or bone;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by involvement of the paranasal sinuses.
Sleep apnea
Snoring and nocturnal sleep
arousal without apneic periods
Moderate apnea and oxygen
desaturation; excessive daytime
sleepiness; medical evaluation
indicated; limiting instrumental
ADL
Oxygen desaturation;
associated with hypertension;
medical intervention indicated;
limiting self care ADL
Cardiovascular or
neuropsychiatric symptoms;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing for short periods during sleep.
Sneezing
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the involuntary expulsion of air from the nose.
Sore throat
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL; limiting ability to swallow
 -
 -
Definition: A disorder characterized by of marked discomfort in the throat
Stridor
 -
 -
Respiratory distress limiting self
care ADL; medical intervention
indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a high pitched breathing sound due to laryngeal or upper airway obstruction.
Tracheal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the trachea and another organ or anatomic site.
Tracheal mucositis
Endoscopic findings only;
minimal hemoptysis, pain, or
respiratory symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe pain; hemorrhage or
respiratory symptoms; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the trachea.
Tracheal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Stridor or respiratory distress
limiting self care ADL;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the trachea.
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70
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Voice alteration
Mild or intermittent change from
normal voice
Moderate or persistent change
from normal voice; still
understandable
Severe voice changes including
predominantly whispered
speech; may require frequent
repetition or face-to-face contact
for understandability; may
require assistive technology
 -
 -
Definition: A disorder characterized by a change in the sound and/or speed of the voice.
Wheezing
Detectable airway noise with
minimal symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe respiratory symptoms
limiting self care ADL; oxygen
therapy or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a high-pitched, whistling sound during breathing. It results from the narrowing or obstruction of the respiratory airways.
Respiratory, thoracic and
mediastinal disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
71
24. Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Alopecia
Hair loss of <50% of normal for
that individual that is not
obvious from a distance but only
on close inspection; a different
hair style may be required to
cover the hair loss but it does
not require a wig or hair piece to
camouflage
Hair loss of >=50% normal for
that individual that is readily
apparent to others; a wig or hair
piece is necessary if the patient
desires to completely
camouflage the hair loss;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by a decrease in density of hair compared to normal for a given individual at a given age and body location.
Body odor
Mild odor; physician intervention
not indicated; self care
interventions
Pronounced odor; psychosocial
impact; patient seeks medical
intervention
 -
 -
 -
Definition: A disorder characterized by an abnormal body smell resulting from the growth of bacteria on the body.
Bullous dermatitis
Asymptomatic; blisters covering
<10% BSA
Blisters covering 10 - 30% BSA;
painful blisters; limiting
instrumental ADL
Blisters covering >30% BSA;
limiting self care ADL
Blisters covering >30% BSA;
associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by inflammation of the skin characterized by the presence of bullae which are filled with fluid.
Dry skin
Covering <10% BSA and no
associated erythema or pruritus
Covering 10 - 30% BSA and
associated with erythema or
pruritus; limiting instrumental
ADL
Covering >30% BSA and
associated with pruritus; limiting
self care ADL
 -
 -
Definition: A disorder characterized by flaky and dull skin; the pores are generally fine, the texture is a papery thin texture.
Erythema multiforme
Target lesions covering <10%
BSA and not associated with
skin tenderness
Target lesions covering 10 -
30% BSA and associated with
skin tenderness
Target lesions covering >30%
BSA and associated with oral or
genital erosions
Target lesions covering >30%
BSA; associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by target lesions (a pink-red ring around a pale center).
Erythroderma
 -
Erythema covering >90% BSA
without associated symptoms;
limiting instrumental ADL
Erythema covering >90% BSA
with associated symptoms (e.g.,
pruritus or tenderness); limiting
self care ADL
Erythema covering >90% BSA
with associated fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by generalized inflammatory erythema and exfoliation. The inflammatory process involves > 90% of the body surface area.
Fat atrophy
Covering <10% BSA and
asymptomatic
Covering 10 - 30% BSA and
associated with erythema or
tenderness; limiting instrumental
ADL
Covering >30% BSA;
associated with erythema or
tenderness; limiting self-care
ADL
 -
 -
Definition: A disorder characterized by shrinking of adipose tissue.
Hirsutism
In women, increase in length,
thickness or density of hair in a
male distribution that the patient
is able to camouflage by
periodic shaving, bleaching, or
removal of hair
In women, increase in length,
thickness or density of hair in a
male distribution that requires
daily shaving or consistent
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by the presence of excess hair growth in women in anatomic sites where growth is considered to be a secondary male characteristic and under
androgen control (beard, moustache, chest, abdomen)
Hyperhidrosis
Limited to one site (palms,
soles, or axillae); self care
interventions
Involving >1 site; patient seeks
medical intervention; associated
with psychosocial impact
Generalized involving sites
other than palms, soles, or
axillae; associated with
electrolyte/hemodynamic
imbalance
 -
 -
Definition: A disorder characterized by excessive perspiration.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
72
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Hypertrichosis
Increase in length, thickness or
density of hair that the patient is
either able to camouflage by
periodic shaving or removal of
hairs or is not concerned
enough about the overgrowth to
use any form of hair removal
Increase in length, thickness or
density of hair at least on the
usual exposed areas of the
body [face (not limited to
beard/moustache area)
plus/minus arms] that requires
frequent  shaving or use of
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by hair density or length beyond the accepted limits of normal in a particular body region, for a particular age or race.
Hypohidrosis
 -
Symptomatic; limiting
instrumental ADL
Increase in body temperature;
limiting self care ADL
Heat stroke
Death
Definition: A disorder characterized by reduced sweating.
Lipohypertrophy
Asymptomatic and covering
<10% BSA
Covering 10 - 30% BSA and
associated tenderness; limiting
instrumental ADL
Covering >30% BSA and
associated tenderness and
narcotics or NSAIDs indicated;
lipohypertrophy; limiting self
care ADL
 -
 -
Definition: A disorder characterized by hypertrophy of the subcutaneous adipose tissue at the site of multiple subcutaneous injections of insulin.
Nail discoloration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the nail plate.
Nail loss
Asymptomatic separation of the
nail bed from the nail plate or
nail loss
Symptomatic separation of the
nail bed from the nail plate or
nail loss; limiting instrumental
ADL
 -
 -
 -
Definition: A disorder characterized by loss of all or a portion of the nail.
Nail ridging
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by vertical or horizontal ridges on the nails.
Pain of skin
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin.
Palmar-plantar
erythrodysesthesia syndrome
Minimal skin changes or
dermatitis (e.g., erythema,
edema, or hyperkeratosis)
without pain
Skin changes (e.g., peeling,
blisters, bleeding, edema, or
hyperkeratosis) with pain;
limiting instrumental ADL
Severe skin changes (e.g.,
peeling, blisters, bleeding,
edema, or hyperkeratosis) with
pain; limiting self care ADL
 -
 -
Definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet.
Periorbital edema
Soft or non-pitting
Indurated or pitting edema;
topical intervention indicated
Edema associated with visual
disturbance; increased
intraocular pressure, glaucoma
or retinal hemorrhage; optic
neuritis; diuretics indicated;
operative intervention indicated
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid around the orbits of the face.
Photosensitivity
Painless erythema and
erythema covering <10% BSA
Tender erythema covering 10 -
30% BSA
Erythema covering >30% BSA
and erythema with blistering;
photosensitivity; oral
corticosteroid therapy indicated;
pain control indicated (e.g.,
narcotics or NSAIDs)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity of the skin to light.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
73
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Pruritus
Mild or localized; topical
intervention indicated
Intense or widespread;
intermittent; skin changes from
scratching (e.g., edema,
papulation, excoriations,
lichenification, oozing/crusts);
oral intervention indicated;
limiting instrumental ADL
Intense or widespread;
constant; limiting self care ADL
or sleep; oral corticosteroid or
immunosuppressive therapy
indicated
 -
 -
Definition: A disorder characterized by an intense itching sensation.
Purpura
Combined area of lesions
covering <10% BSA
Combined area of lesions
covering 10 - 30% BSA;
bleeding with trauma
Combined area of lesions
covering >30% BSA;
spontaneous bleeding
 -
 -
Definition: A disorder characterized by hemorrhagic areas of the skin and mucous membrane. Newer lesions appear reddish in color. Older lesions are usually a darker purple color
and eventually become a brownish-yellow color.
Rash acneiform
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10 - 30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and back.
Rash maculo-papular
Macules/papules covering
<10% BSA with or without
symptoms (e.g., pruritus,
burning, tightness)
Macules/papules covering 10 -
30% BSA with or without
symptoms (e.g., pruritus,
burning, tightness); limiting
instrumental ADL
Macules/papules covering
>30% BSA with or without
associated symptoms; limiting
self care ADL
 -
 -
Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbillform rash, it is one of the most common cutaneous adverse
events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus.
Scalp pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin covering the top and the back of the head.
Skin atrophy
Covering <10% BSA;
associated with telangiectasias
or changes in skin color
Covering 10 - 30% BSA;
associated with striae or
adnexal structure loss
Covering >30% BSA;
associated with ulceration
 -
 -
Definition: A disorder characterized by the degeneration and thinning of the epidermis and dermis.
Skin hyperpigmentation
Hyperpigmentation covering
<10% BSA; no psychosocial
impact
Hyperpigmentation covering
>10% BSA; associated
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by darkening of the skin due to excessive melanin deposition.
Skin hypopigmentation
Hypopigmentation or
depigmentation covering <10%
BSA; no psychosocial impact
Hypopigmentation or
depigmentation covering >10%
BSA; associated psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by loss of skin pigment.
Skin induration
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration, unable to
slide or pinch skin; limiting joint
movement or orifice (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by an area of hardness in the skin.
Skin ulceration
Combined area of ulcers <1 cm;
nonblanchable erythema of
intact skin with associated
warmth or edema
Combined area of ulcers 1 - 2
cm; partial thickness skin loss
involving skin or subcutaneous
fat
Combined area of ulcers >2 cm;
full-thickness skin loss involving
damage to or necrosis of
subcutaneous tissue that may
extend down to fascia
Any size ulcer with extensive
destruction, tissue necrosis, or
damage to muscle, bone, or
supporting structures with or
without full thickness skin loss
Death
Definition: A disorder characterized by circumscribed, inflammatory and necrotic erosive lesion on the skin.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
74
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Stevens-Johnson syndrome
 -
 -
Skin sloughing covering <10%
BSA with associated signs (e.g.,
erythema, purpura, epidermal
detachment and mucous
membrane detachment)
Skin sloughing covering 10 -
30% BSA with associated signs
(e.g., erythema, purpura,
epidermal detachment and
mucous membrane
detachment)
Death
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Telangiectasia
Telangiectasias covering <10%
BSA
Telangiectasias covering >10%
BSA; associated with
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by local dilatation of small vessels resulting in red discoloration of the skin or mucous membranes.
Toxic epidermal necrolysis
 -
 -
 -
Skin sloughing covering >=30%
BSA with associated symptoms
(e.g., erythema, purpura, or
epidermal detachment)
Death
Definition: A disorder characterized by greater than 30% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Urticaria
Urticarial lesions covering <10%
BSA; topical intervention
indicated
Urticarial lesions covering 10 -
30% BSA; oral intervention
indicated
Urticarial lesions covering >30%
BSA; IV intervention indicated
 -
 -
Definition: A disorder characterized by an itchy skin eruption characterized by wheals with pale interiors and well-defined red margins.
Skin and subcutaneous tissue
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Social circumstances 
75
25. Social circumstances
Social circumstances
Grade
Adverse Event
1
2
3
4
5
Menopause
Menopause occurring at age 46
- 53 years of age
Menopause occurring at age 40
- 45 years of age
Menopause occurring before
age 40 years of age
 -
 -
Definition: A disorder characterized by the permanent cessation of menses, usually defined by 12 consecutive months of amenorrhea in a woman over 45 years of age.
Social circumstances - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Surgical and medical procedures 
76
26. Surgical and medical procedures
Surgical and medical procedures
Grade
Adverse Event
1
2
3
4
5
Surgical and medical
procedures - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Vascular disorders 
77
27. Vascular disorders
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Capillary leak syndrome
 -
Symptomatic; medical
intervention indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of intravascular fluids into the extravascular space. This syndrome is observed in patients who demonstrate a state of generalized
leaky capillaries following shock syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. It can lead to generalized edema and multiple organ
failure.
Flushing
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Symptomatic, associated with
hypotension and/or tachycardia;
limiting self care ADL
 -
 -
Definition: A disorder characterized by episodic reddening of the face.
Hematoma
Mild symptoms; intervention not
indicated
Minimally invasive evacuation or
aspiration indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel.
Hot flashes
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable and temporary sensation of intense body warmth, flushing, sometimes accompanied by sweating upon cooling.
Hypertension
Prehypertension (systolic BP
120 - 139 mm Hg or diastolic
BP  80 - 89 mm Hg)
Stage 1 hypertension (systolic
BP 140 - 159 mm Hg or
diastolic BP 90 - 99 mm Hg);
medical intervention indicated;
recurrent or persistent (>=24
hrs); symptomatic increase by
>20 mm Hg (diastolic) or to
>140/90 mm Hg if previously
WNL; monotherapy indicated
Pediatric: recurrent or persistent
(>=24 hrs) BP >ULN;
monotherapy indicated
Stage 2 hypertension (systolic
BP >=160 mm Hg or diastolic
BP >=100 mm Hg); medical
intervention indicated; more
than one drug or more intensive
therapy than previously used
indicated
Pediatric: Same as adult
Life-threatening consequences
(e.g., malignant hypertension,
transient or permanent
neurologic deficit, hypertensive
crisis); urgent intervention
indicated
Pediatric: Same as adult
Death
Definition: A disorder characterized by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure exceeding 140 over 90 mm Hg.
Hypotension
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention or
hospitalization indicated
Life-threatening and urgent
intervention indicated
Death
Definition: A disorder characterized by a blood pressure that is below the normal expected for an individual in a given environment.
Lymph leakage
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the loss of lymph fluid into the surrounding tissue or body cavity.
Lymphedema
Trace thickening or faint
discoloration
Marked discoloration; leathery
skin texture; papillary formation;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by excessive fluid collection in tissues that causes swelling.
Lymphocele
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by a cystic lesion containing lymph.
Peripheral ischemia
 -
Brief (<24 hrs) episode of
ischemia managed non-
surgically and without
permanent deficit
Recurring or prolonged (>=24
hrs) and/or invasive intervention
indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by impaired circulation to an extremity.
Phlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by inflammation of the wall of a vein.
Superficial thrombophlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by a blood clot and inflammation involving a superficial vein of the extremities.
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CTCAE 4.03 - June 14, 2010 : Vascular disorders 
78
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Superior vena cava syndrome
Asymptomatic; incidental finding
of SVC thrombosis
Symptomatic; medical
intervention indicated (e.g.,
anticoagulation, radiation or
chemotherapy)
Severe symptoms; multi-
modality intervention indicated
(e.g., anticoagulation,
chemotherapy, radiation,
stenting)
Life-threatening consequences;
urgent multi-modality
intervention indicated (e.g.,
lysis, thrombectomy, surgery)
Death
Definition: A disorder characterized by obstruction of the blood flow in the superior vena cava. Signs and symptoms include swelling and cyanosis of the face, neck, and upper arms,
cough, orthopnea and headache.
Thromboembolic event
Venous thrombosis (e.g.,
superficial thrombosis)
Venous thrombosis (e.g.,
uncomplicated deep vein
thrombosis), medical
intervention indicated
Thrombosis (e.g.,
uncomplicated pulmonary
embolism [venous], non-embolic
cardiac mural [arterial]
thrombus), medical intervention
indicated
Life-threatening (e.g.,
pulmonary embolism,
cerebrovascular event, arterial
insufficiency); hemodynamic or
neurologic instability; urgent
intervention indicated
Death
Definition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via the blood stream.
Vasculitis
Asymptomatic, intervention not
indicated
Moderate symptoms, medical
intervention indicated
Severe symptoms, medical
intervention indicated (e.g.,
steroids)
Life-threatening; evidence of
peripheral or visceral ischemia;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the wall of a vessel.
Visceral arterial ischemia
 -
Brief (<24 hrs) episode of
ischemia managed medically
and without permanent deficit
Prolonged (>=24 hrs) or
recurring symptoms and/or
invasive intervention indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a decrease in blood supply due to narrowing or blockage of a visceral (mesenteric) artery.
Vascular disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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APPENDIX D. STANDARDIZED DEFINITIONS FOR CARDIOVASCULAR ENDPOINT EVENTS 
Event 
Definitions 
Cardiovascular (CV) Death: 
Death due to Acute MI 
Death due to Acute MI refers to a death by any CV mechanism (eg, arrhythmia, sudden death, HF, stroke, 
pulmonary embolus, peripheral arterial disease) ≤30 daysa after a MI related to the immediate consequences of 
the MI, such as progressive HF or recalcitrant arrhythmia.  There may be assessable mechanisms of CV death 
during this time period, but for simplicity, if the CV death occurs ≤30 days of the MI, it will be considered a 
death due to MI. 
Acute MI should be verified to the extent possible by the diagnostic criteria outlined for acute MI (Clinical Data 
Interchange Standards Consortium [CDISC], Chapter 4) or by autopsy findings showing recent MI or recent 
coronary thrombosis. 
Death resulting from a procedure to treat a MI (percutaneous coronary intervention (PCI), coronary artery 
bypass graft surgery [CABG]), or to treat a complication resulting from MI, should also be considered death due 
to acute MI. 
Death resulting from an elective coronary procedure to treat myocardial ischemia (ie, chronic stable angina) or 
death due to a MI that occurs as a direct consequence of a CV investigation/procedure/operation should be 
considered as a death due to a CV procedure. 
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Definitions 
Sudden Cardiac Death 
Sudden Cardiac Death refers to a death that occurs unexpectedly, not following an acute MI, and includes the 
following deaths: 
a. 
Death witnessed and occurring without new or worsening symptoms 
b. Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, unless the 
symptoms suggest acute MI 
c. 
Death witnessed and attributed to an identified arrhythmia (eg, captured on an electrocardiographic 
(ECG) recording, witnessed on a monitor, or unwitnessed but found on implantable cardioverter-
defibrillator review) 
d. Death after unsuccessful resuscitation from cardiac arrest (eg, implantable cardioverter defibrillator 
(ICD) unresponsive sudden cardiac death, pulseless electrical activity arrest) 
e. 
Death after successful resuscitation from cardiac arrest and without identification of a specific cardiac or 
non-cardiac etiology 
f. 
Unwitnessed death in a subject seen alive and clinically stable ≤24 hours prior to being found dead 
without any evidence supporting a specific non-CV cause of death (information regarding the subject’s 
clinical status preceding death should be provided, if available). 
Unless additional information suggests an alternate specific cause of death (eg, death due to Other CV Causes), 
if a subject is seen alive ≤ 24 hours of being found dead, sudden cardiac death (criterion f above) should be 
recorded.  For subjects who were not observed alive within 24 hours of death, undetermined cause of death 
should be recorded (eg, a subject found dead in bed, but who had not been seen by family for several days). 
Death due to HF  
Death due to HF refers to a death in association with clinically worsening symptoms and/or signs of HF 
regardless of HF etiology (CDISC, Chapter 7).  Deaths due to HF can have various etiologies, including single 
or recurrent MIs, ischemic or non-ischemic cardiomyopathy, hypertension, or valvular disease. 
Death due to Stroke 
Death due to Stroke refers to death after a stroke (hemorrhagic, ischemic, or undetermined) that is either a direct 
consequence of the stroke or a complication of the stroke.  Acute stroke should be verified to the extent possible 
by the diagnostic criteria outlined for stroke (CDISC, Chapter 6). 
Death due to CV Procedures 
Death due to CV Procedures refers to death caused by the immediate complications of a cardiac procedure. 
Death due to CV Hemorrhage 
Death due to CV Hemorrhage refers to death related to hemorrhage such as a non-stroke intracranial 
hemorrhage (CDISC, Chapter 6), non-procedural or non-traumatic vascular rupture (eg, aortic aneurysm), or 
hemorrhage causing cardiac tamponade. 
Death due to Other CV Causes 
Death due to Other CV Causes refers to a CV death not included in the above categories but with a specific, 
known cause (eg, pulmonary embolism or peripheral arterial disease). 
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Event 
Definitions 
Non-CV Death: 
The following is a suggested list of non-
CV causes of death: 
• 
Pulmonary 
• 
Renal 
• 
Gastrointestinal 
• 
Hepatobiliary 
• 
Pancreatic 
• 
Infection (includes sepsis) 
• 
Inflammatory (eg, Systemic 
Inflammatory Response 
Syndrome (SIRS) / immune 
(including autoimmune; may 
include anaphylaxis from 
environmental [eg, food] 
allergies) 
• 
Hemorrhage that is neither CV 
bleeding nor a stroke (see 
Chapter 1, Section 6, and 
Chapter 6) 
• 
Non-CV procedure or surgery 
• 
Trauma 
• 
Suicide 
• 
Non-prescription drug reaction 
or overdose 
• 
Prescription drug reaction or 
overdose (may include 
anaphylaxis) 
• 
Neurological (non-CV) 
• 
Malignancy 
• 
Other non-CV 
Non-CV death is defined as any death with a specific cause that is not thought to be CV in nature, as listed in 
CDISC Chapter 1, or as listed for CV Death.   
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Event 
Definitions 
Undetermined Cause of Death: 
Undetermined Cause of Death (will 
be classified as a CV death) 
Undetermined cause of death refers to a death not attributable to one of the above categories of CV death or is 
due to a non-CV cause.  Inability to classify the cause of death may be due to lack of information (eg, the only 
available information is “subject died”) or there is insufficient supporting information or detail to assign the 
cause of death.  In general, most deaths should be classifiable as CV or non-CV, and the use of this category of 
death, therefore, should be discouraged and should apply to few subjects in well-run clinical trials.    
Cardiovascular Events: 
Myocardial Infarctionb 
a) 
Clinical Presentation 
The clinical presentation should be consistent with diagnosis of myocardial ischemia and infarction.  Other 
findings that might support the diagnosis of MI should be taken into account because a number of conditions are 
associated with elevations in cardiac biomarkers (eg, trauma, surgery, pacing, ablation, HF, hypertrophic 
cardiomyopathy, pulmonary embolism, severe pulmonary hypertension, stroke or subarachnoid hemorrhage, 
infiltrative and inflammatory disorders of cardiac muscle, drug toxicity, burns, critical illness, extreme exertion, 
and chronic kidney disease). 
Supporting information can also be considered from myocardial imaging and coronary imaging.  The totality of 
the data may help differentiate acute MI from the background disease process. 
b) 
Biomarker Elevations 
For cardiac biomarkers, laboratories should report an upper reference limit (URL).  If the ninety-ninth percentile 
of the URL from the respective laboratory performing the assay is not available, then the URL for myocardial 
necrosis from the laboratory should be used.  If the ninety-ninth percentile of the URL or the URL for 
myocardial necrosis is not available, the MI decision limit for the particular laboratory should be used as the 
URL.  Laboratories can also report both the ninety-ninth percentile of the upper reference limit and the MI 
decision limit.  Reference limits from the laboratory performing the assay are preferred over the manufacturer’s 
listed reference limits in an assay’s instructions for use.  In general, troponins are preferred.  Creatine kinase-
myocardial band (CK-MB) should be used if troponins are not available, and total creatine kinase (CK) may be 
used in the absence of CK-MB and troponin. 
For MI subtypes, different biomarker elevations for CK, CK-MB, or troponin will be required.  The specific 
criteria will be referenced to the URL. 
Since it is not practical to stipulate the use of a single biomarker or assay, the locally available results are to be 
used as the basis for adjudication.  However, if possible, using the same cardiac biomarker assay and preferably, 
a core laboratory, for all measurements reduces inter-assay variability. 
Since the prognostic significance of different types of MIs (eg, periprocedural MI versus spontaneous MI) may 
be different, outcomes for these subsets of subjects may be evaluated separately. 
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c) 
ECG Changes 
Electrocardiographic changes can be used to support or confirm a MI. Supporting evidence may be ischemic 
changes and confirmatory information may be new Q waves. 
ECG manifestations of acute myocardial ischemia (in absence of left ventricular hypertrophy [LVH] and left 
bundle branch block [LBBB]) include: 
• 
ST elevation: New ST elevation at the J point in two contiguous leads with the cut-points: ≥0.1 mV in 
all leads other than leads V2-V3 where the following cut-points apply: ≥0.2 mV in men ≥40 years 
(≥0.25 mV in men <40 years) or ≥0.15 mV in women 
• 
ST depression and T-wave changes: New horizontal or down-sloping ST depression ≥0.05 mV in two 
contiguous leads and/or new T inversion ≥ 0.1 mV in two contiguous leads with prominent R wave or 
R/S ratio >1. 
The above ECG criteria illustrate patterns consistent with myocardial ischemia.  In subjects with abnormal 
biomarkers, it is recognized that lesser ECG abnormalities may represent an ischemic response and may be 
accepted under the category of abnormal ECG findings. 
• 
Criteria for pathological Q-wave 
− 
Any Q-wave in leads V2-V3 ≥0.02 seconds or QS complex in leads V2 and V3 
− 
Q-wave ≥0.03 seconds and ≥0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-V6 in 
any two leads of a contiguous lead grouping (I, aVL; V1-V6; II, III, and aVF)c 
• 
ECG changes associated with prior MI 
− 
Pathological Q-waves, as defined above 
− 
R-wave ≥0.04 seconds in V1-V2 and R/S ≥1 with a concordant positive T-wave in the absence of a 
conduction defect 
• 
Criteria for prior MI:  Any one of the following criteria meets the diagnosis for prior MI: 
− 
Pathological Q waves with or without symptoms in the absence of non-ischemic causes 
− 
Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in 
the absence of a non-ischemic cause 
Pathological findings of a prior myocardial infarction 
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Event 
Definitions 
Hospitalization for Unstable Angina 
 
Unstable angina requiring hospitalization is defined as: 
1. Ischemic discomfort (angina, or symptoms thought to be equivalent) ≥10 minutes in 
duration occurring 
• 
at rest, or 
• 
in an accelerating pattern with frequent episodes associated with progressively decreased exercise 
capacity. 
AND 
2. Prompting an unscheduled hospitalization within 24 hours of the most recent 
symptoms.  Hospitalization is defined as an admission to an inpatient unit or a visit to 
an emergency department that results in at least a 24 hour stay (or a change in 
calendar date if the hospital admission or discharge times are not available). 
AND 
3. At least one of the following: 
a. 
New or worsening ST or T wave changes on resting ECG (in the absence of confounders, such as 
LBBB or LVH) 
• 
Transient ST elevation (duration <20 minutes) New ST elevation at the J point in two 
contiguous leads with the cut-points: ≥0.1 mV in all leads other than leads V2-V3 where the 
following cut-points apply: ≥0.2 mV in men ≥40 years (≥0.25 mV in men <40 years) or 
≥0.15 mV in women. 
• 
ST depression and T-wave changes 
• 
New horizontal or down-sloping ST depression ≥0.05 mV in two contiguous leads and/or new 
T inversion ≥0.3 mV in two contiguous leads with prominent R wave or R/S ratio >1. 
b. Definite evidence of inducible myocardial ischemia event as demonstrated by: 
• 
an early positive exercise stress test, defined as ST elevation or ≥2 mm ST depression prior to 
5 mets OR 
• 
stress echocardiography (reversible wall motion abnormality) OR 
• 
myocardial scintigraphy (reversible perfusion defect), OR 
• 
magnetic resonance imaging (MRI; myocardial perfusion deficit under pharmacologic stress). 
• 
And believed to be responsible for the myocardial ischemic symptoms/signs. 
c. 
Angiographic evidence of new or worse ≥70% lesion (≥50% for left main lesion) and/or thrombus 
in an epicardial coronary artery that is believed to be responsible for the myocardial ischemic 
symptoms/signs. 
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Definitions 
d. Need for coronary revascularization procedure (PCI or CABG) for the presumed culprit lesion(s).  
This criterion would be fulfilled if revascularization was undertaken during the unscheduled 
hospitalization, or subsequent to transfer to another institution without interceding home discharge. 
AND 
Negative cardiac biomarkers and no evidence of acute MI 
Transient Ischemic Attack (TIA) 
TIA is defined as a transient episode of focal neurological dysfunction caused by brain, spinal cord, or retinal 
ischemia, without acute infarction. 
Stroke (Includes Ischemic Stroke, 
Hemorrhagic Stroke, Undetermined 
Stroke, or Stroke Disability) 
 
Stroke is defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or 
retinal vascular injury as a result of hemorrhage or infarction. 
A. Ischemic Stroke: Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by infarction of central nervous system tissue. 
Hemorrhage may be a consequence of ischemic stroke.  In this situation, the stroke is an ischemic 
stroke with hemorrhagic transformation and not a hemorrhagic stroke. 
B. Hemorrhagic Stroke: Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or 
spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage. 
C. Undetermined Stroke: Undetermined stroke is defined as an acute episode of focal or global 
neurological dysfunction caused by presumed brain, spinal cord, or retinal vascular injury as a result of 
hemorrhage or infarction but with insufficient information to allow categorization as A or B.  
Stroke Disability: Disability should be measured by a reliable and valid scale in all cases, typically at each visit 
and 90 days after the event.  For example, the modified Rankin Scale may be used to address this requirement: 
Scale 
Disability 
0 
No symptoms at all 
1 
No significant disability despite symptoms; able to carry out all usual duties and activities 
2 
Slight disability; unable to carry out all previous activities, but able to look after own affairs 
without assistance 
3 
Moderate disability; requiring some help, but able to walk without assistance 
4 
Moderately severe disability; unable to walk without assistance and unable to attend to 
own bodily needs without assistance 
5 
Severe disability; bedridden, incontinent and requiring constant nursing care and attention 
6 
Dead 
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Event 
Definitions 
Heart Failure (A HF event includes 
hospitalization for HF and may include 
urgent outpatient visits) 
A HF hospitalization is defined as an event that meets ALL of the following criteria: 
1. The subject is admitted to the hospital with a primary diagnosis of HF 
2. The subject’s length-of-stay in hospital extends for at least 24 hours (or a change in 
calendar date if the hospital admission and discharge times are unavailable) 
3. The subject exhibits documented new or worsening symptoms due to HF on 
presentation, including at least ONE of the following: 
• 
Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal nocturnal dyspnea) 
• 
Decreased exercise tolerance 
• 
Fatigue 
• 
Other symptoms of worsened end-organ perfusion or volume overload (must be specified and 
described by the protocol) 
4. The subject has objective evidence of new or worsening HF, consisting of at least 
TWO physical examination findings OR one physical examination finding and at least 
ONE laboratory criterion), including: 
a. 
Physical examination findings considered to be due to HF, including new or worsened: 
i.Peripheral edema 
ii.Increasing abdominal distention or ascites (in the absence of primary hepatic disease) 
iii.Pulmonary rales/crackles/crepitations 
iv.Increased jugular venous pressure and/or hepatojugular reflux 
v.S3 gallop 
vi.Clinically significant or rapid weight gain thought to be related to fluid retention 
b. Laboratory evidence of new or worsening HF, if obtained within 24 hours of presentation, 
including: 
i. 
Increased B-type natriuretic peptide (BNP)/ N-terminal pro-BNP (NT pro-BNP) 
concentrations consistent with decompensation of HF (such as BNP > 500 pg/mL or NT-
proBNP >2,000 pg/mL).  In subjects with chronically elevated natriuretic peptides, a 
significant increase should be noted above baseline. 
ii.Radiological evidence of pulmonary congestion 
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iii. Non-invasive diagnostic evidence of clinically significant elevated left- or right-sided 
ventricular filling pressure or low cardiac output.  For example, ECG criteria could include: 
E/e’ >15 or D-dominant pulmonary venous inflow pattern, plethoric inferior vena cava with 
minimal collapse on inspiration, or decreased left ventricular outflow tract (LVOT) minute 
stroke distance (time velocity integral [TVI]) 
OR 
iv. Invasive diagnostic evidence with right heart catheterization showing a pulmonary capillary 
wedge pressure (pulmonary artery occlusion pressure) ≥18 mmHg, central venous pressure 
≥12 mmHg, or a cardiac index <2.2 L/min/m2 
Note: All results from diagnostic tests should be reported, if available, even if they do not meet the above 
criteria, because they provide important information for the adjudication of these events. 
5. The subject receives initiation or intensification of treatment specifically for HF, 
including at least ONE of the following: 
a. 
Augmentation in oral diuretic therapy 
b. Intravenous diuretic or vasoactive agent (eg, inotrope, vasopressor, or vasodilator) 
c. 
Mechanical or surgical intervention, including: 
i. 
Mechanical circulatory support (eg, intra-aortic balloon pump, ventricular assist device, 
extracorporeal membrane oxygenation, total artificial heart) 
ii.Mechanical fluid removal (eg, ultrafiltration, hemofiltration, dialysis) 
An urgent HF visit is defined as an event that meets all of the following: 
6. The subject has an urgent, unscheduled office/practice or emergency department visit 
for a primary diagnosis of HF, but not meeting the criteria for a HF hospitalization 
(i.e. urgent outpatient visit) 
7. All signs and symptoms for HF hospitalization (ie, symptoms and physical 
examination findings/laboratory evidence of new or worsening HF, as indicated 
above) must be met 
8. The subject receives initiation or intensification of treatment specifically for HF, as 
detailed in the above section with the exception of oral diuretic therapy, which will 
not be sufficient. 
 
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Interventional Cardiology:  Clinical Definitions 
Clinically-Driven Target Lesion 
Revascularization: 
Revascularization is clinically-driven if the target lesion diameter stenosis is >50% by quantitative coronary 
angiography (QCA) and the subject has clinical or functional ischemia which cannot be explained by another 
native coronary or bypass graft lesion. Clinical or functional ischemia includes any of the following: 
a. 
A history of angina pectoris, presumably related to the target vessel 
b. Objective signs of ischemia at rest (electrocardiographic changes) or during exercise test (or 
equivalent), presumably related to the target vessel 
c. 
Abnormal results of any invasive functional diagnostic test [e.g., coronary flow reserve (CFR) or 
fractional flow reserve (FFR)]  
Comment:  Target lesion revascularization of a >70% diameter stenosis by QCA in the absence of the above 
signs or symptoms may be considered clinically-driven. 
Comment:  In the absence of QCA data or if a ≤50% stenosis is present, TLR may be considered clinically-
driven by the Adjudication Committee (AC) if severe ischemic signs and symptoms attributed to the target 
lesion are present. 
Non-Target Lesion and Non-Target 
Lesion Revascularization: 
A lesion for which revascularization is not attempted or one in which revascularization is performed using a 
non-study device, respectively. 
Non-Target Vessel and Non-Target 
Vessel Revascularization: 
A vessel for which revascularization is not attempted or one in which revascularization is performed using a 
non-study device, respectively. 
Percutaneous Coronary Intervention 
(PCI) Status: 
a. 
Elective: The procedure can be performed on an outpatient basis or during a subsequent hospitalization 
without significant risk of MI or death.  For stable inpatients, the procedure is being performed during this 
hospitalization for convenience and ease of scheduling and NOT because the subject's clinical situation 
demands the procedure prior to discharge. 
b. Urgent: The procedure should be performed on an inpatient basis and prior to discharge because of 
significant concerns that there is risk of myocardial ischemia, MI, and/or death.  Subjects who are 
outpatients or in the emergency department at the time that the cardiac catheterization is requested would 
warrant hospital admission based on their clinical presentation. 
c. 
Emergency:  The procedure should be performed as soon as possible because of substantial concerns that 
ongoing myocardial ischemia and/or MI could lead to death.  "As soon as possible" refers to a subject who 
is of sufficient acuity that one would cancel a scheduled case to perform this procedure immediately in the 
next available room during business hours, or one would activate the on-call team were this to occur 
during off-hours. 
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d. Salvage:  The procedure is a last resort. The subject is in cardiogenic shock when the PCI begins (ie, the 
time at which the first guide wire or intracoronary device is introduced into a coronary artery or bypass 
graft for the purpose of mechanical revascularization) OR within the last ten minutes prior to the start of 
the case or during the diagnostic portion of the case, the subject has also received chest compressions or 
has been on unanticipated circulatory support (eg, intra-aortic balloon pump, extracorporeal membrane 
oxygenation, or cardiopulmonary support). 
Percutaneous Coronary Intervention 
(PCI): 
Placement of an angioplasty guide wire, balloon, or other device (e.g., stent, atherectomy catheter, 
brachytherapy delivery device, or thrombectomy catheter) into a native coronary artery or coronary artery 
bypass graft for the purpose of mechanical coronary revascularization.  In the assessment of the severity of 
coronary lesions with the use of intravascular ultrasound, coronary flow reserve (CFR), or fractional flow 
reserve (FFR), insertion of a guide wire will NOT be considered PCI. 
Procedural Success: 
Achievement of <30 % residual diameter stenosis of the target lesion assessed by visual inspection or QCA and 
no in-hospital major adverse cardiac events (MACE, a composite of death, MI, or repeat coronary 
revascularization of the target lesion).  Ideally, the assessment of the residual stenosis at the end of the 
procedure should be performed by an angiographic core laboratory. 
Comment: For some device interventions (eg, balloon angioplasty), achievement of <50% diameter stenosis 
by visual inspection or QCA is an acceptable definition for procedural success. 
Target Lesion: 
Any lesion treated or attempted to be treated during the PCI with the study device.  The target lesion includes 
the arterial segment treated with the study device (stent, in most cases) plus 5 mm proximal and 5 mm distal to 
the treatment site. 
Target Lesion Failure (TLF): 
The composite of ischemia-driven revascularization of the target lesion, MI related to the target vessel, or 
cardiac death related to the target vessel.  If it cannot be determined with certainty whether the MI or death was 
related to the target vessel, it is considered a TLF. 
Target Lesion Revascularization 
(TLR): 
Any repeat percutaneous intervention of the target lesion (including 5 mm proximal and 5 mm distal to the 
target lesion) or surgical bypass of the target vessel performed for restenosis or other complication involving 
the target lesion.  In the assessment of TLR, angiograms should be assessed by an angiographic core laboratory 
(if designated) and made available to the AC for review upon request. 
Target Vessel: 
A major native coronary artery (eg, left main coronary artery, left anterior descending coronary artery, left 
circumflex coronary artery, or right coronary artery) or bypass graft containing the target lesion.  A native 
coronary artery target vessel includes the arterial segments upstream and downstream to the target lesion plus 
major side branches. 
Target Vessel Failure (TVF): 
The composite of ischemia-driven revascularization of the target vessel, MI related to the target vessel, or 
cardiac death related to the target vessel.  If it cannot be determined with certainty whether the MI or death was 
related to the target vessel, it is considered a TVF. 
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Target Vessel, Non-Target Lesion, 
and Target Vessel, Non-Target 
Lesion Revascularization: 
Any lesion or revascularization of a lesion in the target vessel other than the target lesion, respectively. 
Target Vessel Revascularization 
(TVR): 
Any repeat percutaneous intervention or surgical bypass of any segment of the target vessel. In the assessment 
of TVR, angiograms should be assessed by an angiographic core laboratory (if designated) and made available 
to the CEC for review upon request. 
Vascular Complications: 
• 
Access site hematoma:  Development of a new, localized collection of blood at a vascular access site 
sufficient to produce a palpable mass within 72 hours of a procedure. 
• 
Arteriovenous fistula: Development of a new, unintended communication between an artery and a 
vein occurring at a vascular access site within 72 hours of a procedure. 
• 
Peripheral ischemia:  Development of new arterial insufficiency sufficient to produce clinical signs or 
symptoms of ischemia (pallor, pain, paresthesia) distal to a vascular access site within 72 hours of a 
procedure. 
• 
Peripheral nerve injury:  Development of new sensory or motor loss of peripheral nerve function 
from external nerve compression (e.g., as a result of positioning during a procedure), or internal 
compression or direct nerve damage from the procedure, occurring within 72 hours of a procedure. 
• 
Pseudoaneurysm:  Development of a new localized collection of blood with a persistent 
communication (neck) originating at a vascular access site and occurring within 72h of a procedure. 
• 
Retroperitoneal hemorrhage:  Development of new bleeding into the retroperitoneal space 
originating at a vascular access site and occurring within 72 hours of a procedure. 
Interventional Cardiology:  Angiographic Definitions 
Abrupt Closure: 
New intra-procedural severely reduced flow (TIMI grade 0-1) within the target vessel that persists and requires 
intervention by stenting or other treatment, or results in MI or death. Abrupt closure requires an association 
with a vascular dissection, thrombus, or severe spasm at the treatment site or within the instrumented vessel. 
Coronary Lesions Treated 
Coronary Artery 
Segments 
Definitions 
Right coronary artery 
ostium 
Origin of the right coronary artery, including the first 3 mm of the artery 
Proximal right coronary 
artery 
Proximal portion of the right coronary artery, from the ostium of the right 
coronary artery to the origin of the first right ventricular branch (pRCA) 
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Mid right coronary artery 
Middle portion of the right coronary artery, from the origin of the first right 
ventricular branch to the acute margin (mRCA) 
Distal right coronary 
artery 
Distal portion of the right coronary artery, from the acute margin to the origin 
of the posterior descending artery (dRCA) 
Right posterior 
descending artery 
In right dominant and mixed circulations, the vessel that runs in the posterior 
interventricular groove and supplies septal perforator branches (PDA) 
Posterolateral segmental 
artery 
In right dominant circulations, the distal continuation of the right coronary 
artery in the posterior atrioventricular groove after the origin of the right 
posterior descending artery (PLSA) 
First right posterolateral 
branch 
In right dominant circulations, the first posterolateral branch originating from 
the right posterior atrioventricular artery (RPL1) 
Second right 
posterolateral branch 
In right dominant circulations, the second posterolateral branch originating 
from the right posterior atrioventricular artery (RPL2) 
Third right posterolateral 
branch 
In right dominant circulations, the third posterolateral branch originating from 
the right posterior atrioventricular artery (RPL3) 
Posterior descending 
septal perforator 
Septal perforator vessel originating from the posterior descending artery 
Right ventricular branch 
Branch arising from the right coronary artery to supply the right ventricular 
wall (RV) 
Left main coronary artery 
ostium 
Origin of the left coronary artery, including the first 3 mm of the artery 
Left main coronary artery 
body 
Body of the left main coronary artery, from the ostium to the bifurcation (LM) 
Left main coronary artery 
bifucation 
Distal end of the left main, including the terminal 3 mm through the bifurcation 
of the left main into the left anterior descending and left circumflex arteries 
Left anterior descending 
artery ostium 
Origin of the left anterior descending coronary artery, including the first 3 mm 
of the artery 
Proximal left anterior 
descending 
artery 
Proximal portion of the left anterior descending coronary artery, from the 
ostium to the origin of the first septal (pLAD) 
Mid left anterior 
descending artery 
Middle portion of the left anterior descending coronary artery, from the origin 
of the first septal artery to the origin of the third septal artery (mLAD) 
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Distal left anterior 
descending artery 
Distal portion of the left anterior descending coronary artery, from the origin of 
the third septal artery to the terminus (dLAD) 
First diagonal branch 
First of the three longest branches originating from the left anterior descending 
artery to supply the anterolateral wall of the left ventricle (D1) 
First diagonal lateral 
branch 
Branch of the first diagonal branch 
Second diagonal branch 
Second of the three longest branches originating from the left anterior 
descending artery to supply the anterolateral wall of the left ventricle (D2) 
Second diagonal lateral 
branch 
Branch of the second diagonal branch 
Third diagonal branch 
Third of the three longest branches originating from the left anterior descending 
artery to supply the anterolateral wall of the left ventricle (D3) 
Third diagonal lateral 
branch 
Branch of the third diagonal branch 
Anterior descending 
septal perforator 
Septal perforator vessel originating from the left anterior descending artery to 
supply the interventricular septum 
Left circumflex artery 
ostium 
Origin of the left circumflex coronary artery, including the first 3 mm of the 
artery 
Proximal left circumflex 
artery 
Proximal portion of the left circumflex coronary artery, from the ostium to the 
origin (or the nominal location of) the first marginal branch (pLCX) 
Mid left circumflex artery 
Middle portion of the left circumflex coronary artery, from the origins of (or 
nominal locations of) the first marginal to the second marginal (mLCX) 
Distal left circumflex 
artery 
Distal portion of the left circumflex coronary artery, from the origin of (or the 
nominal location of) the second marginal to the terminus (in right dominant 
systems), or to the origin of the 1st left posterolateral in all other dominance 
systems (dLCX) 
First obtuse marginal 
branch 
First of the three longest branches originating from the left circumflex artery to 
supply the lateral wall of the left ventricle (OM1) 
First obtuse marginal 
lateral branch 
Branch of the first marginal branch 
Second obtuse marginal 
branch 
Second of the three longest branches originating from the left circumflex artery 
to supply the lateral wall of the left ventricle (OM2) 
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Second obtuse marginal 
lateral branch 
Branch of the second marginal branch 
Third obtuse marginal 
branch 
Third of the three longest branches originating from the left circumflex artery to 
supply the lateral wall of the left ventricle (OM3) 
Third obtuse marginal 
lateral branch 
Branch of the third marginal branch 
Left atrioventricular 
artery 
In left dominant and mixed circulations, the distal continuation of the left 
circumflex coronary artery in the posterior atrioventricular groove 
Left posterior descending 
artery 
In left dominant circulations, the vessel that arises from the distal continuation 
of the left atrioventricular artery, travels in the posterior interventricular groove, 
and supplies septal perforator branches (LPDA) 
First left posterolateral 
branch 
In left dominant and mixed circulations, the first posterolateral branch 
originating from the posterior atrioventricular left circumflex artery (LPL1) 
Second left posterolateral 
branch 
In left dominant and mixed circulations, the second posterolateral branch 
originating from the posterior atrioventricular left circumflex artery (LPL2) 
Third left posterolateral 
branch 
In left dominant and mixed circulations, the third posterolateral branch 
originating from the posterior atrioventricular left circumflex artery (LPL3) 
Ramus intermedius 
branch 
Branch vessel whose origin bisects the origins of the left anterior descending 
and circumflex arteries (RI) 
Ramus intermedius 
lateral branch 
Branch of the ramus intermedius branch 
Dissection: 
Based on the National Heart, Lung, and Blood Institute (NHLBI) Dissection Classification System: 
• 
Grade A: Minor radiolucencies within the lumen during contrast injection with no persistence after dye 
clearance  
• 
Grade B: Parallel tracts or double lumen separated by a radiolucent area during contrast injection with no 
persistence after dye clearance 
• 
Grade C: Extraluminal cap with persistence of contrast after dye clearance from the lumen 
• 
Grade D: Spiral luminal filling defect with delayed but complete distal flow 
• 
Grade E: New persistent filling defect with delayed antegrade flow 
• 
Grade F: Non-A-E types with total coronary occlusion and no distal antegrade flow 
Note: Grade E and F dissections may represent thrombus 
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Late Loss: 
Minimum lumen diameter (MLD) assessed at follow-up angiography minus the MLD assessed immediately 
after the index procedure.  MLDs are measured by QCA. 
Minimum Lumen Diameter (MLD): 
The mean minimum lumen diameter (typically measured in-lesion, in-stent, and in-segment) derived from two 
orthogonal views by QCA. 
No Reflow: 
An acute reduction in coronary flow (TIMI grade 0-1) in the absence of dissection, thrombus, spasm, or high-
grade residual stenosis at the original target lesion. 
Percent Diameter Stenosis (% DS): 
The value calculated as 100 x (1 – MLD/RVD) using the mean values determined by QCA from two 
orthogonal views (when possible). 
Reference Vessel Diameter (RVD): 
Defined as the average of normal segments within 10 mm proximal and 10 mm distal to the target lesion from 
two orthogonal views using QCA. 
Restenosis: 
Re-narrowing of the vessel following the treatment of a prior stenosis  
• 
Binary restenosis: A diameter stenosis of > 50% at the previously treated lesion site, including the 
originally treated site plus the adjacent vascular segments 5 mm proximal and 5 mm distal to the site. 
• 
In-stent restenosis (ISR): A previously stented lesion with a > 50% diameter stenosis. 
Thrombus (Angiographic): 
A discrete, mobile, intraluminal filling defect with defined borders with or without associated contrast staining. 
TIMI (Thrombolysis in Myocardial 
Infarction) Flow Grades: 
• 
Grade 0 (no perfusion): There is no antegrade flow beyond the point of occlusion. 
• 
Grade 1 (penetration without perfusion): The contrast material passes beyond the area of 
obstruction but “hangs up” and fails to opacify the entire coronary bed distal to the obstruction for the 
duration of the cineangiographic filming sequence. 
• 
Grade 2 (partial perfusion): The contrast material passes across the obstruction and opacifies the 
coronary bed distal to the obstruction. However, the rate of entry of contrast material into the vessel 
distal to the obstruction or its rate of clearance from the distal bed (or both) is perceptibly slower than 
its entry into or clearance from comparable areas not perfused by the previously occluded vessel (eg, 
the opposite coronary artery or the coronary bed proximal to the obstruction). 
• 
Grade 3 (complete perfusion): Antegrade flow into the bed distal to the obstruction occurs as 
promptly as antegrade flow into the bed proximal to the obstruction and clearance of contrast material 
from the involved bed is as rapid as from an uninvolved bed in the same vessel or the opposite artery. 
Vessels 
• 
Left main coronary artery (LMCA) 
• 
Left anterior descending artery (LAD) with septal and diagonal branches 
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• 
Left circumflex artery (LCX) with obtuse marginal branches 
• 
Ramus intermedius artery 
• 
Right coronary artery (RCA) and any of its branches 
• 
Posterior descending artery 
• 
Saphenous vein bypass graft(s) 
• 
Arterial bypass graft(s): Right internal mammary graft, left internal mammary graft, radial artery graft, 
and gastroepiploic artery graft. 
Peripheral Vascular Intervention 
Peripheral Vascular Intervention 
(PVI): 
Peripheral vascular interventiond is a catheter based or open surgical procedure designed to improve arterial or 
venous blood flow or otherwise modify or revise vascular conduits. Procedures may include, but are not limited 
to, percutaneous transluminal balloon angioplasty, stent placement, thrombectomy, embolectomy, atherectomy, 
dissection repair, aneurysm exclusion, treatment of dialysis conduits, placement of various devices, 
intravascular thrombolysis or other pharmacotherapies, and open surgical bypass or revision. 
In general, the intention to perform percutaneous peripheral vascular intervention is denoted by the insertion of 
a guide wire into a peripheral artery or vein. 
The target vessel(s) and the type of revascularization procedure (e.g., surgical bypass, thrombectomy, 
endarterectomy, percutaneous transluminal angioplasty, stent placement, thromboembolectomy, and 
thrombolysis) should be specified and recorded. For the sake of simplicity, this definition applies to the 
extracranial carotid artery and other non-cardiac arteries and veins and excludes the intracranial vessels and 
lymphatics. 
Procedural Success: 
In the case of percutaneous intervention for obstructive lesions, procedural success is defined as the 
achievement of a satisfactory final residual diameter stenosis by angiography at the end of the procedure (and 
without flow limiting dissection or hemodynamically significant translesional pressure gradient). The specific 
parameter for final percent residual stenosis is typically between <30% and <50%; selection of the appropriate 
percentage may vary depending upon the specific intervention applied, the vascular territory, and anticipated or 
desired therapeutic response.  Procedural success also implies absence of in-hospital major adverse events (eg, 
death, stroke, myocardial infarction, acute onset of limb ischemia, need for urgent/emergent vascular surgery, 
and other procedure-specific major adverse events).  The balloon inflation, stent placement, or other therapeutic 
intervention may be preceded by use of adjunctive devices (eg, percutaneous mechanical thrombectomy, 
directional or rotational atherectomy, laser, and chronic total occlusion crossing device), as predefined in the 
protocol. 
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Procedural Status: Non-Elective and 
Elective: 
e. 
Non-Elective: Non-elective procedures include emergent and urgent procedures.  A non elective 
procedure is a procedure that is performed without delay, because there is clinical consensus that the 
procedure should occur imminently. Non-elective procedures imply a degree of instability of the subject, 
urgency of the medical condition, or instability of the threatening lesion. 
− 
Emergent: A procedure that is performed immediately because of the acute nature of the 
medical condition (e.g., acute limb ischemia, acute aortic dissection), and the increased 
morbidity or mortality associated with a temporal delay in treatment. 
− 
Urgent: An urgent procedure is one that is not an emergency but is required to be performed 
on a timely basis (≤24 hrs) (e.g., a subject who has been stabilized following initial treatment 
of acute limb ischemia, and there is clinical consensus that a definitive procedure should 
occur within the next 24 hours). 
f. 
Elective: An elective procedure is one that is scheduled and is performed on a subject with stable 
disease, or in whom there is no urgency and/or increased morbidity or mortality associated with a 
planned procedure.  
Target Lesion: 
A target lesion is any vascular segment treated or attempted to be treated during the trial procedure with the 
index device. The target lesion is the treated segment starting 10 mm proximal and ending 10 mm distal to the 
index device or therapy (stent, balloon, atherectomy catheter, or aortic stent-graft). 
Target Vessel: 
A target vessel is any vessel (eg, non-cardiac or non-intracranial) that contains the target lesion treated with the 
study device. The target vessel includes the target lesion as well as the entire length of native vessel upstream 
and downstream from the target lesion, including side branches. For the arteries of the leg, the vasculature is 
divided into 3 vessel “levels:” aorto-iliac, femoral-popliteal, and tibial-crural. 
Non-Target Lesion and Non-Target 
Lesion Revascularization: 
A lesion for which revascularization is not attempted or one in which revascularization is performed using a 
non-study device, respectively. 
Non-Target Vessel and Non-Target 
Vessel Revascularization: 
A vessel for which revascularization is not attempted or one in which revascularization is performed using a 
non-study device, respectively. 
Target Vessel, Non-Target Lesion 
and Target Vessel, Non-Target 
Lesion Revascularization: 
Any lesion or revascularization of a lesion in the target vessel other than the target lesion, respectively. 
Target Lesion Revascularization 
(TLR): 
Target lesion revascularization is any repeat intervention of the target lesion (including 10 mm proximal and 
10 mm distal to the index device, as target lesion is defined above) or surgical intervention/bypass of the target 
vessel performed for restenosis or other complication involving the target lesion. In the assessment of TLR, 
angiograms should be assessed by an angiographic core laboratory (if designated).  Angiograms (and core 
laboratory assessment thereof) and other source documentation should be made available to the CEC for 
review upon request. 
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Target Vessel Revascularization 
(TVR): 
Target vessel revascularization is any repeat intervention or surgical bypass of any segment of the target vessel. 
In the assessment of TVR, angiograms should be assessed by an angiographic core laboratory (if designated).  
Angiograms (and core laboratory assessment thereof) and other source documentation should be made 
available to the CEC for review upon request. 
Clinically-Driven Target Lesion 
Revascularization: 
Clinically-driven target lesion revascularization is defined as target lesion revascularization performed due to 
target lesion diameter stenosis >50% AND either evidence of clinical or functional ischemia (eg, 
recurrent/progressive intermittent claudication, critical limb ischemia) OR recurrence of the clinical syndrome 
for which the initial procedure was performed.  Clinically-driven target lesion revascularization occurs in the 
absence of protocol-directed surveillance ultrasound or angiography. 
Vessel Patency: 
Vessel patency at a given time point will be determined by the absence of clinically-driven target lesion 
revascularization and/or absence of recurrent target lesion diameter stenosis >50% by imaging (eg, invasive 
angiography or most commonly, duplex ultrasonography). If patency data are incorporated within the primary 
endpoint of a clinical trial, the angiographic images or duplex ultrasonographic images should be assessed by 
appropriate core laboratories and made available to the AC for review upon request. 
Restenosis: 
Re-narrowing of the artery following the treatment of a prior stenosis  
• 
Binary restenosis: A diameter stenosis of >50% at the previously treated lesion site, including the 
originally treated site plus the adjacent vascular segments 10 mm proximal and 10 mm distal to the site 
(or as otherwise defined by the protocol, as noted above). 
• 
In-stent restenosis (ISR): A previously stented lesion that has >50% diameter stenosis. 
 
 
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Stent Thrombosis 
Stent Thrombosis: Timing 
Stent thrombosis should be reported as a cumulative value over time and at the various individual time points 
as specified below. Time 0 is defined as the time point after the guiding catheter has been removed and the 
subject has left the cardiac catheterization laboratory. 
 
Stent Thrombosis: Timing 
Acute stent thrombosis1 
0-24 hours post stent implantation 
Subacute stent thrombosis1 
>24 hours – 30 days post stent implantation 
Late stent thrombosis2 
>30 days – 1 year post stent implantation 
Very late stent thrombosis2 
>1 year post stent implantation 
1 
Acute or subacute can also be replaced by the term early stent thrombosis. Early stent thrombosis (0-30 days) will be 
used herein. 
2 
Includes “primary” as well as “secondary” late stent thrombosis; “secondary” late stent thrombosis is a stent thrombosis
after a target lesion revascularization. 
 
Stent Thrombosis Categories 
1. Definite Stent Thrombosis 
 
Definite stent thrombosis is considered to have occurred by either angiographic or pathological 
confirmation: 
a. Angiographic confirmation of stent thrombosise 
• 
The presence of a thrombusf that originates in the stent or in the segment 5 mm proximal or distal 
to the stent and presence of at least 1 of the following criteria within a 48-hour time window: 
− 
Acute onset of ischemic symptoms at rest 
− 
New ischemic ECG changes that suggest acute ischemia 
− 
Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous MI) 
− 
Nonocclusive thrombus:  Intracoronary thrombus is defined as a (spheric, ovoid, or irregular) 
noncalcified filling defect or lucency surrounded by contrast material (on 3 sides or within a 
coronary stenosis) seen in multiple projections, or persistence of contrast material within the 
lumen, or a visible embolization of intraluminal material downstream 
− 
Occlusive thrombus:  TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most 
adjacent proximal side branch or main branch (if originates from the side branch). 
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Definitions 
b. Pathological Confirmation of Stent Thrombosis:  Evidence of recent thrombus within the stent 
determined at autopsy or via examination of tissue retrieved following thrombectomy. 
2. Probable Stent Thrombosis:  Clinical definition of probable stent thrombosis is considered to have 
occurred after intracoronary stenting in the following cases: 
a.Any unexplained death within the first 30 daysg 
b. Irrespective of the time after the index procedure, any MI that is related to documented acute 
ischemia in the territory of the implanted stent without angiographic confirmation of stent 
thrombosis and in the absence of any other obvious cause 
3. 
Possible Stent Thrombosis:  Clinical definition of possible stent thrombosis is considered to have 
occurred with any unexplained death from 30 days after intracoronary stenting until end of trial 
follow-up. 
a  The 30-day cut-off is arbitrary. 
b  2012 Third Universal Definition of Myocardial Infarction. 
c The same criteria are used for supplemental leads V7-V9, and for the Cabrera frontal plane lead grouping. 
d Peripheral vascular disease includes veins, arteries, and lymphatics. However, for simplicity, this definition focuses on peripheral artery and venous 
interventions. 
e The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not considered a confirmed stent thrombosis 
(silent occlusion). 
f Intracoronary thrombus. 
g  For studies with ST-elevation MI population, one may consider the exclusion of unexplained death within 30 days as evidence of probable stent 
thrombosis. 
Source:  “Standardized Definitions for Cardiovascular and Stroke Endpoint Events in Clinical Trials,” dated August 20, 2014, and available at the CDISC 
website (http://www.cdisc.org/system/files/all/standard/Draft%20Definitions%20for%20CDISC%20August%2020,%202014.pdf). 
Note:  CEC = Cardiovascular Events Committee, which is referred to in the body of the protocol as the CAC = Cardiovascular Adjudication Committee 
 
 
 
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Event 
Mechanism/Classification 
Definitions 
Hospitalization 
for Unstable 
Angina 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Considerations 
1. Escalation of pharmacotherapy for ischemia, such 
as intravenous nitrates or increasing dosages of β-
blockers, should be considered supportive but not 
diagnostic of unstable angina.  However, a typical 
presentation and admission to the hospital with 
escalation of pharmacotherapy, without any of the 
additional findings listed under item 3 above, 
would be insufficient to support classification as 
hospitalization for unstable angina. 
2. If subjects are admitted with suspected unstable 
angina, and subsequent testing reveals a non- 
cardiac or non-ischemic etiology, this event should 
not be recorded as hospitalization for unstable 
angina.  Potential ischemic events meeting the 
criteria for MI should not be adjudicated as 
unstable angina. 
3. Planned hospitalization or rehospitalization for 
performance of an elective revascularization in 
subjects who do not fulfill the criteria for unstable 
angina should not be considered a hospitalization 
for unstable angina.   
• 
Hospitalization of a subject with stable exertional 
angina for coronary angiography and PCI that is 
prompted by a positive outpatient stress test should 
not be considered hospitalization for unstable 
angina. 
• 
Rehospitalization of a subject meeting the criteria 
for unstable angina who was stabilized, discharged, 
and subsequently readmitted for revascularization, 
Unstable angina requiring hospitalization is defined as: 
1. Ischemic discomfort (angina, or symptoms 
thought to be equivalent) ≥10 minutes in 
duration occurring 
• 
at rest, or 
• 
in an accelerating pattern with frequent episodes 
associated with progressively decreased exercise 
capacity. 
AND 
2. Prompting an unscheduled hospitalization 
within 24 hours of the most recent 
symptoms.  Hospitalization is defined as an 
admission to an inpatient unit or a visit to an 
emergency department that results in at least 
a 24 hour stay (or a change in calendar date 
if the hospital admission or discharge times 
are not available). 
AND 
3. At least one of the following: 
a. 
New or worsening ST or T wave changes on 
resting ECG (in the absence of confounders, 
such as LBBB or LVH) 
• 
Transient ST elevation (duration 
<20 minutes) New ST elevation at the 
J point in two contiguous leads with the cut-
points: ≥0.1 mV in all leads other than leads 
V2-V3 where the following cut-points 
apply: ≥0.2 mV in men ≥40 years (≥0.25mV 
in men <40 years) or ≥0.15 mV in women. 
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Definitions 
Hospitalization 
for Unstable 
Angina 
(Continued) 
does not constitute a second hospitalization for 
unstable angina. 
A subject who undergoes an elective catheterization where incidental 
coronary artery disease is found and who subsequently undergoes 
coronary revascularization will not be considered as meeting the 
hospitalization for unstable angina endpoint. 
• 
ST depression and T-wave changes 
• 
New horizontal or down-sloping ST 
depression ≥0.05 mV in two contiguous 
leads and/or new T inversion ≥0.3 mV in 
two contiguous leads with prominent R 
wave or R/S ratio >1. 
b. Definite evidence of inducible myocardial 
ischemia event as demonstrated by: 
• 
an early positive exercise stress test, defined 
as ST elevation or ≥2 mm ST depression 
prior to 5 mets OR 
• 
stress echocardiography (reversible wall 
motion abnormality) OR 
• 
myocardial scintigraphy (reversible 
perfusion defect), OR 
• 
magnetic resonance imaging (MRI; 
myocardial perfusion deficit under 
pharmacologic stress). 
• 
And believed to be responsible for the 
myocardial ischemic symptoms/signs. 
c. 
Angiographic evidence of new or worse ≥70% 
lesion (≥50% for left main lesion) and/or 
thrombus in an epicardial coronary artery that is 
believed to be responsible for the myocardial 
ischemic symptoms/signs. 
d. Need for coronary revascularization procedure 
(PCI or CABG) for the presumed culprit 
lesion(s).  This criterion would be fulfilled if 
revascularization was undertaken during the 
unscheduled hospitalization, or subsequent to 
transfer to another institution without interceding 
home discharge. 
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Definitions 
AND 
4. Negative cardiac biomarkers and no 
evidence of acute MI 
Transient 
Ischemic 
Attack (TIA) 
and Stroke  
 
 
 
 
 
 
 
 
 
 
TIA 
TIA is defined as a transient episode of focal neurological 
dysfunction caused by brain, spinal cord, or retinal ischemia, 
without acute infarction. 
Stroke Classification: 
A. Ischemic Stroke 
Ischemic stroke is defined as an acute episode of focal cerebral, 
spinal, or retinal dysfunction caused by infarction of central nervous 
system tissue. 
Hemorrhage may be a consequence of ischemic stroke.  In this 
situation, the stroke is an ischemic stroke with hemorrhagic 
transformation and not a hemorrhagic stroke. 
B. Hemorrhagic Stroke 
Hemorrhagic stroke is defined as an acute episode of focal or global 
cerebral or spinal dysfunction caused by intraparenchymal, 
intraventricular, or subarachnoid hemorrhage. 
C. Undetermined Stroke 
Undetermined stroke is defined as an acute episode of focal or global 
neurological dysfunction caused by presumed brain, spinal cord, or 
retinal vascular injury as a result of hemorrhage or infarction but with 
insufficient information to allow categorization as A or B.  
 
Stroke is defined as an acute episode of focal or global 
neurological dysfunction caused by brain, spinal cord, or 
retinal vascular injury as a result of hemorrhage or infarction. 
 
 
 
 
 
 
 
 
 
 
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Definitions 
 
 
Transient 
Ischemic 
Attack (TIA) 
and Stroke 
(Continued) 
 
 
D. Stroke Disability 
Disability should be measured by a reliable and valid scale in all 
cases, typically at each visit and 90 days after the event.  For example, 
the modified Rankin Scale may be used to address this requirement: 
Scale Disability 
0 
No symptoms at all 
1 
No significant disability despite symptoms; able to 
carry out all usual duties and activities 
2 
Slight disability; unable to carry out all previous 
activities, but able to look after own affairs without 
assistance 
3 
Moderate disability; requiring some help, but able to 
walk without assistance 
4 
Moderately severe disability; unable to walk 
without assistance and unable to attend to own 
bodily needs without assistance 
5 
Severe disability; bedridden, incontinent and requiring 
constant nursing care and attention 
6 
Dead 
 
 
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Definitions 
HF Event : 
A HF event 
includes 
hospitalization 
for HF and may 
include urgent 
outpatient 
visits.  HF 
hospitalizations 
should remain 
delineated from 
urgent visits.  If 
urgent visits are 
included in the 
HF endpoint, 
the number of 
urgent visits 
needs to be 
explicitly 
presented 
separately from 
the 
hospitalizations. 
 
 
 
 
 
 
 
 
 
 
A HF hospitalization is defined as an event that meets ALL of 
the following criteria: 
1. The subject is admitted to the hospital with a 
primary diagnosis of HF 
2. The subject’s length-of-stay in hospital 
extends for at least 24 hours (or a change in 
calendar date if the hospital admission and 
discharge times are unavailable) 
3. The subject exhibits documented new or 
worsening symptoms due to HF on 
presentation, including at least ONE of the 
following: 
• 
Dyspnea (dyspnea with exertion, dyspnea at 
rest, orthopnea, paroxysmal nocturnal 
dyspnea) 
• 
Decreased exercise tolerance 
• 
Fatigue 
• 
Other symptoms of worsened end-organ 
perfusion or volume overload (must be 
specified and described by the protocol) 
4. The subject has objective evidence of new 
or worsening HF, consisting of at least TWO 
physical examination findings OR one 
physical examination finding and at least 
ONE laboratory criterion), including: 
a. 
Physical examination findings considered to be 
due to HF, including new or worsened: 
i.Peripheral edema 
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Event 
Mechanism/Classification 
Definitions 
HF Event 
(Continued): 
A HF event 
includes 
hospitalization 
for HF and may 
include urgent 
outpatient 
visits.  HF 
hospitalizations 
should remain 
delineated from 
urgent visits.  If 
urgent visits are 
included in the 
HF endpoint, 
the number of 
urgent visits 
needs to be 
explicitly 
presented 
separately from 
the 
hospitalizations.  
 
 
 
 
 
 
 
 
ii.Increasing abdominal distention or ascites (in 
the absence of primary hepatic disease) 
iii.Pulmonary rales/crackles/crepitations 
iv.Increased jugular venous pressure and/or 
hepatojugular reflux 
v.S3 gallop 
vi.Clinically significant or rapid weight gain 
thought to be related to fluid retention 
b. Laboratory evidence of new or worsening HF, if 
obtained within 24 hours of presentation, 
including: 
i.Increased B-type natriuretic peptide 
(BNP)/ N-terminal pro-BNP (NT pro-BNP) 
concentrations consistent with decompensation 
of HF (such as BNP >500 pg/mL or NT-proBNP 
>2,000 pg/mL).  In subjects with chronically 
elevated natriuretic peptides, a significant 
increase should be noted above baseline. 
ii.Radiological evidence of pulmonary 
congestion 
iii.Non-invasive diagnostic evidence of clinically 
significant elevated left- or right-sided 
ventricular filling pressure or low cardiac output.  
For example, ECG criteria could include: E/e’ 
>15 or D-dominant pulmonary venous inflow 
pattern, plethoric inferior vena cava with 
minimal collapse on inspiration, or decreased left 
ventricular outflow tract (LVOT) minute stroke 
distance (time velocity integral [TVI]) 
OR 
iv.Invasive diagnostic evidence with right heart 
catheterization showing a pulmonary capillary 
wedge pressure (pulmonary artery occlusion 
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Event 
Mechanism/Classification 
Definitions 
HF Event 
(Continued): 
A HF event 
includes 
hospitalization 
for HF and may 
include urgent 
outpatient 
visits.  HF 
hospitalizations 
should remain 
delineated from 
urgent visits.  If 
urgent visits are 
included in the 
HF endpoint, 
the number of 
urgent visits 
needs to be 
explicitly 
presented 
separately from 
the 
hospitalizations.  
 
pressure) ≥18 mmHg, central venous pressure 
≥12 mmHg, or a cardiac index <2.2 L/min/m2 
Note: All results from diagnostic tests should be reported, if 
available, even if they do not meet the above criteria, because 
they provide important information for the adjudication of 
these events. 
5. The subject receives initiation or 
intensification of treatment specifically for 
HF, including at least ONE of the following: 
a. 
Augmentation in oral diuretic therapy 
b. Intravenous diuretic or vasoactive agent (eg, 
inotrope, vasopressor, or vasodilator) 
c. 
Mechanical or surgical intervention, including: 
i.Mechanical circulatory support (eg, intra-aortic 
balloon pump, ventricular assist device, 
extracorporeal membrane oxygenation, total 
artificial heart) 
ii.Mechanical fluid removal (eg, ultrafiltration, 
hemofiltration, dialysis) 
An urgent HF visit is defined as an event that meets all of the 
following: 
6. The subject has an urgent, unscheduled 
office/practice or emergency department 
visit for a primary diagnosis of HF, but not 
meeting the criteria for a HF hospitalization 
(i.e. urgent outpatient visit) 
7. All signs and symptoms for HF 
hospitalization (ie, symptoms and physical 
examination findings/laboratory evidence of 
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new or worsening HF, as indicated above) 
must be met 
8. The subject receives initiation or 
intensification of treatment specifically for 
HF, as detailed in the above section with the 
exception of oral diuretic therapy, which 
will not be sufficient. 
a  ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non ST- 954 Elevation Myocardial Infarction: Executive Summary.  A 
Report of the American College of 955 Cardiology/American Heart Association Task Force on Practice Guidelines (Writing 956 Committee to Revise the 
2002 Guidelines for the Management of Patients With Unstable 957 Angina/Non ST-Elevation Myocardial Infarction):  Developed in Collaboration with 
the 958 American College of Emergency Physicians, the Society for Cardiovascular Angiography 959 and Interventions, and the Society of Thoracic 
Surgeons: Endorsed by the American 960 Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic 961 Emergency 
Medicine, Circulation, 2007, 116:803-877. 
b The same criteria are used for supplemental leads V7-V9, and for the Cabrera frontal plane lead grouping. 
Source:  “Standardized Definitions for Cardiovascular and Stroke Endpoint Events in Clinical Trials,” dated August 20, 2014, and available at the CDISC 
website (http://www.cdisc.org/system/files/all/standard/Draft%20Definitions%20for%20CDISC%20August%2020,%202014.pdf) 
 
 
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APPENDIX E. ATORVASTATIN PRESCRIBING INFORMATION 
 
 
 
 
 
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ATORVASTATIN CALCIUM- atorvastatin calcium trihydrate tablet, film coated 
Greenstone LLC
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
 atorvastatin calcium tablets safely and effectively. See full
 prescribing information for atorvastatin calcium tablets.
 Atorvastatin Calcium Tablets for oral administration
 Initial U.S. Approval: 1996
INDICATIONS AND USAGE
Atorvastatin calcium is an inhibitor of HMG-CoA reductase (statin)
 indicated as an adjunct therapy to diet to:
Reduce the risk of MI, stroke, revascularization procedures, and
 angina in patients without CHD, but with multiple risk factors
 (1.1).
Reduce the risk of MI and stroke in patients with type 2 diabetes
 without CHD, but with multiple risk factors (1.1).
Reduce the risk of non-fatal MI, fatal and non-fatal stroke,
 revascularization procedures, hospitalization for CHF, and angina
 in patients with CHD (1.1).
Reduce elevated total-C, LDL-C, apo B, and TG levels and
 increase HDL-C in adult patients with primary hyperlipidemia
 (heterozygous familial and nonfamilial) and mixed dyslipidemia
 (1.2).
Reduce elevated TG in patients with hypertriglyceridemia and
 primary dysbetalipoproteinemia (1.2).
Reduce total-C and LDL-C in patients with homozygous familial
 hypercholesterolemia (HoFH) (1.2).
Reduce elevated total-C, LDL-C, and apo B levels in boys and
 postmenarchal girls, 10 to 17 years of age, with heterozygous
 familial hypercholesterolemia after failing an adequate trial of
 diet therapy (1.2).
Limitations of Use
Atorvastatin calcium tablets have not been studied in Fredrickson
 Types I and V dyslipidemias.
DOSAGE AND ADMINISTRATION
Dose range: 10 to 80 mg once daily (2.1).
Recommended start dose: 10 or 20 mg once daily (2.1).
Patients requiring large LDL-C reduction (>45%) may start at 40 mg
 once daily (2.1).
Pediatric starting dose: 10 mg once daily; maximum recommended
 dose: 20 mg once daily (2.2).
DOSAGE FORMS AND STRENGTHS
10, 20, 40, and 80 mg tablets (3).
CONTRAINDICATIONS
Active liver disease, which may include unexplained persistent
 elevations in hepatic transaminase levels (4.1).
Women who are pregnant or may become pregnant (4.3).
Nursing mothers (4.4).
Hypersensitivity to any component of this medication (4.2).
WARNINGS AND PRECAUTIONS
Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks
 increase when higher doses are used concomitantly with cyclosporine
 and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole,
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http://labeling.greenstonellc.com/ShowLabeling.aspx?id=983[10/8/2015 12:57:02 PM]
 HIV protease inhibitors). Predisposing factors include advanced age
 (> 65), uncontrolled hypothyroidism, and renal impairment. Rare
 cases of rhabdomyolysis with acute renal failure secondary to
 myoglobinuria have been reported. Advise patients to promptly report
 to their physician unexplained and/or persistent muscle pain,
 tenderness, or weakness. Atorvastatin therapy should be discontinued
 if myopathy is diagnosed or suspected (5.1, 8.5).
Liver enzyme abnormalities: Persistent elevations in hepatic
 transaminases can occur. Check liver enzyme tests before initiating
 therapy and as clinically indicated thereafter (5.2).
A higher incidence of hemorrhagic stroke was seen in patients without
 CHD but with stroke or TIA within the previous 6 months in the
 atorvastatin calcium tablets 80 mg group vs. placebo (5.5).
ADVERSE REACTIONS
The most commonly reported adverse reactions (incidence ≥ 2%) in
 patients treated with atorvastatin calcium tablets in placebo-
controlled trials regardless of causality were: nasopharyngitis,
 arthralgia, diarrhea, pain in extremity, and urinary tract infection
 (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact
 Greenstone LLC at 1-800-438-1985 or FDA at 1-800-FDA-1088
 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Drug Interactions Associated with Increased Risk of
 Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents
Prescribing Recommendations
Cyclosporine, HIV protease
 inhibitors (tipranavir plus
 ritonavir), hepatitis C protease
 inhibitor (telaprevir)
Avoid atorvastatin
HIV protease inhibitor (lopinavir
 plus ritonavir)
Use with caution and lowest
 dose necessary
Clarithromycin, itraconazole,
 HIV protease inhibitors
 (saquinavir plus ritonavir,
 darunavir plus ritonavir,
 fosamprenavir, fosamprenavir
 plus ritonavir )
Do not exceed 20 mg
 atorvastatin daily
HIV protease inhibitor
 (nelfinavir)
Hepatitis C protease inhibitor
 (boceprevir)
Do not exceed 40 mg
 atorvastatin daily
Other Lipid-Lowering Medications: Use with fibrate products or
 lipid-modifying doses (≥1 g/day) of niacin increases the risk of
 adverse skeletal muscle effects. Caution should be used when
 prescribing with atorvastatin calcium tablets (7).
Digoxin: Patients should be monitored appropriately (7.8).
Oral Contraceptives: Values for norethindrone and ethinyl
 estradiol may be increased (7.9).
Rifampin should be simultaneously co-administered with
 atorvastatin calcium tablets (7.7).
USE IN SPECIFIC POPULATIONS
Hepatic impairment: Plasma concentrations markedly increased in
 patients with chronic alcoholic liver disease (12.3).
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See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 3/2015
FULL PRESCRIBING INFORMATION:
 CONTENTS*
1	INDICATIONS AND USAGE
1.1	Prevention of Cardiovascular Disease
1.2	Hyperlipidemia
1.3 Limitations of Use
2 DOSAGE AND ADMINISTRATION
2.1 Hyperlipidemia (Heterozygous Familial and
 Nonfamilial) and Mixed Dyslipidemia (Fredrickson
 Types IIa and IIb)
2.2	Heterozygous Familial Hypercholesterolemia in
 Pediatric Patients (10–17 years of age)
2.3 Homozygous Familial Hypercholesterolemia
2.4 Concomitant Lipid-Lowering Therapy
2.5 Dosage in Patients With Renal Impairment
2.6 Dosage in Patients Taking Cyclosporine,
 Clarithromycin, Itraconazole, or Certain Protease
 Inhibitors
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
4.1 Active liver disease, which may include
 unexplained persistent elevations in hepatic
 transaminase levels
4.2 Hypersensitivity to any component of this
 medication
4.3 Pregnancy
4.4 Nursing mothers
5 WARNINGS AND PRECAUTIONS
5.1 Skeletal Muscle
5.2 Liver Dysfunction
5.3 Endocrine Function
5.4 CNS Toxicity
5.5 Use in Patients with Recent Stroke or TIA
6 ADVERSE REACTIONS
6.1 Clinical Trial Adverse Experiences
6.2	Postmarketing Experience
6.3	Pediatric Patients (ages 10–17 years)
7 DRUG INTERACTIONS
7.1 Strong Inhibitors of CYP 3A4
7.2 Grapefruit Juice
7.3 Cyclosporine
7.4 Gemfibrozil
7.5 Other Fibrates
7.6 Niacin
7.7 Rifampin or other Inducers of Cytochrome P450
 3A4
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7.8 Digoxin
7.9 Oral Contraceptives
7.10 Warfarin
7.11 Colchicine
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6	Hepatic Impairment
10	OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2	Pharmacodynamics
12.3	Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of
 Fertility
14 CLINICAL STUDIES
14.1 Prevention of Cardiovascular Disease
14.2 Hyperlipidemia (Heterozygous Familial and
 Nonfamilial) and Mixed Dyslipidemia (Fredrickson
 Types IIa and IIb)
14.3 Hypertriglyceridemia (Fredrickson Type IV)
14.4 Dysbetalipoproteinemia (Fredrickson Type III)
14.5 Homozygous Familial Hypercholesterolemia
14.6 Heterozygous Familial Hypercholesterolemia in
 Pediatric Patients
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1	Muscle Pain
17.2	Liver Enzymes
17.3	Pregnancy
17.4 Breast-feeding
*
FULL PRESCRIBING INFORMATION
1	INDICATIONS AND USAGE
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at
 significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is
 recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other
 nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD,
 atorvastatin calcium tablets can be started simultaneously with diet.
Sections or subsections omitted from the full prescribing
 information are not listed.
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1.1	Prevention of Cardiovascular Disease
In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart
 disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease,
 atorvastatin calcium tablets are indicated to:
Reduce the risk of myocardial infarction
Reduce the risk of stroke
Reduce the risk for revascularization procedures and angina
In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors
 for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets
 are indicated to:
Reduce the risk of myocardial infarction
Reduce the risk of stroke
In patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to:
Reduce the risk of non-fatal myocardial infarction
Reduce the risk of fatal and non-fatal stroke
Reduce the risk for revascularization procedures
Reduce the risk of hospitalization for CHF
Reduce the risk of angina
1.2	Hyperlipidemia
Atorvastatin calcium tablets are indicated:
As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients
 with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson
 Types IIa and IIb);
As an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV);
For the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond
 adequately to diet;
To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other
 lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable;
As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years
 of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following
 findings are present:
a. LDL-C remains ≥ 190 mg/dL or
b. LDL-C remains ≥ 160 mg/dL and:
there is a positive family history of premature cardiovascular disease or
two or more other CVD risk factors are present in the pediatric patient
1.3 Limitations of Use
Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation
 of chylomicrons (Fredrickson Types I and V).
2 DOSAGE AND ADMINISTRATION
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2.1 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa
 and IIb)
The recommended starting dose of atorvastatin calcium tablets is 10 or 20 mg once daily. Patients who require a large
 reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin calcium
 tablets is 10 to 80 mg once daily. Atorvastatin calcium tablets can be administered as a single dose at any time of the
 day, with or without food. The starting dose and maintenance doses of atorvastatin calcium tablets should be
 individualized according to patient characteristics such as goal of therapy and response (see current NCEP
 Guidelines). After initiation and/or upon titration of atorvastatin calcium tablets, lipid levels should be analyzed
 within 2 to 4 weeks and dosage adjusted accordingly.
2.2	Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10–17 years of age)
The recommended starting dose of atorvastatin calcium tablets is 10 mg/day; the maximum recommended dose is 20
 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized
 according to the recommended goal of therapy [see current NCEP Pediatric Panel Guidelines, Clinical
 Pharmacology (12), and Indications and Usage (1.2)]. Adjustments should be made at intervals of 4 weeks or more.
2.3 Homozygous Familial Hypercholesterolemia
The dosage of atorvastatin calcium tablets in patients with homozygous FH is 10 to 80 mg daily. Atorvastatin calcium
 tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if
 such treatments are unavailable.
2.4 Concomitant Lipid-Lowering Therapy
Atorvastatin calcium tablets may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors
 (statins) and fibrates should generally be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1),
 Drug Interactions (7)].
2.5 Dosage in Patients With Renal Impairment
Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin calcium tablets; thus,
 dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions, Skeletal
 Muscle (5.1), Clinical Pharmacology, Pharmacokinetics (12.3)].
2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors
In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease
 inhibitor (telaprevir), therapy with atorvastatin calcium tablets should be avoided. In patients with HIV taking
 lopinavir plus ritonavir, caution should be used when prescribing atorvastatin calcium tablets and the lowest dose
 necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of
 saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with
 atorvastatin calcium tablets should be limited to 20 mg, and appropriate clinical assessment is recommended to
 ensure that the lowest dose necessary of atorvastatin calcium tablets is employed. In patients taking the HIV protease
 inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with atorvastatin calcium tablets should
 be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of
 atorvastatin calcium tablets is employed [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions
 (7)].
3 DOSAGE FORMS AND STRENGTHS
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White, elliptical, film-coated tablets containing 10, 20, 40, and 80 mg atorvastatin calcium.
4 CONTRAINDICATIONS
4.1 Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels
 
4.2 Hypersensitivity to any component of this medication
 
4.3 Pregnancy
Women who are pregnant or may become pregnant. Atorvastatin calcium tablets may cause fetal harm when
 administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and
 cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and
 discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term
 therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of atorvastatin calcium
 tablets use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine
 exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity.
 ATORVASTATIN CALCIUM TABLETS SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING
 AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN
 INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, atorvastatin
 calcium tablets should be discontinued immediately and the patient apprised of the potential hazard to the fetus [see
 Use in Specific Populations (8.1)].
4.4 Nursing mothers
It is not known whether atorvastatin is excreted into human milk; however a small amount of another drug in this
 class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants,
 women who require atorvastatin calcium tablets treatment should not breastfeed their infants [see Use in Specific
 Populations (8.3)].
5 WARNINGS AND PRECAUTIONS
5.1 Skeletal Muscle
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with
 atorvastatin calcium tablets and with other drugs in this class. A history of renal impairment may be a risk factor
 for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in
 conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The concomitant use of higher
 doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin,
 itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy,
 associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase,
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 which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without
 significant inflammation; improvement with immunosuppressive agents.
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked
 elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness,
 particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing
 atorvastatin calcium tablets. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or
 myopathy is diagnosed or suspected.
The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of
 cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir,
 combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus
 ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals.
 Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, clarithromycin,
 a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or
 fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the
 potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain,
 tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage
 titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken
 concomitantly with the aforementioned drugs (see Drug Interactions (7)). Periodic creatine phosphokinase (CPK)
 determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the
 occurrence of severe myopathy.
Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration
 (2.6), Drug Interactions (7), Clinical Pharmacology (12.3)].
Table 1. Drug Interactions Associated with Increased Risk of
 Myopathy/Rhabdomyolysis
Interacting Agents
Prescribing Recommendations
*
Cyclosporine, HIV protease
 inhibitors (tipranavir plus ritonavir),
 hepatitis C protease inhibitor
 (telaprevir)
Avoid atorvastatin
HIV protease inhibitor (lopinavir
 plus ritonavir)
Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV
 protease inhibitors (saquinavir plus
 ritonavir , darunavir plus ritonavir,
 fosamprenavir, fosamprenavir plus
 ritonavir)
Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
 (boceprevir)
Do not exceed 40 mg atorvastatin daily
Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine,
 and caution should be exercised when prescribing atorvastatin with colchicine [see Drug Interactions (7.11)].
Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious
 condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure
 secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe
 metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
Use with caution and with the lowest dose necessary (12.3)
*
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5.2 Liver Dysfunction
Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver
 function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in
 serum transaminases occurred in 0.7% of patients who received atorvastatin calcium tablets in clinical trials.
 The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.
One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not
 associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or
 discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients
 with persistent LFT elevations continued treatment with a reduced dose of atorvastatin calcium tablets.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin calcium tablets and
 repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in
 patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or
 hyperbilirubinemia or jaundice occurs during treatment with atorvastatin calcium tablets, promptly interrupt therapy.
 If an alternate etiology is not found, do not restart atorvastatin calcium tablets.
Atorvastatin calcium tablets should be used with caution in patients who consume substantial quantities of alcohol
 and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are
 contraindications to the use of atorvastatin calcium tablets [see Contraindications (4.1)].
5.3 Endocrine Function
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors,
 including atorvastatin calcium tablets.
Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production.
 Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal
 reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if
 any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is
 administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such
 as ketoconazole, spironolactone, and cimetidine.
5.4 CNS Toxicity
Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve
 vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating
 doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human
 plasma area-under-the-curve (AUC, 0–24 hours) based on the maximum human dose of 80 mg/day. A single tonic
 convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year
 study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400
 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat)
 the human AUC (0–24) based on the maximum recommended human dose of 80 mg/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of
 perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug
 in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically
 normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the
 mean drug level in humans taking the highest recommended dose.
5.5 Use in Patients with Recent Stroke or TIA
In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study
 where atorvastatin calcium tablets 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a
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 stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin
 calcium tablets 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI:
 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for
 the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly
 higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline
 characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of
 hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]
Liver enzyme abnormalities [see Warnings and Precautions (5.2)]
6.1 Clinical Trial Adverse Experiences
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the
 clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect
 the rates observed in clinical practice.
In the atorvastatin calcium tablets placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin
 calcium tablets vs. 7311 placebo; age range 10–93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4%
 other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin calcium tablets and 9.5% of the
 patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse
 reactions in patients treated with atorvastatin calcium tablets that led to treatment discontinuation and occurred at a
 rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase
 (0.4%), and hepatic enzyme increase (0.4%).
The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in
 patients treated with atorvastatin calcium tablets in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%),
 arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).
Table 2 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate
 greater than placebo in patients treated with atorvastatin calcium tablets (n=8755), from seventeen placebo-controlled
 trials.
Table 2. Clinical adverse reactions occurring in ≥ 2% in patients treated with any dose
 of atorvastatin calcium tablets and at an incidence greater than placebo regardless of
 causality (% of patients).
Adverse Reaction
Any dose
N=8755
10 mg
N=3908
20 mg
N=188
40 mg
N=604
80 mg
N=4055
Placebo
N=7311
Nasopharyngitis
8.3
12.9
5.3
7.0
4.2
8.2
Arthralgia
6.9
8.9
11.7
10.6
4.3
6.5
Diarrhea
6.8
7.3
6.4
14.1
5.2
6.3
Pain in extremity
6.0
8.5
3.7
9.3
3.1
5.9
Urinary tract infection 5.7
6.9
6.4
8.0
4.1
5.6
Dyspepsia
4.7
5.9
3.2
6.0
3.3
4.3
Nausea
4.0
3.7
3.7
7.1
3.8
3.5
Musculoskeletal pain
3.8
5.2
3.2
5.1
2.3
3.6
Muscle Spasms
3.6
4.6
4.8
5.1
2.4
3.0
*
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*
Myalgia
3.5
3.6
5.9
8.4
2.7
3.1
Insomnia
3.0
2.8
1.1
5.3
2.8
2.9
Pharyngolaryngeal
 pain
2.3
3.9
1.6
2.8
0.7
2.1
Other adverse reactions reported in placebo-controlled studies include:
Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis,
 cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and
 nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine
 phosphokinase increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin and
 appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: white blood cells urine positive.
Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
In ASCOT [see Clinical Studies (14.1)] involving 10,305 participants (age range 40–80 years, 19% women; 94.6%
 Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with atorvastatin calcium tablets 10 mg
 daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with atorvastatin calcium
 tablets was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up.
Collaborative Atorvastatin Diabetes Study (CARDS)
In CARDS [see Clinical Studies (14.1)] involving 2,838 subjects (age range 39–77 years, 32% women; 94.3%
 Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes treated with atorvastatin
 calcium tablets 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in the overall frequency of
 adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years.
 No cases of rhabdomyolysis were reported.
Treating to New Targets Study (TNT)
In TNT [see Clinical Studies (14.1)] involving 10,001 subjects (age range 29–78 years, 19% women; 94.1%
 Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with atorvastatin calcium
 tablets 10 mg daily (n=5006) or atorvastatin calcium tablets 80 mg daily (n=4995), there were more serious adverse
 reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%,
 respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of
 4.9 years. Persistent transaminase elevations (≥3 × ULN twice within 4–10 days) occurred in 62 (1.3%) individuals
 with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 × ULN) were
 low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose
 atorvastatin group (6, 0.1%).
Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL)
In IDEAL [see Clinical Studies (14.1)] involving 8,888 subjects (age range 26–80 years, 19% women; 99.3%
 Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with atorvastatin calcium tablets 80 mg/day (n=4439)
 or simvastatin 20–40 mg daily (n=4449), there was no difference in the overall frequency of adverse reactions or
 serious adverse reactions between the treatment groups during a median follow-up of 4.8 years.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
In SPARCL involving 4731 subjects (age range 21–92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6%
 Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the
 previous 6 months treated with atorvastatin calcium tablets 80 mg (n=2365) or placebo (n=2366) for a median
 follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations (≥ 3 × ULN twice
Adverse Reaction ≥ 2% in any dose greater than placebo
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 within 4–10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 × ULN) were
 rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an
 adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group [see
 Warnings and Precautions (5.5)].
In a post-hoc analysis, atorvastatin calcium tablets 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2%
 vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%)
 compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin calcium
 tablets vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin
 group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes).
 Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7
 (16%) atorvastatin calcium tablets vs. 2 (4%) placebo].
There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the
 atorvastatin calcium tablets 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who
 experienced cardiovascular death were numerically smaller in the atorvastatin calcium tablets 80 mg group (3.3%)
 than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were
 numerically larger in the atorvastatin calcium tablets 80 mg group (5.0%) than in the placebo group (4.0%).
6.2	Postmarketing Experience
The following adverse reactions have been identified during postapproval use of atorvastatin calcium tablets. Because
 these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
 estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions associated with atorvastatin therapy reported since market introduction, that are not listed above,
 regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes
 (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis,
 myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, and
 pancreatitis.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and
 Precautions (5.1)].
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia,
 memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins.
 The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom
 onset (1 day to years) and symptom resolution (median of 3 weeks).
6.3	Pediatric Patients (ages 10–17 years)
In a 26-week controlled study in boys and postmenarchal girls (n=140, 31% female; 92% Caucasians, 1.6% Blacks,
 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin calcium tablets 10 to 20 mg daily was
 generally similar to that of placebo [see Clinical Studies (14.6) and Use in Special Populations, Pediatric Use (8.4)].
7 DRUG INTERACTIONS
The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid
 derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV
 protease inhibitors, and itraconazole) [see Warnings and Precautions, Skeletal Muscle (5.1) and Clinical
 Pharmacology (12.3)].
7.1 Strong Inhibitors of CYP 3A4
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Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin calcium tablets
 with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of
 interaction and potentiation of effects depend on the variability of effect on CYP 3A4.
 Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin
 calcium tablets 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin calcium tablets
 alone [see Clinical Pharmacology (12.3)]. Therefore, in patients taking clarithromycin, caution should be used when
 the atorvastatin dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and
 Administration (2.6)].
Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant
 administration of atorvastatin calcium tablets with several combinations of HIV protease inhibitors, as well as with
 the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin calcium tablets alone [see Clinical
 Pharmacology (12.3)]. Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the
 hepatitis C protease inhibitor telaprevir, concomitant use of atorvastatin calcium tablets should be avoided. In
 patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing
 atorvastatin calcium tablets and the lowest dose necessary should be used. In patients taking the HIV protease
 inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose
 of atorvastatin calcium tablets should not exceed 20 mg and should be used with caution [see Warnings and
 Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)]. In patients taking the HIV protease
 inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of atorvastatin calcium tablets should not
 exceed 40 mg and close clinical monitoring is recommended.
Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium
 tablets 40 mg and itraconazole 200 mg [see Clinical Pharmacology (12.3)]. Therefore, in patients taking
 itraconazole, caution should be used when the atorvastatin dose exceeds 20 mg [see Warnings and Precautions,
 Skeletal Muscle (5.1) and Dosage and Administration (2.6)].
7.2 Grapefruit Juice
Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin,
 especially with excessive grapefruit juice consumption (>1.2 liters per day).
7.3 Cyclosporine
Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1
 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased
 with concomitant administration of atorvastatin calcium tablets 10 mg and cyclosporine 5.2 mg/kg/day compared to
 that of atorvastatin calcium tablets alone [see Clinical Pharmacology (12.3)]. The co-administration of atorvastatin
 calcium tablets with cyclosporine should be avoided [see Warnings and Precautions, Skeletal Muscle (5.1)].
7.4 Gemfibrozil
Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with
 gemfibrozil, concomitant administration of atorvastatin calcium tablets with gemfibrozil should be avoided [see
 Warnings and Precautions (5.1)].
7.5 Other Fibrates
Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with
 concurrent administration of other fibrates, atorvastatin calcium tablets should be administered with caution when
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 used concomitantly with other fibrates [see Warnings and Precautions (5.1)].
7.6 Niacin
The risk of skeletal muscle effects may be enhanced when atorvastatin calcium tablets are used in combination with
 niacin; a reduction in atorvastatin calcium tablets dosage should be considered in this setting [see Warnings and
 Precautions (5.1)].
7.7 Rifampin or other Inducers of Cytochrome P450 3A4
Concomitant administration of atorvastatin calcium tablets with inducers of cytochrome P450 3A4 (e.g., efavirenz,
 rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction
 mechanism of rifampin, simultaneous co-administration of atorvastatin calcium tablets with rifampin is
 recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a
 significant reduction in atorvastatin plasma concentrations.
7.8 Digoxin
When multiple doses of atorvastatin calcium tablets and digoxin were coadministered, steady state plasma digoxin
 concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
7.9 Oral Contraceptives
Co-administration of atorvastatin calcium tablets and an oral contraceptive increased AUC values for norethindrone
 and ethinyl estradiol [see Clinical Pharmacology (12.3)]. These increases should be considered when selecting an
 oral contraceptive for a woman taking atorvastatin.
7.10 Warfarin
Atorvastatin calcium tablets had no clinically significant effect on prothrombin time when administered to patients
 receiving chronic warfarin treatment.
7.11 Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine,
 and caution should be exercised when prescribing atorvastatin with colchicine.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category X
Atorvastatin calcium tablets are contraindicated in women who are or may become pregnant. Serum cholesterol and
 triglycerides increase during normal pregnancy. Lipid lowering drugs offer no benefit during pregnancy because
 cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process,
 and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of
 primary hypercholesterolemia therapy.
There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have been rare reports
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 of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed
 pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and
 fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able
 to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these
 cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma.
 Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day.
 These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface
 area (mg/m ) [see Contraindications, Pregnancy (4.3)].
In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there
 was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day.
 Body weight was decreased on days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was
 decreased at birth and at days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at
 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These
 doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day.
Statins may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium tablets should be
 administered to women of childbearing potential only when such patients are highly unlikely to conceive and have
 been informed of the potential hazards. If the woman becomes pregnant while taking atorvastatin, it should be
 discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known
 clinical benefit with continued use during pregnancy.
8.3 Nursing Mothers
It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does
 pass into breast milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in
 their mother's milk. Animal breast milk drug levels may not accurately reflect human breast milk levels. Because
 another drug in this class passes into human milk and because statins have a potential to cause serious adverse
 reactions in nursing infants, women requiring atorvastatin treatment should be advised not to nurse their infants [see
 Contraindications (4)].
8.4 Pediatric Use
Safety and effectiveness in patients 10–17 years of age with heterozygous familial hypercholesterolemia have been
 evaluated in a controlled clinical trial of 6 months' duration in adolescent boys and postmenarchal girls. Patients
 treated with atorvastatin calcium tablets had an adverse experience profile generally similar to that of patients treated
 with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment,
 were infections. Doses greater than 20 mg have not been studied in this patient population. In this limited
 controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length
 in girls [see Clinical Studies (14.6); Adverse Reactions, Pediatric Patients (ages 10–17 years) (6.3); and Dosage and
 Administration, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10–17 years of age) (2.2)].
 Adolescent females should be counseled on appropriate contraceptive methods while on atorvastatin therapy [see
 Contraindications, Pregnancy (4.3) and Use in Specific Populations, Pregnancy (8.1)]. Atorvastatin calcium
 tablets have not been studied in controlled clinical trials involving pre-pubertal patients or patients younger
 than 10 years of age.
Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of patients with
 homozygous FH including 8 pediatric patients [see Clinical Studies, Homozygous Familial Hypercholesterolemia
 (14.5)].
8.5 Geriatric Use
Of the 39,828 patients who received atorvastatin calcium tablets in clinical studies, 15,813 (40%) were ≥65 years old
2
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 and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these
 subjects and younger subjects, and other reported clinical experience has not identified differences in responses
 between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Since
 advanced age (≥65 years) is a predisposing factor for myopathy, atorvastatin should be prescribed with caution in the
 elderly.
8.6	Hepatic Impairment
Atorvastatin calcium tablets are contraindicated in patients with active liver disease which may include unexplained
 persistent elevations in hepatic transaminase levels [see Contraindications (4) and Pharmacokinetics (12.3)].
10	OVERDOSAGE
There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient should be treated
 symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins,
 hemodialysis is not expected to significantly enhance atorvastatin clearance.
11 DESCRIPTION
Atorvastatin calcium is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early
 and rate-limiting step in cholesterol biosynthesis.
Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of
 atorvastatin calcium is (C
H
FN O ) Ca•3H O and its molecular weight is 1209.42. Its structural formula is:
Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and
 below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile;
 slightly soluble in ethanol; and freely soluble in methanol.
Atorvastatin calcium tablets for oral administration contain 10, 20, 40, or 80 mg atorvastatin and the following
 inactive ingredients: calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl
 cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-
1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that
33
34 
2
5 2
2
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 converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.
 Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation,
 these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-
density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the
 liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from
 VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that
 elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B)
 promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of
 HDL-C are associated with a decreased cardiovascular risk.
In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase
 and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to
 enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles.
 Atorvastatin reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population
 that rarely responds to other lipid-lowering medication(s).
A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane
 complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport
 complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have
 established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and
 inversely with the level of HDL-C.
Atorvastatin reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial
 forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin also reduces VLDL-C and TG and produces
 variable increases in HDL-C and apolipoprotein A-1. Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, TG,
 and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin reduces
 intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein
 (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad
 with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for
 coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for
 CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular
 morbidity and mortality has not been determined.
12.2	Pharmacodynamics
Atorvastatin calcium, as well as some of its metabolites, is pharmacologically active in humans. The liver is the
 primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than
 systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be
 based on therapeutic response [see Dosage and Administration (2)].
12.3	Pharmacokinetics
Absorption: Atorvastatin calcium tablets are rapidly absorbed after oral administration; maximum plasma
 concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium dose.
 The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of
 HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to
 presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the
 rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC,
 LDL-C reduction is similar whether atorvastatin calcium tablets are given with or without food. Plasma atorvastatin
 concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared
 with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see
 Dosage and Administration (2)].
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Distribution: Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to
 plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells.
 Based on observations in rats, atorvastatin is likely to be secreted in human milk [see Contraindications, Nursing
 Mothers (4.4) and Use in Specific Populations, Nursing Mothers (8.3)].
Metabolism: Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-
oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is
 equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is
 attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome
 P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration
 with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1)]. In animals, the ortho-hydroxy
 metabolite undergoes further glucuronidation.
Excretion: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic
 metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination
 half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA
 reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin
 calcium tablets is recovered in urine following oral administration.
Specific Populations
Geriatric: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in
 healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering
 at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations,
 Geriatric Use (8.5)].
Pediatric: Pharmacokinetic data in the pediatric population are not available.
Gender: Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for
 Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with
 atorvastatin between men and women.
Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin;
 thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration, Dosage in
 Patients with Renal Impairment (2.5), Warnings and Precautions, Skeletal Muscle (5.1)].
Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not
 expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.
Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are
 markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC
 are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see
 Contraindications (4.1)].
TABLE 3. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin
Co-administered drug and dosing regimen
Atorvastatin
Change in
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Dose (mg)
Change in AUC  Cmax
*
†
‡
§
¶
#
Cyclosporine 5.2 mg/kg/day, stable dose
10 mg QD for 28 days
↑ 8.7 fold
↑10.7 fold
Tipranavir 500 mg BID/ritonavir 200 mg BID,
 7 days
10 mg, SD
↑ 9.4 fold
↑ 8.6 fold
Telaprevir 750 mg q8h, 10 days
20 mg, SD
↑ 7.88 fold
↑ 10.6 fold
Saquinavir 400 mg BID/ ritonavir 400 mg
 BID, 15 days
40 mg QD for 4 days
↑ 3.9 fold
↑ 4.3 fold
Clarithromycin 500 mg BID, 9 days
80 mg QD for 8 days
↑ 4.4 fold
↑ 5.4 fold
Darunavir 300 mg BID/ritonavir 100 mg BID, 9
 days
10 mg QD for 4 days
↑ 3.4 fold
↑ 2.25 fold
Itraconazole 200 mg QD, 4 days
40 mg SD
↑ 3.3 fold
↑ 20%
Fosamprenavir 700 mg BID/ritonavir 100 mg
 BID, 14 days
10 mg QD for 4 days
↑ 2.53 fold
↑ 2.84 fold
Fosamprenavir 1400 mg BID, 14 days
10 mg QD for 4 days
↑ 2.3 fold
↑ 4.04 fold
Nelfinavir 1250 mg BID, 14 days
10 mg QD for 28 days
↑ 74%
↑ 2.2 fold
Grapefruit Juice, 240 mL QD 
40 mg, SD
↑ 37%
↑ 16%
Diltiazem 240 mg QD, 28 days
40 mg, SD
↑ 51%
No change
Erythromycin 500 mg QID, 7 days
10 mg, SD
↑ 33%
↑ 38%
Amlodipine 10 mg, single dose
80 mg, SD
↑ 15%
↓ 12 %
Cimetidine 300 mg QID, 2 weeks
10 mg QD for 2 weeks
↓ Less than 1%
↓ 11%
Colestipol 10 mg BID, 28 weeks
40 mg QD for 28 weeks
Not determined
↓ 26%
Maalox TC® 30 mL QD, 17 days
10 mg QD for 15 days
↓ 33%
↓ 34%
Efavirenz 600 mg QD, 14 days
10 mg for 3 days
↓ 41%
↓ 1%
Rifampin 600 mg QD, 7 days (co-administered)
 
40 mg SD
↑ 30%
↑ 2.7 fold
Rifampin 600 mg QD, 5 days (doses separated)
 
40 mg SD
↓ 80%
↓ 40%
Gemfibrozil 600mg BID, 7 days
40mg SD
↑ 35%
↓ Less than 1%
Fenofibrate 160mg QD, 7 days
40mg SD
↑ 3%
↑ 2%
Boceprevir 800 mg TID, 7 days
40 mg SD
↑2.30 fold
↑2.66 fold
TABLE 4. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs
Atorvastatin
Co-administered drug and dosing regimen
*
*
Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change).
 Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change).
See Sections 5.1 and 7 for clinical significance.
The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used
 clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose
 necessary should be used.
Greater increases in AUC (up to 2.5 fold) and/or Cmax (up to 71%) have been reported with excessive grapefruit consumption (≥
 750 mL – 1.2 liters per day).
Single sample taken 8–16 h post dose.
Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended,
 as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in
 atorvastatin plasma concentrations.
†
†
†
†,‡
†
†
†
†
†
†
†
§
¶
†
#
†
#
†
†
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Drug/Dose (mg)
Change in AUC
Change in Cmax
*
80 mg QD for 15 days Antipyrine, 600 mg SD
↑ 3%
↓ 11%
80 mg QD for 14 days  Digoxin 0.25 mg QD, 20
 days
↑ 15%
↑ 20 %
40 mg QD for 22 days Oral contraceptive QD, 2
 months
- norethindrone 1mg
- ethinyl estradiol 35µg
↑ 28%
↑ 19%
↑ 23%
↑ 30%
10 mg, SD
Tipranavir 500 mg
 BID/ritonavir 200 mg BID, 7
 days
No change
No change
10 mg QD for 4 days Fosamprenavir 1400 mg BID,
 14 days
↓ 27%
↓ 18%
10 mg QD for 4 days
Fosamprenavir 700 mg
 BID/ritonavir 100 mg BID,
 14 days
No change
No change
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in
 muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This
 dose represents a plasma AUC (0–24) value of approximately 16 times the mean human plasma drug exposure after
 an 80 mg oral dose.
A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver
 adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC
 (0–24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose.
In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation:
 the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese
 hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in
 the in vivo mouse micronucleus test.
Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility.
 There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3
 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg
 and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had
 decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no
 adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120
 mg/kg for two years.
14 CLINICAL STUDIES
14.1 Prevention of Cardiovascular Disease
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin on fatal and non-fatal
See Section 7 for clinical significance.
*
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 coronary heart disease was assessed in 10,305 hypertensive patients 40–80 years of age (mean of 63 years), without a
 previous myocardial infarction and with TC levels ≤251 mg/dL (6.5 mmol/L). Additionally, all patients had at least 3
 of the following cardiovascular risk factors: male gender (81.1%), age >55 years (84.5%), smoking (33.2%), diabetes
 (24.3%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14.3%), peripheral vascular disease (5.1%),
 left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%),
 proteinuria/albuminuria (62.4%). In this double-blind, placebo-controlled study, patients were treated with anti-
hypertensive therapy (Goal BP <140/90 mm Hg for non-diabetic patients; <130/80 mm Hg for diabetic patients) and
 allocated to either atorvastatin calcium tablets 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive
 method which took into account the distribution of nine baseline characteristics of patients already enrolled and
 minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of
 3.3 years.
The effect of 10 mg/day of atorvastatin calcium tablets on lipid levels was similar to that seen in previous clinical
 trials.
Atorvastatin significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the
 placebo group vs. 40 events in the atorvastatin calcium tablets group) or non-fatal MI (108 events in the placebo
 group vs. 60 events in the atorvastatin calcium tablets group)] with a relative risk reduction of 36% [(based on
 incidences of 1.9% for atorvastatin calcium tablets vs. 3.0% for placebo), p=0.0005 (see Figure 1)]. The risk
 reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of
 atorvastatin was seen regardless of baseline LDL levels. Due to the small number of events, results for women were
 inconclusive.
Figure 1: Effect of Atorvastatin 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or
 Coronary Heart Disease Death (in ASCOT-LLA)
Atorvastatin also significantly decreased the relative risk for revascularization procedures by 42%. Although the
 reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was
 observed with a 26% relative risk reduction (incidences of 1.7% for atorvastatin calcium tablets and 2.3% for
 placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes
 (p=0.51) or noncardiovascular causes (p=0.17).
In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin on cardiovascular disease
 (CVD) endpoints was assessed in 2838 subjects (94% white, 68% male), ages 40–75 with type 2 diabetes based on
 WHO criteria, without prior history of cardiovascular disease and with LDL ≤ 160 mg/dL and TG ≤ 600 mg/dL. In
 addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension
 (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were
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 enrolled in the study. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly
 allocated to either atorvastatin calcium tablets 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed
 for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular
 events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary
 analysis was the time to first occurrence of the primary endpoint.
Baseline characteristics of subjects were: mean age of 62 years, mean HbA  7.7%; median LDL-C 120 mg/dL;
 median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.
The effect of atorvastatin 10 mg/day on lipid levels was similar to that seen in previous clinical trials.
Atorvastatin significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the
 atorvastatin calcium tablets group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR
 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 2). An effect of atorvastatin calcium tablets was seen regardless of
 age, sex, or baseline lipid levels.
Atorvastatin significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium tablets group vs. 39
 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events
 in the atorvastatin calcium tablets group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86)
 (p=0.007). There was no significant difference between the treatment groups for angina, revascularization
 procedures, and acute CHD death.
There were 61 deaths in the atorvastatin calcium tablets group vs. 82 deaths in the placebo group (HR 0.73, p=0.059).
 Figure 2: Effect of Atorvastatin 10 mg/day on Time to Occurrence of Major Cardiovascular Event
 (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS
In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium tablets 80 mg/day vs. atorvastatin
 calcium tablets 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white,
 81% male, 38% ≥65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level
 <130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin calcium tablets 10 mg/day.
 Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium tablets and followed for a
 median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major
 cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and
 fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73,
 145, 128, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin calcium tablets and 99, 177, 152, 129, and
 48 mg/dL during treatment with 10 mg of atorvastatin calcium tablets.
Treatment with atorvastatin calcium tablets 80 mg/day significantly reduced the rate of MCVE (434 events in the 80
 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69,
1c
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 0.89), p=0.0002 (see Figure 3 and Table 5). The overall risk reduction was consistent regardless of age (<65, ≥65) or
 gender.
Figure 3: Effect of Atorvastatin 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular
 Events (TNT)
TABLE 5. Overview of Efficacy Results in TNT
Endpoint
Atorvastatin
10 mg
(N=5006)
Atorvastatin
80 mg
(N=4995)
HR  (95%CI)
PRIMARY ENDPOINT
n
(%)
n
(%)
First major cardiovascular endpoint
548
(10.9)
434
(8.7)
0.78 (0.69, 0.89)
Components of the Primary Endpoint
  CHD death
127
(2.5)
101
(2.0)
0.80 (0.61, 1.03)
  Non-fatal, non-procedure related MI
308
(6.2)
243
(4.9)
0.78 (0.66, 0.93)
  Resuscitated cardiac arrest
26
(0.5)
25
(0.5)
0.96 (0.56, 1.67)
  Stroke (fatal and non-fatal)
155
(3.1)
117
(2.3)
0.75 (0.59, 0.96)
SECONDARY ENDPOINTS
First CHF with hospitalization
164
(3.3)
122
(2.4)
0.74 (0.59, 0.94)
First PVD endpoint
282
(5.6)
275
(5.5)
0.97 (0.83, 1.15)
First CABG or other coronary revascularization
 procedure
904
(18.1)
667
(13.4)
0.72 (0.65, 0.80)
First documented angina endpoint
615
(12.3)
545
(10.9)
0.88 (0.79, 0.99)
All-cause mortality
282
(5.6)
284
(5.7)
1.01 (0.85, 1.19)
Components of All-Cause Mortality
  Cardiovascular death
155
(3.1)
126
(2.5)
0.81 (0.64, 1.03)
  Noncardiovascular death
127
(2.5)
158
(3.2)
1.25 (0.99, 1.57)
    Cancer death
75
(1.5)
85
(1.7)
1.13 (0.83, 1.55)
    Other non-CV death
43
(0.9)
58
(1.2)
1.35 (0.91, 2.00)
    Suicide, homicide, and other traumatic non-CV
*
†
‡
‡
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HR=hazard ratio; CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction;
 CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular disease; CABG=coronary artery
 bypass graft
Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons
*
†
‡
 death
9
(0.2)
15
(0.3)
1.67 (0.73, 3.82)
Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium tablets 80 mg/day
 significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD
 death or resuscitated cardiac arrest (Table 5). Of the predefined secondary endpoints, treatment with atorvastatin
 calcium tablets 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for
 heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only
 observed in the 8% of patients with a prior history of CHF.
There was no significant difference between the treatment groups for all-cause mortality (Table 5). The proportions of
 subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were
 numerically smaller in the atorvastatin calcium tablets 80 mg group than in the atorvastatin calcium tablets 10 mg
 treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in
 the atorvastatin calcium tablets 80 mg group than in the atorvastatin calcium tablets 10 mg treatment group.
In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with
 atorvastatin calcium tablets 80 mg/day was compared to treatment with simvastatin 20–40 mg/day in 8,888 subjects
 up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved. Patients were
 mainly male (81%), white (99%) with an average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at
 randomization; 76% were on statin therapy. In this prospective, randomized, open-label, blinded endpoint (PROBE)
 trial with no run-in period, subjects were followed for a median duration of 4.8 years. The mean LDL-C, TC, TG,
 HDL, and non-HDL cholesterol levels at Week 12 were 78, 145, 115, 45, and 100 mg/dL during treatment with 80
 mg of atorvastatin calcium tablets and 105, 179, 142, 47, and 132 mg/dL during treatment with 20–40 mg of
 simvastatin.
There was no significant difference between the treatment groups for the primary endpoint, the rate of first major
 coronary event (fatal CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the atorvastatin calcium
 tablets 80 mg/day group vs. 463 (10.4%) in the simvastatin 20–40 mg/day group, HR 0.89, 95% CI ( 0.78, 1.01),
 p=0.07.
There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the
 atorvastatin calcium tablets 80 mg/day group vs. 374 (8.4%) in the simvastatin 20–40 mg/day group. The proportions
 of subjects who experienced CV or non-CV death were similar for the atorvastatin calcium tablets 80 mg group and
 the simvastatin 20–40 mg group.
14.2 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa
 and IIb)
Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia
 and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved
 within 4 weeks and maintained during chronic therapy.
Atorvastatin calcium tablets are effective in a wide variety of patient populations with hyperlipidemia, with and
 without hypertriglyceridemia, in men and women, and in the elderly.
In two multicenter, placebo-controlled, dose-response studies in patients with hyperlipidemia, atorvastatin calcium
 tablets given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are
 provided in Table 6.)
Atorvastatin 80 mg: atorvastatin 10 mg
Secondary endpoints not included in primary endpoint
Component of other secondary endpoints
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TABLE 6.	Dose Response in Patients With Primary Hyperlipidemia (Adjusted
 Mean % Change From Baseline)
Dose
N
TC
LDL-C
Apo B
TG
HDL-C
Non-HDL-
C/ HDL-C
*
Placebo
21
4
4
3
10
-3
7
10
22
-29
-39
-32
-19
6
-34
20
20
-33
-43
-35
-26
9
-41
40
21
-37
-50
-42
-29
6
-45
80
23
-45
-60
-50
-37
5
-53
In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median
 (25  and 75  percentile) percent changes from baseline in HDL-C for atorvastatin calcium tablets 10, 20, 40, and 80
 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled
 data demonstrated consistent and significant decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.
In three multicenter, double-blind studies in patients with hyperlipidemia, atorvastatin was compared to other statins.
 After randomization, patients were treated for 16 weeks with either atorvastatin calcium tablets 10 mg per day or a
 fixed dose of the comparative agent (Table 7).
TABLE 7. Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-
Controlled Trials)
Treatment
(Daily Dose)
N
Total-C
LDL-C
Apo B
TG
HDL-C
Non-HDL-
C/ HDL-C
*
†
‡
§
Study 1
Atorvastatin 10
 mg
707
-27
-36
-28
-17
+7
-37
Lovastatin 20 mg
191
-19
-27
-20
-6
+7
-28
95% CI for Diff
-9.2, -6.5
-10.7, -7.1
-10.0, -6.5
-15.2, -7.1
-1.7, 2.0
-11.1, -7.1
Study 2
Atorvastatin 10
 mg
222
-25
-35
-27
-17
+6
-36
Pravastatin 20 mg
77
-17
-23
-17
-9
+8
-28
95% CI for Diff
-10.8, -6.1
-14.5, -8.2
-13.4, -7.4
-14.1, -0.7
-4.9, 1.6
-11.5, -4.1
Study 3
Atorvastatin 10
 mg
132
-29
-37
-34
-23
+7
-39
Simvastatin 10 mg
45
-24
-30
-30
-15
+7
-33
95% CI for Diff
-8.7, -2.7
-10.1, -2.6
-8.0, -1.1
-15.1, -0.7
-4.3, 3.9
-9.6, -1.9
The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 7 is
*
Results are pooled from 2 dose-response studies.
th
th
Significantly different from lovastatin, ANCOVA, p ≤0.05
A negative value for the 95% CI for the difference between treatments favors atorvastatin for all except HDL-C, for which a
 positive value favors atorvastatin. If the range does not include 0, this indicates a statistically significant difference.
Significantly different from pravastatin, ANCOVA, p ≤0.05
Significantly different from simvastatin, ANCOVA, p ≤0.05
*
*
*
*
*
†
‡
‡
‡
‡
‡
†
§
§
§
§
§
†
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 not known. Table 7 does not contain data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin,
 pravastatin, and simvastatin. The drugs compared in the studies summarized in the table are not necessarily
 interchangeable.
14.3 Hypertriglyceridemia (Fredrickson Type IV)
The response to atorvastatin in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is
 shown in the table below (Table 8). For the atorvastatin calcium tablets-treated patients, median (min, max) baseline
 TG level was 565 (267–1502).
TABLE 8. Combined Patients With Isolated Elevated TG: Median (min, max) Percentage Change From
 Baseline
Placebo
(N=12)
atorvastatin 10 mg
(N=37)
atorvastatin 20 mg
(N=13)
atorvastatin 80 mg
(N=14)
Triglycerides
-12.4 (-36.6, 82.7)
-41.0 (-76.2, 49.4)
-38.7 (-62.7, 29.5)
-51.8 (-82.8, 41.3)
Total-C
-2.3 (-15.5, 24.4)
-28.2 (-44.9, -6.8)
-34.9 (-49.6, -15.2)
-44.4 (-63.5, -3.8)
LDL-C
3.6 (-31.3, 31.6)
-26.5 (-57.7, 9.8)
-30.4 (-53.9, 0.3)
-40.5 (-60.6, -13.8)
HDL-C
3.8 (-18.6, 13.4)
13.8 (-9.7, 61.5)
11.0 (-3.2, 25.2)
7.5 (-10.8, 37.2)
VLDL-C
-1.0 (-31.9, 53.2)
-48.8 (-85.8, 57.3)
-44.6 (-62.2, -10.8)
-62.0 (-88.2, 37.6)
non-HDL-C
-2.8 (-17.6, 30.0)
-33.0 (-52.1, -13.3)
-42.7 (-53.7, -17.4)
-51.5 (-72.9, -4.3)
14.4 Dysbetalipoproteinemia (Fredrickson Type III)
The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with
 dysbetalipoproteinemia (Fredrickson Type III) are shown in the table below (Table 9).
TABLE 9. Open-Label Crossover Study of 16 Patients With
 Dysbetalipoproteinemia (Fredrickson Type III)
Median % Change (min, max)
Median (min, max) at
 Baseline (mg/dL)
atorvastatin 10
 mg
atorvastatin 80
 mg
Total-C
442 (225, 1320)
-37 (-85, 17)
-58 (-90, -31)
Triglycerides
678 (273, 5990)
-39 (-92, -8)
-53 (-95, -30)
IDL-C + VLDL-C
215 (111, 613)
-32 (-76, 9)
-63 (-90, -8)
non-HDL-C
411 (218, 1272)
-43 (-87, -19)
-64 (-92, -36)
14.5 Homozygous Familial Hypercholesterolemia
In a study without a concurrent control group, 29 patients ages 6 to 37 years with homozygous FH received maximum
 daily doses of 20 to 80 mg of atorvastatin calcium tablets. The mean LDL-C reduction in this study was 18%.
 Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%);
 the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor
 function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining
 3 receptor-negative patients had a mean LDL-C reduction of 22%.
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14.6 Heterozygous Familial Hypercholesterolemia in Pediatric Patients
In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10–17
 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (FH) or severe
 hypercholesterolemia, were randomized to atorvastatin calcium tablets (n=140) or placebo (n=47) for 26 weeks and
 then all received atorvastatin calcium tablets for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level
 ≥ 190 mg/dL or 2) a baseline LDL-C level ≥ 160 mg/dL and positive family history of FH or documented premature
 cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range:
 138.5–385.0 mg/dL) in the atorvastatin calcium tablets group compared to 230.0 mg/dL (range: 160.0–324.5 mg/dL)
 in the placebo group. The dosage of atorvastatin calcium tablets (once daily) was 10 mg for the first 4 weeks and
 uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin calcium tablets-treated patients
 who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (55.7%).
Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the
 26-week double-blind phase (see Table 10).
TABLE 10. Lipid-altering Effects of Atorvastatin in Adolescent Boys and Girls
 with Heterozygous Familial Hypercholesterolemia or Severe
 Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in
 Intention-to-Treat Population)
DOSAGE
N
Total-C
LDL-C
HDL-C
TG
Apolipoprotein
 B
Placebo
47
-1.5
-0.4
-1.9
1.0
0.7
Atorvastatin
140
-31.4
-39.6
2.8
-12.0
-34.0
The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0–242.0 mg/dL) in the atorvastatin group compared to
 228.5 mg/dL (range: 152.0–385.0 mg/dL) in the placebo group during the 26-week double-blind phase.
The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children. The long-term
 efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
15 REFERENCES
National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol
 Levels in Children and Adolescents, Pediatrics. 89(3):495–501. 1992.
16 HOW SUPPLIED/STORAGE AND HANDLING
10 mg tablets: coded "PD 155" on one side and "10" on the other.
NDC 59762-0155-1
bottles of 90
NDC 59762-0155-2
bottles of 1000
20 mg tablets: coded "PD 156" on one side and "20" on the other.
NDC 59762-0156-1
bottles of 90
NDC 59762-0156-2
bottles of 1000
40 mg tablets: coded "PD 157" on one side and "40" on the other.
NDC 59762-0157-1
bottles of 90
1
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NDC 59762-0157-2
bottles of 500
80 mg tablets: coded "PD 158" on one side and "80" on the other.
NDC 59762-0158-1
bottles of 90
NDC 59762-0158-2
bottles of 500
Storage
Store at controlled room temperature 20 – 25°C (68 – 77°F) [see USP].
17 PATIENT COUNSELING INFORMATION
Patients taking atorvastatin calcium tablets should be advised that cholesterol is a chronic condition and they should
 adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a
 regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment.
Patients should be advised about substances they should not take concomitantly with atorvastatin [see
 Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals
 prescribing a new medication that they are taking atorvastatin calcium tablets.
17.1	Muscle Pain
All patients starting therapy with atorvastatin calcium tablets should be advised of the risk of myopathy and told to
 report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or
 fever or if these muscle signs or symptoms persist after discontinuing atorvastatin calcium tablets. The risk of this
 occurring is increased when taking certain types of medication or consuming larger quantities (>1 liter) of grapefruit
 juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional.
17.2	Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of atorvastatin calcium tablets and if
 signs or symptoms of liver injury occur. All patients treated with atorvastatin calcium tablets should be advised to
 report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal
 discomfort, dark urine, or jaundice. .
17.3	Pregnancy
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while
 using atorvastatin calcium tablets. Discuss future pregnancy plans with your patients, and discuss when to stop
 atorvastatin calcium tablets if they are trying to conceive. Patients should be advised that if they become pregnant,
 they should stop taking atorvastatin calcium tablets and call their healthcare professional.
17.4 Breast-feeding
Women who are breastfeeding should be advised to not use atorvastatin calcium tablets. Patients who have a lipid
 disorder and are breast-feeding, should be advised to discuss the options with their healthcare professional.
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LAB-0644-3.0
PATIENT INFORMATION
Atorvastatin Calcium Tablets
Read the Patient Information that comes with atorvastatin calcium tablets before you start taking it and each time you
 get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your
 condition or treatment.
If you have any questions about atorvastatin calcium tablets, ask your doctor or pharmacist.
What Are Atorvastatin Calcium Tablets?
Atorvastatin calcium is a prescription medicine that lowers cholesterol in your blood. It lowers the LDL-C ("bad"
 cholesterol) and triglycerides in your blood. It can raise your HDL-C ("good" cholesterol) as well. Atorvastatin
 calcium tablets are for adults and children over 10 whose cholesterol does not come down enough with exercise and
 a low-fat diet alone.
Atorvastatin calcium tablets can lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in
 patients who have heart disease or risk factors for heart disease such as:
age, smoking, high blood pressure, low HDL-C, heart disease in the family.
Atorvastatin calcium tablets can lower the risk for heart attack or stroke in patients with diabetes and risk factors such
 as:
eye problems, kidney problems, smoking, or high blood pressure.
Atorvastatin calcium tablets start to work in about 2 weeks.
What is Cholesterol?
Cholesterol and triglycerides are fats that are made in your body. They are also found in foods. You need some
 cholesterol for good health, but too much is not good for you. Cholesterol and triglycerides can clog your blood
 vessels. It is especially important to lower your cholesterol if you have heart disease, smoke, have diabetes or high
 blood pressure, are older, or if heart disease starts early in your family.
Who Should Not Take Atorvastatin Calcium Tablets?
Do not take atorvastatin calcium tablets if you:
are pregnant or think you may be pregnant, or are planning to become pregnant. Atorvastatin calcium tablets may
 harm your unborn baby. If you get pregnant, stop taking atorvastatin calcium tablets and call your doctor right
 away.
are breast feeding. Atorvastatin calcium tablets can pass into your breast milk and may harm your baby.
have liver problems.
are allergic to atorvastatin calcium tablets or any of its ingredients. The active ingredient is atorvastatin. See the
 end of this leaflet for a complete list of ingredients in atorvastatin calcium tablets.
Atorvastatin calcium tablets have not been studied in children under 10 years of age.
Before You Start Atorvastatin Calcium Tablets
Tell your doctor if you:
have muscle aches or weakness
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drink more than 2 glasses of alcohol daily
have diabetes
have a thyroid problem
have kidney problems
Some medicines should not be taken with atorvastatin calcium tablets. Tell your doctor about all the medicines you
 take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Atorvastatin calcium
 tablets and certain other medicines can interact causing serious side effects. Especially tell your doctor if you take
 medicines for:
your immune system
cholesterol
infections
birth control
heart failure
HIV or AIDS
Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist.
How Should I Take Atorvastatin Calcium Tablets?
Take atorvastatin calcium tablets exactly as prescribed by your doctor. Do not change your dose or stop
 atorvastatin calcium tablets without talking to your doctor. Your doctor may do blood tests to check your
 cholesterol levels during your treatment with atorvastatin calcium tablets. Your dose of atorvastatin calcium
 tablets may be changed based on these blood test results.
Take atorvastatin calcium tablets each day at any time of day at about the same time each day. Atorvastatin
 calcium tablets can be taken with or without food.
Don't break atorvastatin calcium tablets before taking.
Your doctor should start you on a low-fat diet before giving you atorvastatin calcium tablets. Stay on this low-fat
 diet when you take atorvastatin calcium tablets.
If you miss a dose of atorvastatin calcium tablets, take it as soon as you remember. Do not take atorvastatin
 calcium tablets if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at
 your regular time. Do not take 2 doses of atorvastatin calcium tablets at the same time.
If you take too much atorvastatin calcium tablets or overdose, call your doctor or Poison Control Center right
 away. Or go to the nearest emergency room.
What Should I Avoid While Taking Atorvastatin Calcium Tablets?
Talk to your doctor before you start any new medicines. This includes prescription and non-prescription
 medicines, vitamins, and herbal supplements. Atorvastatin calcium tablets and certain other medicines can
 interact causing serious side effects.
Do not get pregnant. If you get pregnant, stop taking atorvastatin calcium tablets right away and call your doctor.
What are the Possible Side Effects of Atorvastatin Calcium Tablets?
Atorvastatin calcium tablets can cause serious side effects. These side effects have happened only to a small
 number of people. Your doctor can monitor you for them. These side effects usually go away if your dose is
 lowered or atorvastatin calcium tablets are stopped.
These serious side effects include:
Muscle problems. Atorvastatin calcium tablets can cause serious muscle problems that can lead to kidney
 problems, including kidney failure. You have a higher chance for muscle problems if you are taking certain other
 medicines with atorvastatin calcium tablets.
Liver problems. Your doctor should do blood tests to check your liver before you start taking atorvastatin
 calcium tablets, and if you have symptoms of liver problems while you take atorvastatin calcium tablets. Call
 your doctor right away if you have the following symptoms of liver problems:
feel tired or weak
loss of appetite
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upper belly pain
dark amber colored urine
yellowing of your skin or the whites of your eyes
Call your doctor right away if you have:
muscle problems like weakness, tenderness, or pain that happen without a good reason, especially if you also have
 a fever or feel more tired than usual. This may be an early sign of a rare muscle problem.
muscle problems that do not go away even after your doctor has advised you to stop taking atorvastatin calcium
 tablets. Your doctor may do further tests to diagnose the cause of your muscle problems.
allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing
 or swallowing which may require treatment right away.
nausea and vomiting.
passing brown or dark-colored urine.
you feel more tired than usual
your skin and whites of your eyes get yellow.
stomach pain.
allergic skin reactions.
In clinical studies, patients reported the following common side effects while taking atorvastatin calcium tablets:
 diarrhea, upset stomach, muscle and joint pain, and alterations in some laboratory blood tests.
The following additional side effects have been reported with atorvastatin calcium tablets: tiredness, tendon
 problems, memory loss, and confusion.
Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away.
These are not all the side effects of atorvastatin calcium tablets. Ask your doctor or pharmacist for a complete list.
How do I store Atorvastatin Calcium Tablets?
Store atorvastatin calcium tablets at room temperature, 68 to 77°F (20 to 25°C).
Do not keep medicine that is out of date or that you no longer need.
Keep atorvastatin calcium tablets and all medicines out of the reach of children. Be sure that if you throw
 medicine away, it is out of the reach of children.
General Information about Atorvastatin Calcium Tablets
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use
 atorvastatin calcium tablets for a condition for which it was not prescribed. Do not give atorvastatin calcium tablets
 to other people, even if they have the same problem you have. It may harm them.
This leaflet summarizes the most important information about atorvastatin calcium tablets. If you would like more
 information, talk with your doctor. You can ask your doctor or pharmacist for information about atorvastatin calcium
 tablets that is written for health professionals.
What are the Ingredients in Atorvastatin Calcium Tablets?
Active Ingredient: atorvastatin calcium
Inactive Ingredients: calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl
 cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-
1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.
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Greenstone LLC
LAB-0645-1.0 November 2012
 
Revised: 3/2015
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Protocol 747-209  
Version 4:  19 Dec 2016 
Page 310 
 
Confidential and Proprietary 
APPENDIX F. 747-209 PROTOCOL VERSION 2 SUMMARY OF CHANGES 
 
Background 
Protocol 747-209 has been prepared as a Phase 2 trial to evaluate the effect of OCA on LDL metabolism in subjects with 
biopsy-confirmed NASH and to assess the ability of atorvastatin to modulate this effect. 
Protocol 747-209 Version 2 (dated 22 October 2015) incorporates suggestions made by the FDA regarding the 747-303 protocol 
that are also relevant to this study.   
Rationale 
Protocol 747-209 Version 2 has been prepared to: 
1. Clarify stopping rules for subjects presenting with a CTCAE of ≥Grade 3, per FDA’s comments on the 747-303 protocol. 
2. Clarify that subjects discontinued due to significant drug-induced liver injury will be followed until the AE has resolved, 
stabilized, or is not of clinical concern. 
3. Clarify atorvastatin safety profile. 
4. Include a description for the cardiovascular events adjudication committee, and add Appendix D to define major 
cardiovascular events. 
In addition, Protocol 747-209 Version 2 also: 
1. Clarifies contraception requirements. 
2. Adds additional exploratory objectives:  markers of cardiovascular safety 
3. Clarifies exclusion criteria related to chronic liver diseases at Screening. 
4. Removes the requirement that a study site must have prior experience treating patients with NASH to participate in this 
study. 
5. Clarifies PD assessments; markers of inflammation, fibrosis, and apoptosis; and PK assessments in the Schedule of Study 
Procedures tables, and in the text. 
6. Clarifies timepoints for PK blood sample collection. 
7. Corrects the title of Appendix A to reflect ACA/AHA guidance for the use of statins. 
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Summary of Changes 
The following revisions were made to the protocol in Protocol Version 2.  
Note:  (1) Revised text in Version 2 is indicated in bold font, and the text deleted from the Original protocol is crossed out in the 
table below.  (2) Minor/editorial changes, including additional abbreviations defined are not listed individually in the summary 
table below.  
Section 
Original Text (Original protocol) 
Revised Text (Version 2) 
Global changes 
(throughout 
document) 
 
CK-18-M65 added in addition to CK-18-M30 assessment as a 
marker for hepatic apoptosis and fibrosis under Exploratory 
Endpoints 
 
 
Data and Safety Monitoring Committee (DSMC) changed to 
Data Monitoring Committee (DMC) 
Study Personnel 
Contact 
Information 
(Cover Page) 
Emergency Contact Information 
Medical Monitor – 24-hour Emergency Reporting 
Medical Monitor 
Investigators are encouraged to call the NASH medical 
monitor hotline at +1 844 250 6396 or send an email to the 
NASH medical monitor at 
NASH209@interceptpharma.com with safety questions as 
these lines of contact are monitored 24 hours a day. 
 
 
Contact: 
Roya Hooshmand-Rad, MD PhD,  
Executive Director, Clinical Research  
Intercept Pharmaceuticals, Inc. 
(Intercept) 
Telephone: 
+1 844 250 6396  
Email: 
rhooshmand-
rad@interceptpharma.com 
SAE Fax: 
+ 1 800 497 8521 
SAE Email: 
sae@interceptpharma.com 
Primary 
Medical 
Monitor 
Contact: 
Roya Hooshmand-Rad, MD PhD 
Executive Director, Clinical Research 
Intercept Pharmaceuticals, Inc. (Intercept 
Email: 
rhooshmand-rad@interceptpharma.com 
 
 
 
 
Or if Not Available: 
 
 
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Revised Text (Version 2) 
Contact: 
Barbara Scholz, MD,  
Medical Director, Drug Safety  
Intercept 
Telephone: 
+1 844 250 6396  
Email: 
barbara.scholz@interceptpharma.com 
 
Secondary Contact: 
Barbara Scholz, MD, 
Medical Director, Drug Safety 
Intercept 
Telephone: 
+1 858 353 1350 (Pacific time 
zone) 
Email: 
barbara.scholz@interceptpharma.co
m 
Synopsis 
(Exploratory 
Objectives) 
Liver 
biochemistry and 
markers of liver 
function 
Albumin, ALP, ALT, AST, , direct 
bilirubin, GGT, INR,  total 
bilirubin  
 
Liver biochemistry 
and markers of 
liver function 
Albumin, ALP (isoenzymes), ALT, 
AST, , direct bilirubin, GGT, INR,  
total bilirubin  
 
NOTE: ALP (isoenzyme) was also added to the list of 
laboratory assessments in Section 11.1 (Table 4) and 
Section 12.2.6 (Table 9). 
Synopsis 
(Exploratory 
Objectives) 
And  
Section 6.3 
(Exploratory 
Objectives) 
 
Cardiovascular risk scores (eg, Framingham Risk Score 
[FRS] and Reynolds score) 
Synopsis 
(Methodology) 
And 
Section 7.1 
Overall Study 
Design 
(Double-Blind 
Phase) 
 
Subjects who discontinue investigational product or 
atorvastatin during the double-blind phase are still 
expected to attend scheduled study visits and are to be 
followed through the Week 16 Visit. 
Subjects who discontinue atorvastatin during the double-
blind phase are eligible to continue OCA during the 
double-blind phase and enroll into the LTSE at the 
discretion of the Investigator, provided they continue to 
meet exclusion criteria #4 (LDL <200 mg/dL).    
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Revised Text (Version 2) 
Synopsis 
(Study Design 
Diagram) 
And 
Section 7.1.1 
Study Design, 
Figure 1 
 
Footnote Added: 
Δ = Telephone safety contact at Week 6, Week 10, and 
Week 14 
Synopsis 
(Key Inclusion 
Criteria) 
And 
Section 8.2 
Subject Inclusion 
Criteria 
6.  Contraception:  Female subjects of childbearing 
potential must use ≥1 effective method of contraception 
during both the double-blind and LTSE phases of the study 
and 4 weeks following the last dose of investigational 
product or at study termination (whichever is greater).  
Effective methods of contraception are considered to be 
those listed as follows: 
•Double-barrier method, ie, (a) condom (male or female) 
or (b) diaphragm, with spermicide; or 
•Intrauterine device; or 
•Vasectomy (partner); or 
•Hormonal (eg, contraceptive pill, patch, intramuscular 
implant or injection); or 
•Abstinence, if in line with the preferred and usual lifestyle 
of the subject  
6.  Contraception:  Female subjects of childbearing potential 
must use ≥1 effective method of contraception during the 
study and until 30 days   following the last dose of 
investigational product.  Effective methods of contraception 
are considered to be those listed below. 
•Double-barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide 
•Intrauterine device 
•Vasectomy (partner) 
•Hormonal (eg, contraceptive pill, patch, intramuscular 
implant or injection) 
•Abstinence (defined as refraining from heterosexual 
intercourse) 
Synopsis 
(Key Exclusion 
Criteria) 
3.LDL cholesterol >190 mg/dL and already on statin 
therapy at Screening Visit 1. 
3.LDL cholesterol ≥190 mg/dL and already on statin therapy 
at Screening Visit 1. 
And 
Section 8.3 
Subject Exclusion 
Criteria 
10.  Evidence of other forms of chronic liver disease 
including but not limited to:  
•Concomitant hepatitis B or C virus infection      
• 
10.  Evidence of other forms of chronic liver disease 
including but not limited to:  
•Positive test result at Screening for hepatitis B surface 
antigen or hepatitis C antibody (and positive hepatitis C 
virus [HCV] ribonucleic acid [RNA]) 
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Revised Text (Version 2) 
 
11.  Presence of clinically significant hepatic 
decompensation, including: 
•History of liver transplant, current placement on a liver 
transplant list, or current Model for End-Stage Liver 
Disease (MELD) score >12.  Subjects who are placed on a 
transplant list despite a relatively early disease stage (eg, 
per regional guidelines) may be eligible as long as they do 
not meet any of the other exclusion criteria. 
•History (within the past 12 months) or presence of: 
oVariceal bleed 
oUncontrolled ascites 
oHepatic encephalopathy 
oSpontaneous bacterial peritonitis 
oHepatorenal or hepatopulmonary syndromes 
11.  History of liver transplant, current placement on a liver 
transplant list, or current Model for End-Stage Liver Disease 
(MELD) score >12.  Subjects who are placed on a transplant 
list despite a relatively early disease stage (eg, per regional 
guidelines) may be eligible as long as they do not meet any of 
the other exclusion criteria. 
 
 
 
12.  Presence of hepatic decompensation, including: 
- Gastroesophageal varices 
- Ascites 
- Hepatic encephalopathy 
- Spontaneous bacterial peritonitis 
- Hepatorenal or hepatopulmonary syndromes 
 
14.  Creatine phosphokinase >5x ULN at any Screening 
visit. 
14.  Creatine phosphokinase >5x ULN at Screening Visit 2. 
 
19a.  Coronary revascularization (percutaneous coronary 
intervention or coronary artery bypass grafting) 
19a.  Peripheral or Coronary revascularization (percutaneous 
coronary intervention or coronary artery bypass grafting) 
 
 
Note:  Exclusion criteria numbered 12 through 27 in the 
Original Protocol updated to numbers 13 through 28 in 
Version 2 as a result of new exclusion criteria number 12 
above. 
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Revised Text (Version 2) 
Synopsis 
(Statistical 
Methods) 
Secondary Endpoints 
Safety and 
tolerability 
TEAEs, physical exams, ECGs, 
vital signs, clinical laboratory 
assessments (including lipid profile 
changes)  
Secondary Endpoints 
Safety and 
tolerability 
TEAEs (including cardiovascular 
events), physical exams, ECGs, vital 
signs, clinical laboratory assessments 
(including lipid profile changes)  
Synopsis 
(Statistical 
Methods) 
And 
Section 11.1 
Efficacy 
Assessments 
(Table 4) 
Exploratory Endpoints 
Liver biochemistry 
and markers of 
liver function 
Albumin, ALP, ALT, AST, 
creatinine, GGT, total bilirubin, 
conjugated (direct) bilirubin, INR 
Marker for hepatic 
apoptosis and 
fibrosis 
CK-18-M30 
 
Exploratory Endpoints 
Liver biochemistry 
and markers of liver 
function 
Albumin, ALP, ALT, AST, direct 
bilirubin, GGT, INR, total bilirubin  
Marker for hepatic 
apoptosis and 
fibrosis 
CK-18-M30 and CK-18-M65 
Cardiovascular 
risk scores 
FRS and Reynolds scores 
Synopsis 
(Sample Size 
Justification) 
And 
Section 13.2 
Determination of 
Sample Size 
It is the intent of this study to characterize the components 
of LDL metabolism (cholesterol concentration, particle 
size, particle concentration) in subjects with NASH before 
and after treatment with OCA and to assess the changes 
induced by HMG Coenzyme A reductase inhibitor 
(atorvastatin) therapy.  Assuming a 22 U/L increase from 
baseline with a standard deviation of 20 in LDL in the 
OCA 25 mg group, a sample size of 20 subjects per group 
will provide greater than 99.9% power to demonstrate the 
statistically significant difference of LDL increase from 
baseline with a 2-sided type I error of 0.05 
It is the intent of this study to characterize the components of 
LDL metabolism (cholesterol concentration, particle size, 
particle concentration) in subjects with NASH before and 
after treatment with OCA and to assess the changes induced 
by HMG Coenzyme A reductase inhibitor (atorvastatin) 
therapy.  Assuming, 22 mg/dL increase from baseline with a 
standard deviation of 24 in LDL in the OCA 25 mg group 
without atorvastatin therapy after 16 weeks of treatment 
based on data from FLINT, a sample size of 20 subjects per 
group will provide greater than 97.3% power to demonstrate 
the statistically significant difference of LDL increase from 
baseline with a 2-sided type I error of 0.05.  
Section 5.6.4.1 
Rationale for 
At risk subjects include subjects with existing 
cardiovascular disease (including but not limited to stable 
or unstable angina, previous myocardial infarction or 
At risk subjects include subjects with existing cardiovascular 
disease (including but not limited to stable or unstable angina, 
previous myocardial infarction or stroke or a previous 
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Revised Text (Version 2) 
statin withdrawal 
(Paragraph 5) 
stroke or a previous coronary revascularization procedure), 
significant dyslipidemia (as defined by LDL >190 mg/dL) 
despite the use of statin therapy, unstable hypertension, 
and familial hypercholesterolemia. 
peripheral or coronary revascularization procedure), 
significant dyslipidemia (as defined by LDL ≥190 mg/dL) 
despite the use of statin therapy, unstable hypertension, and 
familial hypercholesterolemia 
Section 5.8. 
Summary of 
Known Potential 
Risks with 
Atorvastatin 
(Section 5.8 added to Version 2) 
Muscle complaints are the most frequent adverse reports 
among patients treated with statins, with the most severe 
side effects including myopathy and rhabdomyolysis.  The 
Statin Muscle Safety Task Force (Rosenson 2014) has 
provided a classification of the spectrum of statin-
associated muscle AEs that may be seen in clinical 
practice and can be used in characterizing reports of 
muscle-related events.  
a. Myalgia – unexplained muscle discomfort 
often described as “flu-like” symptoms 
− 
Muscle aches 
− 
Muscle soreness 
− 
Muscle stiffness 
− 
Muscle tenderness 
− 
Muscle cramps with or shortly after 
exercise (not nocturnal cramping) 
b. Myopathy – muscle weakness (not attributed 
to pain and not necessarily associated with 
elevated CPK) 
c. Myositis – muscle inflammation 
d. Myonecrosis – muscle enzyme elevations or 
hyperCPKemia 
− 
Mild >3x baseline or ULN 
− 
Moderate ≥10x baseline or ULN 
− 
Severe ≥50x baseline or ULN 
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e. Clinical Rhabdomyolysis - Myonecrosis with 
myoglobinuria or acute renal failure (increase 
in serum creatinine ≥0.5 mg/dL  
There is no evidence that these muscle-related AEs are a 
continuum beginning with myalgia and progressing to 
more severe manifestations of myopathy; rather events 
occur independent of each other.  Myalgia events, with 
frequencies ranging from 1% to 5% in clinical trials to 
11% to 29% in observational cohorts, typically occur 
within 1 month of statin initiation and resolve within 2 
weeks of statin cessation (Rosenson 2014).  Retrospective 
analyses have suggested that patients who discontinue 
statins due to intolerance are able to tolerate statins long-
term following re-challenge (Zhang 2013, Mampuya 
2013).   
Historically, statins have been associated with biochemical 
abnormalities of liver function, but available data suggest 
that increases in liver transaminases associated with 
statins are asymptomatic and generally reversible (Desai 
2014).  In the absence of liver disease, US guidelines 
(Stone 2013) recommend that baseline transaminase levels 
should be checked before initiating statin therapy and 
subsequent testing should only be done in the presence of 
symptoms suggestive of hepatic disease.  As this study is 
being conducted in subjects with confirmed NASH, liver 
enzymes will be frequently monitored and Section 8.4.1.2, 
Section 8.4.1.3, and Appendix B provide detailed guidance 
for handling elevated liver biochemistry values.  
Statins modestly increase the risk of type 2 diabetes 
mellitus in individuals with risk factors for diabetes.  
Individuals receiving statin therapy should be evaluated 
for new-onset diabetes according to the current diabetes 
screening guidelines (American Diabetes Association 
2013). 
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Confusion and memory loss have been reported with 
statins, but medical evidence supporting a causal effect is 
weak or nonexistent (Simic 2015).  However, any reports 
of cognitive events should be appropriately evaluated, 
particularly in individuals whose symptoms persist 
despite statin discontinuation. 
In this study, any AEs (including signs and symptoms 
described above) regardless of relationship to 
investigational product or study medication, must be 
documented appropriately (See Section 12)  
7.1 
Overall Study 
Design 
(Table 1) 
 
Added Week 6 (Contact), Week 10 (Contact), and Week 14 
(Contact) with associated X in AEs, Prior and Concomitant 
Medications, and Collect bottles/Investigational Product 
Accountability/Compliance; Collect Bottles/Atorvastatin 
Accountability/Compliance (for Week 10 and Week 14). 
 
 
Added procedure “Hepatitis B Virus and Hepatitis C Virus 
Tests” at Screening Visit 1. 
 
 
 
Transient Elastography timepoint added:  ET/EOS. 
(Also, added this procedure to Section 9.7.15) 
 
 
The list of assessments replaced with 3 broad subcategories:  
PD Assessments; Markers of Inflammation, Fibrosis, or 
Apoptosis; and Vitamin D. 
 
 
 Added footnote l to Serum Chemistry 
 
Urine  Based β-hCG Pregnancy Testq 
Pregnancy Testq 
 
 
Added hepatitis B and hepatitis C tests at Screening Visit 1 
 
d Heart rate, blood pressure, temperature, and respiratory 
rate 
d Sitting heart rate, blood pressure, temperature, and 
respiratory rate 
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n Serum samples will be collected for lipoprotein 
analyses… 
n Serum and plasma samples will be collected for lipoprotein 
analyses… 
 
q Serum pregnancy test will be administered if urine-based 
β-hCG pregnancy test is positive. 
q Serum pregnancy test will be administered if urine-based 
β-hCG pregnancy test is positive.  Screening pregnancy 
tests will be serum-based tests. 
 
r Blood sample for future exploratory analysis, including 
markers of cardiovascular risk (adiponectin, plasminogen 
activator inhibitor-[(PAI-1], and B-type natriuretic peptide 
[BNP]). 
r Includes markers of cardiovascular risk (adiponectin, 
plasminogen activator inhibitor-[(PAI-1], and B-type 
natriuretic peptide [BNP]). 
 
s At selected investigational sites, subjects will have the 
option to provide blood samples for measurement of OCA 
PK. 
s At selected investigational sites, subjects will have the 
option to provide blood samples for measurement of OCA 
PK.  PK samples will be collected within 30 minutes prior 
to dosing and again at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 
6 hours postdose.  Subjects should not drink additional 
water for 1 hour after taking the dose of investigational 
product and will remain fasted until the 1 hour sample is 
collected. 
7.1 
Overall Study 
Design 
(Table 2) 
Header row updated as follows 
Month 3 
Month 6 
Month 9 
 
 
Month 3, 
Month 15 
Month 6,  
Month 18 
Month 9,  
Month 21 
 
 
 
The list of assessments replaced with 3 broad subcategories:  
PD Assessments; Markers of Inflammation, Fibrosis, or 
Apoptosis; and Vitamin D. 
 
 
Additional timepoints added as follows: 
AUDIT alcohol measures:  EOS/ET 
(Also, added this procedure to Section 9.7.20.) 
 
 
Timepoints removed as follows: 
Reverse Cholesterol Transport analysis:  Month 3, Month 9, 
Month 15, and Month 21. 
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d Heart rate, blood pressure, temperature, and respiratory 
rate. 
d Sitting heart rate, blood pressure, temperature, and 
respiratory rate. 
 
 
i NOTE:  Any time atorvastatin is up-titrated or re-
initiated, a telephone safety contact must be conducted to 
assess AEs, concomitant medications, and atorvastatin 
compliance. 
 
 
All subsequent footnotes have been adjusted by one 
7.4.2 
Atorvastatin Dose 
Adjustments 
 
Added: 
If at any time during the double-blind or LTSE phases, 
serum chemistry results indicate LDLc <40 mg/dL, the 
subject should be brought back to the site within 1 to 2 
weeks after the first result is obtained for an unscheduled 
(repeat) laboratory assessment.  If LDLc <40 mg/dL is 
obtained on 2 consecutive visits, the subject may 
discontinue or reduce the dose of atorvastatin. 
Subjects may also interrupt or discontinue atorvastatin 
due to tolerability issues including muscle-related 
symptoms (Section 5.8) and abnormal liver biochemistry.  
Any muscle-related complaints should be assessed per the 
ACC/AHA Guidelines (Appendix A) and statin dose 
adjusted accordingly:   
• 
To avoid unnecessary discontinuation of statins, 
obtain a history of prior or current muscle 
symptoms to establish a baseline prior to initiation 
of statin therapy. 
• 
If mild to moderate muscle symptoms develop 
during statin therapy: 
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o Discontinue the statin until symptoms can 
be evaluated. 
o Evaluate the patient for other conditions 
that might increase the risk for muscle 
symptoms. 
o If muscle symptoms resolve, and if no 
contraindication exists, re-challenge the 
subject with the same or a reduced dose of 
atorvastatin to establish a causal 
relationship between the muscle symptoms 
and statin therapy. 
o Once a low dose statin is tolerated, the 
dose may be gradually increased as 
tolerated and clinically indicated. 
o If after 2 months without statin treatment, 
muscle symptoms or elevated CPK levels 
do not completely resolve, consider other 
causes of muscle symptoms. 
o If persistent muscle symptoms are 
determined to arise from a condition 
unrelated to statin therapy, or if the 
predisposing condition has been treated, 
resume statin therapy at the original dose. 
• 
If unexplained severe muscle symptoms or fatigue 
develop during statin therapy, discontinue the 
statin and address the possibility of 
rhabdomyolysis by evaluating CPK and 
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creatinine, and performing urinalysis for 
myoglobinuria. 
Elevations in liver biochemistry should be monitored per 
protocol subject withdrawal criteria (Section 8.4 and 
Appendix B). 
Subjects who discontinue atorvastatin may continue on 
investigational product through the double-blind and 
LTSE phases, as deemed appropriate by the Investigator 
and Medical Monitor, and provided they continue to meet 
exclusion criteria #4 (LDL <200 mg/dL). 
8.1 
Subject 
Population 
Approximately 80 subjects with biopsy-confirmed NASH 
without evidence of hepatic decompensation who meet 
eligibility criteria will be enrolled at approximately 30 
investigational sites in the US with experience in treating 
patients with NASH. 
Approximately 80 subjects with biopsy-confirmed NASH 
without evidence of hepatic decompensation who meet 
eligibility criteria will be enrolled at approximately 30 
investigational sites in the US. 
8.4  
Subject 
Withdrawal 
Criteria 
Subsections were rearranged as follows: 
8.4.1 Reasons for Mandatory Discontinuation of 
Investigational Product 
8.4.1.1 Pregnancy 
8.4.1.2  Severe Drug-Induced Liver Injury 
8.4.1.3  Clinical Laboratory Values 
 
 
 
 
 
 
 
 
 
8.4.1 Reasons for Mandatory Discontinuation of 
Investigational Product or Atorvastatin 
8.4.1.1 Adverse Events ≥Grade 3 in Severity and Possibly, 
Probably, or Definitely Related to Investigational 
Product 
8.4.1.2  Pregnancy 
8.4.1.3  Severe Drug-Induced Liver Injury 
8.4.1.4  Myonecrosis 
8.4.2  Reasons for Mandatory Interruption of 
Investigational Product 
8.4.2.1  Adverse Events ≥Grade 4 in Severity and Not or 
Unlikely Related to Investigational Product 
8.4.2.2  Suspected Mild or Moderate Drug-Induced Liver 
Injury 
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8.4.2  Other Reasons for Study or Treatment 
Discontinuation of Subjects 
8.4.3  Subject Discontinuation Notification 
8.4.3  Other Reasons for Study or Treatment Discontinuation 
of Subjects 
8.4.4  Subject Discontinuation Notification 
8.4.1.1 
Adverse Events 
≥Grade 3 in 
Severity… 
 
If a subject experiences an AE that is ≥Grade 3 in severity 
(Section 12.1.4) that is considered possibly, probably, or 
definitely related to investigational product, the 
investigational product must be discontinued. 
8.4.1.2 
Pregnancy 
Whenever the site is notified of a possible pregnancy, the 
subject should be asked to come in for an unscheduled 
visit to perform a serum pregnancy test.  If a female 
subject becomes pregnant, the subject must stop taking 
investigational product immediately and be withdrawn 
from the study.  The subject must be followed by the 
Investigator through pregnancy outcome.  The mother (and 
infant) will be followed as considered appropriate by the 
Investigator and the Medical Monitor.  For reporting 
purposes, pregnancy is not considered an AE. 
Whenever the site is notified of a possible pregnancy, the 
subject should be asked to come in for an unscheduled visit to 
perform a serum pregnancy test.  If a female subject becomes 
pregnant, she must discontinue treatment with 
investigational product and atorvastatin immediately, but 
should continue with the study visit schedule and must be 
followed by the Investigator through pregnancy outcome.  
The mother (and infant) will be followed as considered 
appropriate by the Investigator and the Medical Monitor.  As 
described in Section 12.1.8.1, pregnancy is not considered an 
AE for reporting purposes. 
8.4.1.3 
Severe Drug-
Induced Liver 
Injury 
(Paragraph 2) 
Subjects should be encouraged to continue study visits 
despite stopping investigational product for continued 
study data collection but may withdraw consent at any 
time. 
Subjects who discontinue due to significant drug-induced 
liver injury must be followed until the AE has resolved, 
stabilized, or is not of clinical concern. 
8.4.1.4 
Myonecrosis 
 
Moderate myonecrosis as defined by creatine kinase ≥10x 
the untreated baseline levels or ULN.  Muscle-related 
symptoms that do not necessitate mandatory 
discontinuation of investigational product or atorvastatin 
are detailed in Section 5.8. 
8.4.2.1 
Adverse Events 
 
If a subject experiences an AE categorized as ≥Grade 4 in 
severity and not or unlikely related to investigational 
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≥Grade 4 in 
Severity and... 
product, at least a mandatory interruption of 
investigational product is required. 
8.4.2.2 
Suspected Mild 
or Moderate 
Drug-Induced 
Liver Injury 
Deleted Section 8.4.1.3. (Clinical Laboratory Values) of 
the Original Protocol, and replaced with Section 8.4.2.2 
(new text shown in the right column). 
 
Development of the following clinical laboratory values 
during the course of the double-blind and LTSE phases of 
the study mandates investigational product 
discontinuation: 
•An aminotransferase (aspartate aminotransferase [AST] 
or ALT) elevation that is > 3x ULN/baseline/nadir, or 
•Total bilirubin >1.5 mg/dL (25.7 μmol/L) AND >2x the 
predose value (average of all pretreatment values), or 
•When myopathy is diagnosed or suspected (confirm with 
CPK prior to permanent discontinuation; discontinue if 
CPK >10x ULN) 
Note:  The mean of all Screening and Baseline values 
constitute the predose values. 
If a subject is required to discontinue investigational 
product due to an increase in aminotransferase or bilirubin, 
the subject must be followed at appropriate intervals until 
these parameters have returned to within the normal range 
or prestudy values, and/or are stable, or there is no ongoing 
clinical concern. 
 
 
 
Because transient fluctuations of ALT or AST are 
common, and progression to severe drug-induced liver 
injury or acute liver failure is uncommon, automatic 
discontinuation of investigational product with an 
elevation of ALT or AST that is >3x ULN/baseline/nadir 
or total bilirubin >2x ULN/baseline/nadir, as described in 
Appendix B, may be unnecessary.  If a subject develops 
signs of a mild or moderate event of drug-induced liver 
injury, regardless of causality, investigational product 
should be interrupted until the event has resolved or 
returned to baseline, but the subject should continue with 
the study visit schedule.  The subject may restart 
treatment after resolution of the event or return to 
baseline.  Follow-up procedures, including laboratory 
evaluations and physical examinations, must be 
performed after a maximum of 2 weeks of re-treatment 
and may be conducted at a local clinic if the subject is 
unable to return to the site.  Results must be reported 
immediately to the site so the Investigator can determine 
if the subject will be allowed to continue treatment. 
9.2. 
Concomitant 
Medications 
Relevant information about all concomitant medications 
(including prescribed, over-the-counter, or herbal 
preparations) taken prior to (ie, within 30 days of Day 1) 
and during the study must be recorded in the source 
documents and eCRF, as well as any dose or dose regimen 
changes that occur during the study. 
Relevant information about all concomitant medications 
(including prescribed, over-the-counter, or herbal 
preparations) taken prior to (ie, within 12 months of Day 1) 
and during the study must be recorded in the source 
documents and eCRF, as well as any dose or dose regimen 
changes that occur during the study. 
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9.2.3  
Management of 
Changes in 
Cholesterol 
During the double-blind phase of the study, the dose of 
atorvastatin administration should be as described in this 
protocol through Week 12.  At the Week 12 Visit, 
Investigators may increase or decrease the dose of 
atorvastatin as clinically indicated. 
 
During the double-blind phase of the study, the dose of 
atorvastatin administration should be as described in this 
protocol through Week 12 unless tolerability issues develop 
as referenced in Section 7.4.2.  At the Week 12 Visit, 
Investigators may increase or decrease the dose of 
atorvastatin as clinically indicated. 
9.2.4 
Prohibited 
Medications 
And 
Table 3 
 
•Prohibited throughout the double-blind phase of the 
study: 
 
•Prohibited throughout the double-blind phase of the study: 
- Medications contraindicated in the atorvastatin 
label, including HIV and Hepatitis C protease 
inhibitors, clarithromycin, and itraconazole (refer 
to atorvastatin prescribing information in 
Appendix E for complete list).  These medications 
are also prohibited during the LTSE phase if the 
subject continues to receive atorvastatin during 
the LTSE. 
 
Note:  These medications were also added to Table 3. 
9.4.2 
Emergency 
Unblinding 
Procedures 
The DSMC (refer to Section 13.8) will have access to the 
IWRS and will be able to unblind individual subjects.  The 
DSMC will be provided aggregate data to review during 
closed sessions. 
The DMC (refer to Section 13.8) will have access to the 
IWRS and will be able to unblind individual subjects.  The 
DMC will review aggregate data during closed sessions. 
9.6.1 
Fasting 
Requirements at 
Study Visits 
All subjects must have been fasting for at least 8 hours 
prior to Screening Visit 2 (Week -1 Visit) and all 
subsequent study visits, as all analytes will be assayed in 
fasting blood or plasma samples (Table 1 and Table 2). 
All subjects must have been fasting for at least 8 hours prior 
to Screening Visit 2 (Week -1 Visit) and all subsequent study 
visits, as all analytes will be assayed in fasting blood, serum, 
or plasma samples (Table 1 and Table 2). 
9.6.2 
Grapefruit and 
Grapefruit Juice 
Grapefruit and grapefruit juice consumption should be 
discouraged following initiation of atorvastatin (please 
refer to atorvastatin prescribing information [reference: 
Appendix A]). 
Grapefruit and grapefruit juice consumption should be 
discouraged following initiation of atorvastatin due to 
possible increases in plasma concentration of atorvastatin 
(please refer to atorvastatin prescribing information 
[Appendix E]). 
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9.7.1 
Visit Windows 
The Week -1 Visit should occur within ±1 days of the visit 
day. 
The Week -1 Visit should occur within ±1 days of the 
Randomization/Day 1 Visit. 
 
 
(A row added to in-text table) 
Week 6, Week 10, and Week 14 
(Contact visits) 
±4 days 
9.7.3 
Screening Visit 1 
Procedures 
Subjects who are statin free (ie, no statin use within 4 
weeks of Screening) must return for fasted serum 
chemistry labs and may proceed to the Randomization/Day 
1 Visit once screening labs are available and eligibility is 
confirmed; subjects who need to wash out statin therapy 
are required to have a Week -1 Visit 4 weeks after 
Screening Visit 1. 
 
•Record prior (if within 6 months of Day 1) and current 
concomitant medications. 
 
 
 
 
 
•Perform a urine-based β-hCG pregnancy test for female 
subjects of childbearing potential.  Perform serum 
pregnancy test in females of childbearing potential, if urine 
β-hCG pregnancy test is positive. 
Subjects who are statin free (ie, no statin use within 4 weeks 
of Screening) must return for fasted serum chemistry labs at 
Screening Visit 2, and may proceed to the 
Randomization/Day 1 Visit once screening labs are available 
and eligibility is confirmed; subjects who need to wash out 
statin therapy are required to have a Week -1 Visit 4 weeks 
after Screening Visit 1. 
 
•Record prior (if within 12 months of Day 1) and current 
concomitant medications. 
 
•Obtain serum sample for hepatitis B surface antigen or 
hepatitis C antibody (and positive HCV ribonucleic acid 
[RNA]) testing to confirm study eligibility. 
 
•Perform serum pregnancy test in females of childbearing 
potential. 
9.7.5. 
Randomization/D
ay 1 Visit 
Procedures 
•Record prior (within 30 days of Day 1) and current 
concomitant medications. 
•Record prior (since Screening Visit 1) and current 
concomitant medications. 
9.7.5 
Serial blood samples will be obtained for measurement of 
OCA and its conjugates prior to dosing and at 0.5, 0.75, 1, 
Serial blood samples will be obtained for measurement of 
OCA and its conjugates 30 minutes prior to dosing and at 
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Additional Day 1 
Procedures for 
PK Subjects 
And 
9.7.13.1 
Additional Week 
16 Procedures for 
PK Subjects 
1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose.  Subjects should 
not drink additional water for 1 hour after taking the dose 
of investigational product and will remain fasted until the 
4-hour sample is collected.  Lunch will be provided 
following collection of the 4-hour PK sample; the lunch 
will be a meal replacement drink with nutrition 
information that has been submitted to and approved by 
the Sponsor in advance. 
0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose.  
Subjects should not drink additional water for 1 hour after 
taking the dose of investigational product and will remain 
fasted until the 1-hour sample is collected.  Meal will be 
provided following collection of the 1-hour PK sample; the 
lunch will be a meal replacement drink with nutrition 
information that has been submitted to and approved by the 
Sponsor in advance. 
9.7.5 
Randomization/D
ay 1 Visit 
Procedures 
And 
Sections 9.7.7, 
9.7.9, 9.7.11, 
9.7.13, 9.7.15, 
9.7.18, 9.7.19, 
9.7.20 
– Plasma bile acids, 7α-hydroxy-4-cholesten-3-one (C4), 
and FGF-19; serum IL-6, cytokeratin-18 neoepitope M30 
(CK-18-M30), high-sensitivity C-reactive protein (hs-
CRP), TNF-α, and Vitamin D; and markers of glucose 
metabolism (C-peptide, insulin, fasting plasma glucose, 
and HbA1c) 
 
– PD assessments; markers of inflammation, fibrosis and 
apoptosis; and markers of glucose metabolism (see Table 
4 and Table 9) 
– Vitamin D 
9.7.8 
(Week 6 Safety 
Contact) 
And 
9.7.10 
(Week 10 Safety 
Contact) 
And 
9.7.12 
(Week 14 Safety 
Contact) 
Note:  The numbering of 9.7 subsections is changed in 
Version 2 compared to that in the Original protocol from 
Section 9.7.9 onwards due to the addition of new 
Subsections 9.7.8, 9.7 10, and 9.7.12. 
• 
This is a telephone contact with the subject to 
- Review and record AEs 
- Review and record concomitant 
medications 
- Assess investigational product and 
atorvastatin compliance 
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9.7.18 
LTSE Month 3, 
Month 6, Month 
9, Month 15, 
Month 18, and 
Month 21 Visit 
Procedures 
•Perform a physical examination (only at Month 3 Visit). 
•Perform a physical examination (only at Month 3 and 
Month 15 Visits). 
(Section 9.7.15 of 
Original 
Protocol) 
•Determine alcohol consumption (using AUDIT 
questionnaire [only at Month 6 Visit]). 
•Determine alcohol consumption (using AUDIT questionnaire 
[only at Month 6 and Month 18 Visits]). 
 
•Collect used bottles of atorvastatin, assess atorvastatin 
compliance, and perform atorvastatin accountability. 
•Collect used bottles of atorvastatin, assess atorvastatin 
compliance, and perform atorvastatin accountability.  
- NOTE:  If atorvastatin dose is up-titrated or re-
initiated after dose interruption, a telephone 
safety contact must be conducted 2 weeks 
following the change in dose to assess for AEs, 
concomitant medications, and investigational 
product and atorvastatin compliance. 
 
•Obtain blood samples for:  
- Lipoprotein analyses and reverse cholesterol 
transport analytes  
•Obtain blood samples for:  
- Lipoprotein analyses 
- Reverse cholesterol transport analytes (only at 
Month 6 and Month 18 Visits) 
9.7.20 
LTSE End of 
Study/Early 
Termination 
Procedures 
 
•Determine alcohol consumption (using AUDIT 
questionnaire). 
9.7.21 
Unscheduled 
Safety Visits 
An increase in aminotransferases (ALT or AST) to >3× 
baseline (and >ULN) or total bilirubin >2× baseline (and 
>ULN) should be followed by repeat testing within 48 to 
72 hours of the serum chemistry to confirm the 
An increase in aminotransferases (ALT or AST) to >3× 
baseline (and >ULN) or total bilirubin >2× baseline (and 
>ULN) should be followed by repeat testing within 48 to 72 
hours of the serum chemistry to confirm the abnormalities 
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abnormalities and to determine if they are increasing or 
decreasing. 
and to determine if they are increasing or decreasing 
(Appendix B). 
10.5 
Atorvastatin 
Tablets 
Atorvastatin tablets for oral administration contain 10 mg, 
20 mg, 40 mg, or 80 mg atorvastatin… 
Atorvastatin tablets for oral administration contain 10 mg, 20 
mg, and 40 mg atorvastatin.  
10.5.3 
Atorvastatin 
Dispensation 
At subsequent visits, atorvastatin will be dispensed as 
clinically indicated. 
At subsequent visits, atorvastatin will be dispensed as 
clinically indicated.  For doses higher than 20 mg, subject 
may take multiple atorvastatin tablets for a total dose of 
40 mg or 80 mg, as clinically indicated. 
11.1 
Efficacy 
Assessments 
(Table 4) 
(Deleted the following row) 
Bile acid synthesis 
and concentrations 
C4 (7α-hydroxy-4-cholesten-3-one), 
conjugated and unconjugated bile 
acids (possible) 
 
11.1.1 
Efficacy 
Laboratory 
Assessments 
The complete list of planned laboratory assessments 
supporting primary, secondary, and exploratory objectives 
of the study is shown in Table 4, and includes parameters 
related to LDL metabolism, lipoprotein metabolism, 
reverse cholesterol transport, liver biochemistry and 
markers of liver function, markers of inflammation, 
glycemic control, and NASH disease severity marker CK-
18-M30. 
The complete list of planned laboratory assessments 
supporting primary, secondary, and exploratory objectives of 
the study is shown in Table 4, and includes parameters related 
to LDL metabolism, lipoprotein metabolism, reverse 
cholesterol transport, liver biochemistry and markers of liver 
function, markers of inflammation, glycemic control, OCA 
PD markers, and NASH disease severity markers CK-18-
M30 and CK-18-M65. 
11.1.2.1 
Central Reading 
of Liver 
Histology 
Kleiner 2012 
Kleiner 2005 
11.2 
Pharmacokinetic 
and 
Pharmacodynamic 
Assessments 
 
 
 
 
 
Added the following new subsection: 
 
11.2.1 Pharmacodynamic Assessments 
 
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11.2.1. OCA, Bile Acids, and FGF-19 
Original subsection 11.2.1 is now 11.2.2. and is re-named as 
below 
 
11.2.2. Pharmacokinetic Assessments 
11.2.1. 
Pharmacodynami
c Assessments 
 
11.2.1. Pharmacodynamic Assessments 
PD assessments will be collected according to the Schedule 
of Study Procedures (Table 1 and Table 2) from all 
subjects to measure C4, FGF-19, and possibly conjugated 
and unconjugated bile acids (dependent on the results of 
the C4 and FGF-19 assessments). 
11.2.2 
Pharmacokinetic 
Assessments 
(Paragraph 1) 
11.2.1. OCA, Bile Acids, and FGF-19 
Subjects who participate in the PK and/or PD assessment 
will provide blood samples for the measurement of OCA 
and its conjugates, C4, FGF-19, and possibly bile acids, 
prior to administration of investigational product (predose) 
on Day 1 and at the Week 16 Visit. 
11.2.2. Pharmacokinetic Assessments 
Subjects who opt to participate in the PK assessment will 
provide blood samples for the measurement of OCA and its 
conjugates.  The first sample should be collected within 
30 minutes prior to administration of investigational product 
(predose) on Day 1 and at the Week 16 Visit. 
11.2.2 
Pharmacokinetic 
Assessments 
(Paragraph 2) 
Paragraph 2 deleted: 
 
Instructions regarding the number and type of samples, 
including the PK assessments, to be collected at each visit, 
the required sample volumes, sample collection methods, 
sample processing, labeling, and shipping will be provided 
in a study-specific laboratory manual.  All necessary 
collection supplies will be provided by the central 
laboratory and will be appropriately assembled for the 
specific evaluations required at each visit. 
 
12.1.8.1 
Pregnancy and 
Follow-Up 
Pregnancies are not considered AEs in and of themselves; 
however, if a female study participant becomes pregnant 
while she is enrolled in the clinical study, she must 
discontinue treatment with investigational product 
immediately (see Section 8.4.1.1) and the Sponsor must be 
Pregnancies are not considered AEs in and of themselves; 
however, if a female study participant becomes pregnant 
while she is enrolled in the clinical study, she must 
discontinue treatment with investigational product and 
atorvastatin immediately (see Section 8.4.1.1) and the 
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notified within 24 hours of the Investigator’s learning of 
the pregnancy by completing the Pregnancy Report eCRF 
in the EDC system. 
 
Women who discontinue the study due to pregnancy may 
not re-enroll in the study at any point. 
Sponsor must be notified within 24 hours of the Investigator’s 
learning of the pregnancy by completing the Pregnancy 
Report eCRF in the EDC system. 
 
Women who discontinue the study due to pregnancy may not 
re-enroll in the study at any point, but should continue with 
the study visit schedule and must be followed by the 
Investigator through pregnancy outcome. 
12.2.6 
Laboratory 
Assessments 
(Table 9) 
Serum 
chemistry  
Albumin, BUN, creatinine, conjugated 
(direct) bilirubin, total bilirubin, AST, 
ALT, ALP, GGT, creatinine, electrolytes 
(calcium, chloride, magnesium, 
phosphorus, potassium, sodium), total 
protein, bicarbonate, free fatty acids; and 
blood lipids (total cholesterol, LDL, HDL, 
and VLDL fractions and TGs) 
 
Serum 
chemistry  
Albumin, BUN, creatinine, conjugated 
(direct) bilirubin, total bilirubin, AST, 
ALT, ALP, GGT, creatine 
phosphokinase, electrolytes (calcium, 
chloride, magnesium, phosphorus, 
potassium, sodium), total protein, 
bicarbonate, free fatty acids; and blood 
lipids (total cholesterol, LDL, HDL, and 
VLDL fractions and TGs) 
 
 
 
Hepatiti
s virus 
screenin
g tests 
Hepatitis B surface antigen, 
hepatitis C antibody, and 
HCV ribonucleic acid 
[RNA] 
 
13.6.3.8 
Cardiovascular 
Risk Scores 
New Section 13.6.3.8 Added 
The cardiovascular risk score includes the FRS and 
Reynolds scores.  Each score is derived from a subject’s 
age, sex, smoking status, total cholesterol and HDL levels, 
systolic blood pressure, and other factors including family 
history, BMI, ethnicity, and medications.  Cardiovascular 
scores will be calculated at the time of data analysis.  
These markers will be summarized by treatment group 
using descriptive statistics at Baseline and at each on-
study evaluation.  The change and percentage change 
from Baseline will also be summarized. 
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13.9. 
Adjudication 
Committees 
 
All suspected major adverse cardiovascular events 
(MACE), and drug-related hepatic injury events that 
occur after administration of the first dose of 
investigational product will be reviewed by the following 
blinded adjudication committees, depending on event 
type, before inclusion in any analysis.  The 2 committees 
and event types they are responsible for adjudicating are 
as follows: 
•Cardiovascular Events Committee (CEC):  Adjudicates 
all suspected MACE (Appendix D) 
•Hepatic Safety Committee:  Adjudicates all suspected 
drug-related hepatic injury events 
Each adjudication committee will have a charter that 
documents the reporting of events by the study site; 
definition of the suspected events to be adjudicated; 
supply of source documentation to the committee; and the 
entire data flow and process from committee membership, 
review of the events by the committee, reporting of the 
final assessment, and the working procedures of the 
committee.   
The adjudication committee members will include experts 
with relevant adjudication experience; they will not be 
involved in the study as Investigators, DMC members, or 
consultants.  Any candidate found to have a conflict or 
whose name is listed on the FDA debarment list will not 
be offered membership.  Conflicts of interest are assessed 
regularly, and if members are found to have a new 
conflict of interest they will be replaced. 
The adjudication of suspected events will be based on 
available source documentation, including but not limited 
to individual clinical study data, hospital records, 
histology, discharge summaries, and/or death certificates.  
The adjudication committees will not receive any 
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individual subject treatment or site-specific information.  
The assessment of events will be conducted in compliance 
with study-specific procedures, manuals, GCP, and all 
other applicable regulatory requirements, including the 
archiving of essential documents.    
19. 
List of 
References 
 
American Diabetes Association. Standards of medical care 
in diabetes-2013. Diabetes Care. 2013;36(Suppl 1):S11-
S66. 
Desai CS, Martin SS, Blumenthal RS. Non-cardiovascular 
effects associated with statins. BMJ 2014;349:g3743 
Kleiner D, Brunt E, Van Natta M, et al. Design and 
validation of a histological scoring system for nonalcoholic 
fatty liver disease. Hepatology 2005;41:1313-1321. 
Mampuya WM, Frid D, Rocco M, et al. Treatment 
strategies in patients with statin intolerance: the 
Cleveland Clinic experience.  Am Heart J. 2013;166:597-
603. 
Rosenson RS, Baker SK, Jacobson TA et al. An 
assessment by the statin muscle safety task force: 2014 
update. J Clin Lipid. 2014;8:S58-S71. 
Simic I, Reiner Z. Adverse effects of statins – myths and 
reality. Curr Pharm Des. 2015;21:1220-1226. 
Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of 
statins in routine care settings: a cohort study. Ann Intern 
Med. 2013;158:526-534.  
 
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Appendix A 
APPENDIX A.EUROPEAN AND NICE GUIDANCE 
FOR THE USE OF STATINS 
APPENDIX A.  AMERICAN COLLEGE OF 
CARDIOLOGY/AMERICAN HEART ASSOCIATION 
GUIDANCE FOR THE USE OF STATINS 
Appendix B 
For subjects who progress to cirrhosis and decompensation 
while participating in the study, elevation in liver 
biochemistry and development of other laboratory and 
clinical abnormalities may be expected.  Clinical outcomes 
should be reported and recorded as described in Section 
12.1.5 and appropriate action should be taken regarding 
investigational product use and study participation as 
described in Section 8.4. 
 
In subjects with abnormal ALT/AST or bilirubin at 
baseline, fold increase should be assessed against 
baseline levels instead of ULN as follows:  3× 
baseline ALT/AST (and >200 IU/L), or total bilirubin 
>2× baseline (and >2 mg/dL). 
For subjects who progress to cirrhosis and decompensation 
while participating in the study, elevation in liver 
biochemistry and development of other laboratory and 
clinical abnormalities may be expected.  Clinical adverse 
events (AEs) should be reported and recorded as described in 
Section 12.1.5 and appropriate action should be taken 
regarding investigational product use and study participation 
as described in Section 8.4. 
 
In subjects with abnormal ALT/AST or bilirubin at baseline, 
fold increase should be assessed against baseline levels 
instead of ULN as follows:  3× baseline ALT/AST, or total 
bilirubin >2× baseline (and >2 mg/dL). 
Appendix D 
 
APPENDIX D.  STANDARDIZED DEFINITIONS FOR 
CARDIOVASCULAR ENDPOINT EVENTS  
 
 
 
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APPENDIX G. 747-209 PROTOCOL VERSION 3 SUMMARY OF CHANGES 
Protocol 747-209 was revised to add a modified randomization scheme to the LTSE in order to maintain the blind of the 
double-blind phase.  The list of conjugates or metabolites of OCA for assessment was expanded to include OCA glucuronide.  
Additionally, various aspects of the study design and study population were clarified.   
Summary of Changes 
The following revisions were made to the protocol in Protocol Version 3.  Revised and new text in Version 3 is indicated in bold 
font, and the text deleted from Protocol Version 3 is crossed out in the table below.  Minor/editorial changes are not listed 
individually in the summary table below. 
Section 
Original Text 
Revised Text 
Global change 
Oral temperature 
Body temperature 
Global change 
OCA, tauro-OCA, glyco-OCA, total OCA, potentially other 
conjugates or metabolites not yet identified 
OCA, tauro-OCA, glyco-OCA, total OCA, OCA glucuronide, 
potentially other conjugates or metabolites not yet identified 
Title Page 
 
 
 
 
Version 2: 22 October 2015 
The CONTROL Study 
Combination OCA aNd STatin for MonitoRing Of Lipids 
 
Version 3: 14 June 2016 
Study Personnel 
Contact 
Information 
 
Primary 
Medical 
Monitor 
Contact: 
Roya Hooshmand-Rad, MD, PhD  
Executive Director, Clinical Research 
Intercept Pharmaceuticals, Inc. (Intercept) 
Email: 
rhooshmand-rad@interceptpharma.com 
 
 
 
 
 
 
 
 
The following individual medical monitors may also be 
contacted through the NASH medical monitor hotline and 
email address. 
Primary Medical 
Monitor 
Contact: 
 
Mobile Phone: 
Email 
Emad Basta, MD 
(Lead) Medical Monitor/Medical 
Expert 
PRA Health Sciences 
+1 630 235 6201 
CONTROL@PRAHS.com 
NASH Medical 
Monitor 
Hotline: 
+1 844 250 6396  
 
NASH209@interceptpharma.com 
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Secondary 
Contact: 
 
 
 
 
 
 
Barbara Scholz, MD 
Medical Director, Drug Safety 
Intercept  
Telephone: 
Email: 
+1 858 353 1350 (Pacific time zone) 
barbara.scholz@interceptpharma.com 
 
Email 
 
 
Secondary 
Contact: 
Roya Hooshmand-Rad, MD, PhD 
Executive Director, Medical Safety and 
Pharmacovigilance 
Intercept Pharmaceuticals, Inc. (Intercept) 
Mobile 
Phone: 
Email: 
 
Secondary 
Contact:  
 
Mobile 
Phone: 
Email: 
+1 858 880 6485 (Pacific time zone) 
rhooshmand-rad@interceptpharma.com 
 
Barbara Scholz, MD 
Medical Director, Drug Safety 
Intercept 
+1 858 353 1350 (Pacific time zone) 
barbara.scholz@interceptpharma.com 
Synopsis 
Objectives, 
6.3 Exploratory 
Objectives 
To evaluate improvement in noninvasive-radiological assessment 
of fibrosis via transient elastography (TE; at sites where available, 
and evaluated at the end of LTSE) 
To evaluate improvement in noninvasive-radiological 
assessment of fibrosis via transient elastography (TE; at sites 
where available) 
Synopsis 
Methodology,  
7.1 Overall Study 
Design 
Statin-treated subjects will be required to stop statin treatment 
(after signing informed consent) for a total of 5 weeks prior to 
randomization.   
Screening Period: 
Subjects using statins within 30 days of the initial Screening visit 
(Screening Visit 1) are required to stop statin therapy immediately 
following this initial visit and must undergo a 4-week statin 
washout period.  One week prior to randomization (Screening 
Visit 2; Week -1), these subjects will have a pre-randomization 
visit for assessment of their fasting LDL cholesterol levels.  
Statin-treated subjects will be required to stop statin treatment 
(after signing informed consent) for up to 5 weeks, including a 
4-week statin washout period, prior to Randomization/Day1.   
Screening Period: 
Subjects using statins within 30 days of the initial Screening 
visit (Screening Visit 1) are required to stop statin therapy 
immediately following this initial visit and must undergo a 4-
week statin washout period prior to Screening Visit 2.  At 
Screening Visit 2, these subjects will have a pre-randomization 
visit for assessment of their fasting LDL cholesterol levels.  
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26) of subjects will have fibrosis stage 2, stage 3, or 
stage 4 
Synopsis, Key 
Inclusion Criteria 
8.2 Subject 
Inclusion Criteria 
 
6. Contraception:  Female subjects of childbearing 
potential must use ≥1 effective method of 
contraception during the study and until 30 days 
following the last dose of investigational 
product.  Effective methods of contraception 
are considered to be those listed below. 
• 
Double-barrier method, ie, (a) condom (male or 
female) or (b) diaphragm, with spermicide 
• 
Intrauterine device 
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection) 
• 
Abstinence (defined as refraining from heterosexual 
intercourse) 
6. Contraception:  Female subjects of 
childbearing potential must use ≥1 effective 
method of contraception during the study and 
until 30 days following the last dose of 
investigational product.  Effective methods of 
contraception are considered to be those listed 
below. 
• 
Barrier method, ie, condom (male or female) with 
spermicide or diaphragm with spermicide 
• 
Intrauterine device 
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection) 
• 
Abstinence (defined as refraining from 
heterosexual intercourse) 
Synopsis, Key 
Exclusion 
Criteria 
8.3 Subject 
Exclusion 
Criteria 
8. Uncontrolled diabetes defined as HbA1c≥9.0% 
within 60 days prior to randomization (Day 1). 
9. Administration of any of the following 
medications as specified below: 
• 
Prohibited 30 days prior to Day 1:   
- 
bile acid sequestrants including cholestyramine  
• 
Prohibited 3 months prior to Day 1:   
- 
nicotinic acid and derivatives, ezetimibe, or  
- 
any prescription or over-the-counter medication 
or herbal remedy with putative NASH efficacy 
(except Vitamin E or TZDs), 
- 
fenofibrate or other fibrates, or 
8. Uncontrolled diabetes defined as 
HbA1c≥9.5% within 60 days prior to 
randomization (Day 1) 
9. Administration of any of the following 
medications as specified below: 
• 
Prohibited 30 days prior to Day 1: 
− 
bile acid sequestrants including 
cholestyramine, and its derivatives 
• 
Prohibited 3 months prior to Day 1:   
− 
nicotinic acid and derivatives, ezetimibe, or  
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- 
Any over-the-counter or health foods used to 
treat lipids including plant sterols and berberine 
 
 
 
 
10. Evidence of other forms of chronic liver disease 
including but not limited to:  
• 
Positive test result at Screening for hepatitis B surface 
antigen or hepatitis C antibody (and positive hepatitis 
C virus [HCV] ribonucleic acid [RNA])  
• 
Primary biliary cirrhosis, primary sclerosing 
cholangitis, autoimmune hepatitis or overlap 
syndrome 
• 
Alcoholic liver disease 
• 
Wilson’s disease or hemochromatosis or iron 
overload as defined by presence of 3+ or 4+ stainable 
iron on liver biopsy 
• 
Alpha-1-antitrypsin (A1AT) deficiency as defined by 
diagnostic features in liver histology (confirmed by 
A1AT level less than normal; exclusion at the 
Investigator’s discretion) 
• 
Prior known drug-induced liver injury within 5 years 
before Day 1 
• 
Known or suspected hepatocellular carcinoma  
 
 
17. Platelet count <100,000/mm3 at any Screening Visit 
24. Receipt of any investigational product not being 
evaluated for the treatment of diabetes or NASH within 
30 days prior to Day 1 or within 5 half-lives of the 
compound (whichever was longer) before Day 1 
− 
any prescription or over-the-counter 
medication or herbal remedy with putative 
NASH efficacy (except Vitamin E or TZDs), 
or 
− 
ursodeoxycholic acid, or 
− 
fenofibrate or other fibrates, or 
− 
Any over-the-counter or health foods used to 
treat lipids including plant sterols and 
berberine 
10. Evidence of other forms of known chronic 
liver disease including but not limited to:  
• 
Positive test result at Screening for hepatitis B 
surface antigen 
• 
Active hepatitis C virus (HCV) infection (positive 
for HCV ribonucleic acid [RNA] at Screening) or 
history of positive HCV RNA test result  
• 
Primary biliary cirrhosis (also known as primary 
biliary cholangitis), primary sclerosing 
cholangitis, autoimmune hepatitis or overlap 
syndrome 
• 
Alcoholic liver disease 
• 
Wilson’s disease or hemochromatosis or iron 
overload as defined by presence of 3+ or 
4+ stainable iron on liver biopsy 
• 
Alpha-1-antitrypsin (A1AT) deficiency as defined 
by diagnostic features in liver histology (confirmed 
by A1AT level less than normal; exclusion at the 
Investigator’s discretion) 
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• 
Prior known drug-induced liver injury within 
5 years before Day 1 
• 
Known or suspected hepatocellular carcinoma  
17. Platelet count <75 000/mm3 at any Screening Visit 
24. Receipt of any investigational product not being 
evaluated for the treatment of diabetes or NASH 
from Screening Visit 1 to Day 1, within 30 days 
prior to Day 1, or within 5 half-lives of the 
compound before Day 1 (whichever was longer) 
29.→Acute cholecystitis or acute biliary obstruction 
 
Synopsis, 
Duration of 
Subject 
Participation 
Screening period for statin-using subjects:  4-week statin 
washout period + Screening (5 weeks (statin-using subjects 
only)  
Screening period for statin-using subjects:  Up to 5 weeks 
(including a 4-week statin washout period)  
Synopsis, Criteria 
for Evaluation 
11.1 Efficacy 
Assessments, 
Table 4 
Exploratory Endpoints 
OCA 
pharmacokinetics  
OCA, tauro-OCA, glyco-OCA, total 
OCA, potentially other conjugates or 
metabolites not yet identified  
Noninvasive 
radiological liver 
fibrosis 
measurements 
By TE (where available, and evaluated 
at the end of LTSE) 
 
Exploratory Endpoints 
OCA 
pharmacokinetics  
OCA, tauro-OCA, glyco-OCA, total 
OCA, OCA glucuronide, potentially 
other conjugates or metabolites not yet 
identified  
Noninvasive 
radiological liver 
fibrosis 
measurements 
By TE (where available) 
List of 
Abbreviations 
and Definitions 
of Terms 
PBC 
primary biliary cirrhosis  
 
PBC 
primary biliary cholangitis (also known as 
primary biliary cirrhosis) 
CAC 
Cardiovascular Adjudication 
Committee 
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5.5 Clinical 
Experience with 
Obeticholic Acid 
OCA is under investigation for the treatment of multiple chronic 
liver diseases, including the treatment of NASH, primary biliary 
cirrhosis (PBC), primary sclerosing cholangitis (PSC), and biliary 
atresia.  The clinical development program for OCA includes the 
following 3 studies conducted using subjects with NAFLD or 
NASH: “ 
“ 
• 
Study D8602001:  An ongoing Phase 2 study being 
conducted by Intercept’s development partner (Sumitomo 
Dainippon Pharma Co., Ltd) to evaluate the efficacy and 
safety of 3 doses of OCA versus placebo in NASH. 
Study D8602001 is ongoing and remains blinded. 
OCA is under investigation for the treatment of multiple chronic 
liver diseases, including the treatment of NASH, primary biliary 
cholangitis (PBC, also called primary biliary cholangitis (PBC, 
also known as primary biliary cirrhosis [Beuers 2015a, 
Beuers 2015b, Beuers 2015c]), primary sclerosing cholangitis 
(PSC), and biliary atresia.  The clinical development program for 
OCA includes the following 3 studies conducted using subjects 
with NAFLD or NASH: 
• 
Study D8602001:  A Phase 2 study conducted by 
Intercept’s Asian development partner (Sumitomo 
Dainippon Pharma Co., Ltd) to evaluate the efficacy and 
safety of 3 doses of OCA versus placebo in NASH 
Study D8602001 demonstrated a dose-dependent increase in 
the percentage of OCA-treated subjects compared to placebo 
subjects who achieved the primary endpoint (p = 0.053, not 
significant).   The 40 mg OCA dose group achieved statistical 
significance for the primary endpoint compared to placebo 
(p = 0.0496).  Dose-dependent trends not reaching statistical 
significance were also observed for several other pre-
specified histologic endpoints, including the proportion of 
subjects with steatosis and inflammation improvement, 
ballooning resolution, and NASH resolution.  In the 
completer analysis, similar dose-dependent effects were 
observed, with 51% of patients in the 40 mg dose group 
compared to 22% in the placebo group meeting the primary 
endpoint (p = 0.0061).  With the exception of dose-dependent 
pruritus, OCA appeared to be generally safe and well 
tolerated.  The number of pruritus-associated 
discontinuations were 0, 0, 2, and 5 subjects in the placebo, 
10 mg, 20 mg, and 40 mg OCA groups, respectively.  
Changes in lipid parameters were directionally similar to 
those observed in the FLINT study.  No other meaningful 
differences in the rate of AEs between the OCA and placebo 
groups were noted.  
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5.6.6 Rationale 
for Timing of 
Unblinding 
Process and 
Implications in 
LTSE 
 
For those subjects continuing into the LTSE:  Following 
completion of all study procedures associated with the double-
blind period, subjects will be unblinded via the interactive web 
response system (IWRS) to determine the open-label OCA dose to 
be initiated in the LTSE.  This will allow double-blind, placebo-
treated subjects to initiate OCA at an appropriate dose, and OCA-
treated subjects to maintain or increase their dose based on 
therapeutic response and tolerability rather than forcing fixed 
dosing to maintain the blind.  
As Study 747-209 is a randomized, double-blind study, the 
double-blind data will not be unblinded until all double-
blind data are final and the database is locked.  Accordingly, 
all subjects continuing in the LTSE, investigators, and the 
Sponsor will remain blinded to subjects’ DB treatment 
regimen.  Subjects who were receiving placebo or 5 mg OCA 
in the DB phase will be randomized to receive either OCA 
10 mg or OCA 25 mg in the LTSE.  Subjects who were 
receiving OCA 10 mg or OCA 25 mg in the DB phase will 
continue on the same dose throughout the LTSE.  Using this 
approach, blinding of the trial will be maintained. 
5.8 Summary of 
Known Potential 
Risks with 
Atorvastatin 
 
If treatment with statins is initiated, women of childbearing 
potential must be informed that statin use is contraindicated 
during pregnancy.  Methods of contraception should be 
reviewed and modified, if necessary, to ensure highly 
effective methods with failure rates <1% per year, such as 
implants, injectables, combined oral contraceptives, some 
intrauterine devices, sexual abstinence, or history of 
vasectomy of partner are used. 
7.1.2 Schedule of 
Study 
Procedures, 
Double-Blind 
Period 
 
 
 
 
 
 
a  Subjects using statins within 4 weeks of Screening are required to 
stop administering statin therapy after Screening Visit 1, and 
must undergo a 5-week washout period prior to randomization. 
b  Screening Visit 2 is required for all subjects.  All subjects must 
have been fasting for at least 8 hours prior to the visit.  For 
subjects undergoing a 4-week washout period, this visit will 
occur at Week -1.  For subjects not taking statins at 
Screening Visit 1, this visit can occur at any time after Screening 
Visit 1 and up to 1 week prior to randomization.  For subjects 
Added Weeks row to clarify timing of Screening Visits 
Modified Visit windows for Screening Visit 1:  Day -35 to Day 
-7 
Modified Visit window for Screening Visit 2:  Day -7 to Day -1 
a  Subjects using statins within 4 weeks of Screening are required 
to stop administering statin therapy after Screening Visit 1, and 
must complete a 4-week statin washout prior to performing 
assessments at Screening Visit 2. 
b  Screening Visit 2 is required for all subjects.  All subjects must 
have been fasting for at least 8 hours prior to the visit.  The 
Randomization/Day 1 Visit may occur as soon as screening 
labs are available and eligibility is confirmed for all 
subjects.  For subjects undergoing a 4-week washout period, 
Screening Visit 2 may occur on day 28 (±1) day of the 
washout period.  For subjects not taking statins at 
Screening Visit 1, Screening Visit 2 can occur at any time 
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using statins within 4 weeks prior to Screening Visit 1, Screening 
Visit 2 can occur at any time after 4 weeks have lapsed since the 
subject’s last statin dose.  
d  Sitting heart rate, blood pressure, temperature, and respiratory 
rate 
i  and none of the exclusion criteria, may be randomized.” 
  
k  Blood samples for all analyses will be collected predose (before 
administering investigational product) on indicated visit days. 
 
within 28 days after Screening Visit 1.  All Screening 
assessments must be completed ≤35 days prior to the 
Randomization/Day 1 Visit. 
d Sitting heart rate, blood pressure, body temperature, and 
respiratory rate 
i and none of the exclusion criteria, may be randomized.  
Subjects randomized to placebo or OCA 5 mg during the 
double-blind period will be randomized to OCA 10 or 25 mg 
during the LTSE 
k  Blood samples for all analyses will be collected predose (before 
administering investigational product or atorvastatin) on 
indicated visit days. 
 
7.1.2 Schedule of 
Study 
Procedures, 
LTSE 
Month 1 Contact 
 
 
 
 
 
 
a The first visit after start of LTSE (Month 1 Visit) is relative to 
Week 16 Visit of the double-blind phase (LTSE Day 1 Visit).  
This is not a study site visit.  The subject should be contacted 
approximately 1 month after the start of the LTSE, and 
compliance with OCA treatment instructions, concomitant 
medications, and AEs should be assessed. 
d  Sitting heart rate, blood pressure, temperature, and respiratory 
rate 
 
Month 1 
Added: 
• 
Fast ≥8 h Prior to Visit 
• 
Vital Signs 
• 
Collect Bottles/Atorvastatin 
Accountability/Compliance 
• 
Serum Chemistry/Hematology/Coagulation 
Parameters 
• 
Markers of glucose metabolism, including C-peptide, 
insulin, fasting plasma glucose, HbA1c 
• 
Urine Based β-hCG Pregnancy Test 
 
a  The first visit after start of LTSE (Month 1 Visit) is relative to 
Week 16 Visit of the double-blind phase (LTSE Day 1 Visit).   
d  Sitting heart rate, blood pressure, body temperature, and 
respiratory rate 
 
7.3 Treatment 
Assignment 
Eligible subjects will be randomized into 4 groups in a 1:1:1:1 
ratio to receive OCA 5 mg, OCA 10 mg, OCA 25 mg, or placebo 
during the double-blind phase of the study.  Randomization will 
Eligible subjects will be randomized into 4 groups in a 1:1:1:1 
ratio to receive OCA 5 mg, OCA 10 mg, OCA 25 mg, or 
placebo during the double-blind phase of the study.  
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be stratified by LDL concentration (fasting serum LDL cholesterol 
at Screening Visit 2; ≤125 mg/dL or >125 mg/dL) and baseline 
fibrosis stage (stage 1, 2 or stage 3, 4).  All subjects will also 
receive atorvastatin starting at Week 4 at 10 mg daily, escalating 
to 20 mg at Week 8 (if 10 mg daily is tolerated), with further dose 
adjustments to be performed as clinically indicated at Week 12, 
and throughout the LTSE phase.  Subjects randomized to placebo 
or OCA 5 mg will receive OCA 10 mg during the LTSE; subjects 
randomized to OCA 10 mg or OCA 25 mg will receive OCA 
25 mg during the LTSE.  The study design schematic is shown in 
Figure 1.  
Randomization will be stratified by LDL concentration (fasting 
serum LDL cholesterol at Screening Visit 2; ≤125 mg/dL or 
>125 mg/dL) and baseline fibrosis stage (stage 1, 2 or stage 3, 
4).  All subjects will also receive atorvastatin starting at Week 4 
at 10 mg daily, escalating to 20 mg at Week 8 (if 10 mg daily is 
tolerated), with further dose adjustments to be performed as 
clinically indicated at Week 12, and throughout the LTSE phase.  
Subjects will receive open-label OCA 10 mg or OCA 25 mg 
during the LTSE depending on their double-blind randomized 
dose (see Section 7.1).  The study design schematic is shown in 
Figre 1.  
7.4.1 
Investigational 
Product Dose 
Adjustments 
During the LTSE phase, all subjects will be treated with OCA.  
Subjects randomized to placebo or OCA 5 mg during the double-
blind phase will receive OCA 10 mg upon entry into and 
throughout the LTSE phase.  Subjects randomized to OCA 10 mg 
with no tolerability concerns will titrate to OCA 25 mg.  Subjects 
randomized to OCA 25 mg will continue to receive this dose 
throughout the LTSE.  Subjects may continue with atorvastatin 
therapy as clinically indicated.  
During the LTSE phase, all subjects will be treated with OCA.  
Subjects randomized to placebo or OCA 5 mg during the 
double-blind phase will be re-randomized in a 1:1 ratio 
through IWRS to OCA 10 mg or OCA 25 mg upon entry into 
and throughout the LTSE phase.  Subjects randomized to OCA 
10 mg will continue to receive OCA 10 mg throughout the 
LTSE.  Subjects randomized to OCA 25 mg will continue to 
receive OCA 25 mg throughout the LTSE.  Subjects may 
continue with atorvastatin therapy as clinically indicated.  
8.4.1.3 Severe 
Drug-Induced 
Liver Injury 
Subjects who develop significant drug-induced liver injury, which 
is considered to be causally related to the investigational product, 
should be discontinued from investigational product and should 
not be rechallenged.  Significant injury as described in 
Appendix B, or evidence of functional hepatic impairment as 
indicated by rising bilirubin or INR.  Natural progression of the 
underlying condition and other causal factors such as a common 
bile duct stone or development of other concurrent liver disease 
should be considered before the investigational product is 
permanently discontinued.   
Severe drug induced-liver injury that is not considered related to 
investigational product must be discussed with the Sponsor before 
resuming treatment.  Subjects who discontinue due to significant 
drug-induced liver injury must be followed until the AE has 
resolved, stabilized, or is not of clinical concern. 
If a subject develops signs and symptoms of a severe drug-
induced liver injury, regardless of causality, investigational 
product and atorvastatin should be interrupted until the 
event has resolved or returned to baseline, but the subject 
should continue with the study visit schedule.  Subjects who 
develop significant drug-induced liver injury, which is 
considered to be causally related to the investigational product 
or atorvastatin, should be discontinued from investigational 
product or atorvastatin, as appropriate and should not be 
rechallenged.  Significant injury as described in Appendix B, 
and includes evidence of functional hepatic impairment as 
indicated by rising bilirubin or INR.  Natural progression of the 
underlying condition and other causal factors such as a common 
bile duct stone or development of other concurrent liver disease 
should be considered before the investigational product is 
permanently discontinued.   
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Severe drug induced-liver injury that is not considered related to 
investigational product or atorvastatin must be discussed with 
the Sponsor before investigational product or atorvastatin is 
reinitiated.  Follow-up procedures for subjects resuming 
treatment, including laboratory evaluations and physical 
examinations, must be performed after a maximum of 2 
weeks of re-treatment and may be conducted at a local clinic 
if the subject is unable to return to the site.  Results must be 
reported immediately to the site so the Investigator can 
determine if the subject is to be allowed to continue 
treatment.  Subjects who discontinue due to significant drug-
induced liver injury must be followed until the AE has resolved, 
stabilized, or is not of clinical concern. 
9.1 
Investigational 
Product and 
Atorvastatin 
Treatment 
Regimen 
The investigational products are either OCA or placebo.  
 
While placebo, OCA, and atorvastatin are all study 
medications provided by the Sponsor, for the purposes of 
this protocol, investigational product refers to OCA or placebo, 
and study medication, where used, refers to atorvastatin. 
9.1.2 LTSE 
Following completion of Week 16 Visit procedures, subjects who 
are participating in the LTSE will be unblinded via the IWRS.  
Subjects who were receiving OCA during the double-blind phase 
will continue to receive either OCA 10 mg or OCA 25 mg once 
daily during the LTSE.  Subjects randomized to placebo or 5 mg 
OCA during the double-blind phase will initiate dosing at OCA 
10 mg in the LTSE.  Subjects randomized to OCA 10 mg during 
the double-blind phase will titrate to OCA 25 mg on Day 1 of the 
LTSE.  Subjects randomized to OCA 25 mg during the double-
blind phase will continue to receive OCA 25 mg. 
Following completion of Week 16 Visit procedures, all subjects 
will be treated with open-label OCA 10 mg or OCA 25 mg.  
Subjects randomized to placebo or OCA 5 mg during the 
double-blind phase will be randomized in a 1:1 ratio to 
receive OCA 10 mg or OCA 25 mg upon entry into and 
throughout the LTSE phase.  Subjects randomized to OCA 
10 mg or OCA 25 mg during the double-blind phase will 
continue on the same dose throughout the LTSE.    
9.2.5 Standard of 
Care and Other 
Concomitant 
Medications 
Subjects taking BAS or aluminum hydroxide- or smectite-
containing antacids should be instructed to stagger their dosing of 
investigational product, ensuring at least 4 hours between doses of 
the BAS and/or antacids and the investigational product (ie, BAS 
should be administered 4 hours before or 4 hours after 
investigational product administration). 
Subjects taking BAS (including cholestyramine and its 
derivatives, colestipol, colesevelam, or other sequestrants) or 
aluminum hydroxide- or smectite-containing antacids should be 
instructed to stagger their dosing of investigational product, 
ensuring at least 4 hours between doses of the BAS and/or 
antacids and the investigational product (ie, BAS should be 
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administered 4 hours before or 4 hours after investigational 
product administration). 
Taken concomitantly, OCA and warfarin may decrease INR, 
thus INR should be monitored and the dosage of warfarin 
adjusted, as needed, to maintain the target INR range. 
The effect of OCA on drug metabolizing enzymes has been 
evaluated in both in vitro and clinical studies.  The PK 
profile of caffeine, a sensitive CYP1A2 substrate, showed 
weak effect of OCA on CYP1A2.  Based on these results, 
OCA may increase the exposure of narrow therapeutic index 
drugs that are substrates for CYP1A2, such as theophylline 
and tizanidine. 
9.4 
Randomization 
and Blinding 
The Investigator or designee will be required to register the 
subject in the IWRS and may be prompted to provide patient data 
necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned and 
investigational product (OCA or placebo) dispensing information 
will be provided (eg, bottle numbers allocated) while maintaining 
the study blind.  The subjects, Investigator, and study site staff 
will be blinded to the subject’s treatment allocation during the 
subject’s participation in the double-blind phase of the study. 
 
The Investigator or designee will be required to register the 
subject in the IWRS and may be prompted to provide patient 
data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned and 
investigational product (OCA or placebo) dispensing 
information will be provided (eg, bottle numbers allocated) 
while maintaining the study blind.  The subjects, Investigator, 
and study site staff will be blinded to the subject’s treatment 
allocation in the double-blind phase of the study until all 
subjects have completed the double-blind phase of the study 
and the database locked. 
In the LTSE phase, all subjects will be treated with open-
label OCA 10 mg or OCA 25 mg: subjects randomized to 
placebo or OCA 5 mg during the double-blind phase will be 
randomized in a 1:1 ratio to receive OCA 10 mg or OCA 25 
mg upon entry into and throughout the LTSE phase and 
subjects randomized to OCA 10 mg or OCA 25 mg during 
the double-blind phase will continue on the same dose 
throughout the LTSE.   
9.4.2 Emergency 
Unblinding 
Procedures 
Randomization codes and corresponding treatment assignments 
will be made available to the Investigator for emergency use only 
through the IWRS system.  When possible, the Medical Monitor 
Randomization codes and corresponding treatment assignments 
will be made available to the Investigator and the Medical 
Monitor for emergency use only through the IWRS system.  
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should be consulted in the event that a medical emergency 
necessitates unblinding (ie, in situations where knowledge of the 
blinded treatment is necessary for further medical management of 
the subject).  If it is not reasonable to inform the Medical Monitor 
in advance of unblinding, the Investigator must promptly 
document the case in the subject’s source record.  Subsequently, 
the Investigator should contact the Medical Monitor to explain any 
premature unblinding of treatment assignment (eg, accidental 
unblinding or unblinding due to a serious AE [SAE]).  Procedures 
for unblinding a subject’s treatment will be provided separately to 
the Investigator.  Similarly, if the Medical Monitor breaks the 
blind for the purpose of evaluating an emergent safety issue or for 
regulatory reporting purposes, the Medical Monitor will document 
within study correspondence the rationale, circumstances, and the 
person(s) being informed about the unblinding.   
When possible, the Medical Monitor should be consulted in the 
event that a medical emergency necessitates unblinding (ie, in 
situations where knowledge of the blinded treatment is necessary 
for further medical management of the subject).  If it is not 
reasonable to inform the Medical Monitor in advance of 
unblinding, the Investigator must promptly document the case in 
the subject’s source record.  Subsequently, the Investigator 
should contact the Medical Monitor to explain any premature 
unblinding of treatment assignment (eg, accidental unblinding or 
unblinding due to a serious AE [SAE]).  Procedures for 
unblinding a subject’s treatment will be provided separately to 
the Investigator.  The Medical Monitor will document within 
study correspondence the rationale, circumstances, and the 
person(s) being informed about the unblinding.   
9.7.1 Visit 
Windows 
Screening Visit 1 should occur ≤35 days prior to the Day 1 Visit.  
Subjects who are taking statins at the time of screening or within 
4 weeks of Screening Visit 1 are required to stop statin therapy for 
4 weeks, and provide a fasting blood sample at Screening Visit 2 
(Week -1 Visit) to confirm eligibility.  Subjects who have not 
taken statins within 4 weeks of Screening Visit 1 are not required 
to enter into the washout period and may proceed to Screening 
Visit 2 (Week -1) to provide a fasting blood sample. The Week -1 
Visit should occur within ±1 days of the Randomization/Day1 
Visit. 
 
Visit or Procedure 
Visit Window and/or Interval 
Screening Visit 1 
Visit(s) are to occur ≤5 weeks 
(35 days) before Day 1.  
LTSE Visits: Month 3, 
Month 6, Month 9, 
Month 12, Month 15, 
Month 18, and 
Month 21 
±1 week (7 days); the LTSE visits are 
relative to LTSE Day 1 (ie, Week 16 
of double-blind phase) 
All Screening assessments should occur ≤35 days prior to the 
Randomization/Day 1 Visit.  Subjects who are taking statins at 
the time of screening or within 30 days of Screening Visit 1 are 
required to stop statin therapy for 4 weeks (28 (±1) days), and 
provide a fasting blood sample at Screening Visit 2 to confirm 
eligibility.  Subjects who have not taken statins within 30 days 
of Screening Visit 1 are not required to enter into the washout 
period and may proceed to Screening Visit 2 to provide a fasting 
blood sample. The Randomization/Day 1 Visit may occur as 
soon as all screening labs are available and eligibility is 
confirmed. 
 
Visit or Procedure 
Visit Window and/or Interval 
Screening Visit 1 
Visit(s) are to occur ≤5 weeks 
(35 days) prior to Day 1.  
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LTSE Visits:  Month 
1, Month 3, Month 6, 
Month 9, Month 12, 
Month 15, Month 18, 
and Month 21 
±1 week (7 days); the LTSE visits 
are relative to LTSE Day 1 (ie, 
Week 16 of double-blind phase) 
9.7.3 Screening 
Visit 1 
Procedures (≤35 
Days Before Day 
1) 
The Screening Visit assessments must be performed within 
≤5 weeks prior to Day 1 to determine whether the subject meets 
all the inclusion criteria and none of the exclusion criteria.  
Subjects who do not fulfill all eligibility criteria will not be 
enrolled in the study.   
Subjects who are statin-free (ie, no statin use within 4 weeks of 
Screening) must return for fasted serum chemistry labs at 
Screening Visit 2, and may proceed to the Randomization/Day 1 
Visit once screening labs are available and eligibility is confirmed; 
subjects who need to wash out statin therapy are required to “have 
a Week -1 Visit 4 weeks after Screening Visit 1.” 
Additional Screening Visit 1 procedure for subjects currently 
taking statins: 
• 
Subjects who are currently taking statins, defined as 
statin use within 4 weeks of Screening, will be instructed 
to discontinue statin therapy following Screening Visit 1.  
These subjects must complete a 5-week statin washout 
prior to being randomized.  After 4 weeks of statin 
washout, subjects will return for Screening Visit 2/Week 
-1 Visit to provide blood samples for fasted serum 
chemistry. 
The Screening Visit assessments must be performed ≤5 weeks 
prior to Day 1 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Subjects 
who do not fulfill all eligibility criteria will not be enrolled in the 
study.   
Subjects who are statin-free (ie, no statin use within 30 days of 
Screening) must return for fasted serum chemistry labs at 
Screening Visit 2, and may proceed to the Randomization/Day 1 
Visit once screening labs are available and eligibility is 
confirmed; subjects who need to wash out statin therapy are 
required to return for Screening Visit 2 following the washout 
period.   
Additional Screening Visit 1 procedure for subjects currently 
taking statins: 
• Subjects who are currently taking statins, defined as statin 
use within 30 days of Screening, will be instructed to 
discontinue statin therapy following Screening Visit 1.  
After 4 weeks of statin washout, subjects will return for 
Screening Visit 2 to provide blood samples for fasted 
serum chemistry. 
9.7.4 Screening 
Visit 2/Week -1 
Visit Procedures 
Subjects who were receiving statin therapy at the time of 
screening. 
• 
Verify that subjects have completed a 4-week washout 
period. 
All Subjects: 
All subjects will return for Screening Visit 2 to confirm 
eligibility criteria and provide blood samples for fasted 
serum chemistry. 
For subjects who were receiving statin therapy at the time of 
screening. 
• 
Verify that subjects have completed a 4-week washout 
period. 
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For all subjects:… 
9.7.14 Additional 
Procedures at 
Week 16/LTSE 
Day 1 
Subject who will continue into the LTSE phase after completing 
the procedures listed for the Week 16 Visit… 
• 
Dispense investigational product as instructed 
Subjects who continue into the LTSE phase after completing the 
procedures listed for the Week 16 Visit… 
• 
Record the visit in IWRS, randomize the subject to one 
of the open-label treatment groups, and dispense open-
label investigational product according to IWRS 
instructions. 
9.7.16 LTSE 
Visits 
LTSE Visits will occur every 3 months (eg, at Months 3, 6, 9, and 
12) following completion of the Week 16/LTSE Day 1 Visit.  The 
visit procedures described below will repeat annually for the 
duration of the LTSE.  For example, once a subject completes a 
year (Month 12 Visit) in the LTSE, their next visit should be 3 
months later and the procedures described for the Month 3 LTSE 
Visit should be followed. 
LTSE Visits should occur within ±1 week of the visit day and 
the timing of all visits should be relative to the double-blind 
Week 16 Visit (ie, the start of the LTSE; LTSE Day 1).  For 
example, if the Month 6 Visit occurred 1 week late, the 
Month 9 Visit should still be approximately 9 months after 
the Week 16 Visit.  
9.7.16 LTSE 
Visits 
LTSE Visits should occur within ±1 week of the visit day and the 
timing of all visits should be relative to the double-blind Week 16 
Visit (ie, the start of the LTSE; LTSE Day 1).  For example, if the 
Month 6 Visit occurred 1 week late, the Month 9 Visit should still 
be approximately 9 months after the Week 16 Visit. 
The first LTSE visit following LTSE Day 1 will occur at 
LTSE Month 1.  The next visit will occur at LTSE Month 3 
and every 3 months thereafter (eg, at Months 6, 9, and 12) for 
the duration of the LTSE.  The quarterly visit procedures 
described below will repeat annually for the duration of the 
LTSE.  For example, once a subject completes a year (Month 12 
Visit) in the LTSE, their next visit should be 3 months later and 
the procedures described for the Month 3 LTSE Visit should be 
followed. 
9.7.17 LTSE 
Month 1 
Contact/Visit 
Procedures 
Approximately 1 month into the LTSE, the subject should be 
contacted to assess compliance with OCA treatment, review and 
record concomitant medications, and assess and record AEs.  This 
is not a clinic visit.  This contact is not repeated in subsequent 
years of participation.  
• 
Verify that the subject has fasted for at least 8 
hours. 
− 
Record fasting status in the source and eCRF. 
− 
If the subject reports having eaten within 8 
hours, document accordingly in the source and 
eCRF and remind the subject that fasting is 
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required prior to all study visits, but water is 
permitted. 
• 
Assess and record vital signs (body temperature, 
sitting heart rate, respiratory rate, and sitting blood 
pressure). 
• 
Assess and record AEs. 
• 
Review and record concomitant medications. 
• 
Collect used bottles of investigational product, assess 
investigational product compliance, and perform 
investigational product accountability.  Following 
product accountability, redispense the same bottle of 
investigational product for use until the next visit. 
• 
Collect used bottles of atorvastatin, assess 
atorvastatin compliance, and perform atorvastatin 
accountability.  Following atorvastatin 
accountability, if the subjects is continuing with the 
same dose of atorvastatin, redispense the same 
bottle for use until the next visit. 
• 
NOTE:  If atorvastatin dose is up-titrated or re-
initiated after dose interruption, a telephone safety 
contact must be conducted 2 weeks following the 
change in dose to assess for AEs, concomitant 
medications, and investigational product and 
atorvastatin compliance. 
• 
Obtain blood samples for:  
• 
Serum chemistry (will include basic lipid panel and 
liver biochemistry panel), hematology, and 
coagulation 
• 
Markers of glucose metabolism 
• 
CPK, if myopathy suspected 
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• 
Perform a urine based β-hCG pregnancy test in 
female subjects of childbearing potential.  Perform 
serum pregnancy test in females of childbearing 
potential if urine β-hCG pregnancy test is positive. 
• 
Reiterate dosing instructions for investigational 
product and advise the subject: 
− 
Take the investigational product at 
approximately the same time each day 
− 
NOT to take investigational product or 
atorvastatin (if applicable) or on the morning 
of the next visit 
− 
To bring the investigational product and 
atorvastatin (if applicable) bottle(s); s/he will 
dose at the clinic 
− 
To fast overnight (at least 8 hours) prior to the 
next visit.  Fasting is required prior to all study 
visits, but water is permitted. 
10  
Study Medication 
Materials and 
Management 
STUDY MEDICATION MATERIALS AND 
MANAGEMENT 
INVESTIGATIONAL PRODUCT AND STUDY 
MEDICATION 
10.1 
Investigational 
Product (OCA or 
Placebo) LTSE 
Phase: 
5-mg, 10-mg and 25-mg OCA tablets for the LTSE Phase will be 
supplied as white or yellow tablets.   
• 
White OCA tablets are round and debossed with 
“INT” on one side and “3547” on the other side. 
• 
5 mg yellow tablets:  Round and debossed with 
“INT” on one side and “5” on the other side. 
10-mg and 25-mg OCA tablets for the LTSE Phase will be 
supplied as white or yellow tablets.   
• 
White OCA tablets are round and debossed with “INT” 
on one side and “3547” on the other side. 
 
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• 
10 mg yellow tablets:  Triangular and debossed with 
“INT” on one side and “10” on the other side. 
• 
5 mg yellow tablets:  Oval and debossed with “INT” on 
one side and “25” on the other side. 
 
10.3 
Investigational 
Product Storage 
Investigational product should be stored at the clinical study sites 
in the containers in which they are received from the Sponsor’s 
supplier, at 15-25°C and protected from excess humidity. 
Investigational product should be stored in the containers in 
which they are received from the Sponsor’s supplier, at 15-25°C. 
11.1.2.1 Central 
Reading of Liver 
Histology 
All biopsy assessments, including determination of study 
eligibility based on NASH diagnosis and fibrosis staging during 
Screening, will be performed centrally by an independent 
pathologist.  Key features of NASH (ie, steatosis, lobular 
inflammation, and hepatocellular ballooning) will be graded in 
accordance with the NASH CRN criteria for scoring 
(Kleiner 2005).  Fibrosis staging for eligibility will also be 
performed in accordance with NASH CRN criteria for fibrosis 
staging.   
All biopsy assessments, including determination of study 
eligibility based on NASH diagnosis and fibrosis staging during 
Screening, will be performed centrally by an independent 
pathologist.  The central pathologist must confirm 
histological presence of NASH and a minimum NAS of 4 
with a score of at least 1 in each component of NAS.  Key 
features of NASH (ie, steatosis, lobular inflammation, and 
hepatocellular ballooning) will be graded in accordance with the 
NASH CRN criteria for scoring (Kleiner 2005) as summarized 
in Table 5.  Fibrosis staging for eligibility will also be 
performed in accordance with NASH CRN criteria for fibrosis 
staging.   
Table 5:  NASH CRN Scoring System for Determining 
Eligibility and Primary Histological 
Endpoint Assessment 
NAFLD Activity Score 
(NAS) 
Fibrosis Staging 
Parameter 
Scoring 
Criteria 
Paramete
r 
Staging 
Criteria 
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Steatosis 
0 = <5%  
1 = 5% - 
33% 
2 = >33% 
- 66%  
3 = >66%  
Stage 0 
No Fibrosis 
Lobular 
Inflammatio
n 
0 = No 
Foci 
1 = <2 
Foci per 
200 × 
field  
2 = 2-4 
Foci per 
200 × 
field   
3 = > 4 
Foci per 
200 × 
field  
Stage 1  
Stage 1a 
Stage 1b 
Stage 1c  
Perisinusoidal 
or Periportal 
Mild, zone 3, 
persinusoidal 
Moderate, 
zone 3, 
perisinusoida
l 
Portal / 
periportal   
Ballooning 
0 = None  
1 = Few 
balloon 
cells  
2 = Many 
cells / 
prominen
t 
balloonin
g  
Stage 2 
Perisinusoidal 
and portal / 
periportal 
Stage 3 
Bridging 
fibrosis 
Stage 4 
Cirrhosis  
In addition to the primary scoring system of NASH CRN, 
biopsy samples will also be scored based on modified Ishak 
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scoring (Ishak 1995) for all subjects.  Any extra biopsy tissue 
may undergo exploratory histological evaluations. 
11.2.2 
Pharmacokinetic 
Assessments 
The first sample should be collected within 30 minutes prior to 
administration of investigational product (predose) on Day 1 at the 
Week 16 Visit. 
The first sample should be collected within 30 minutes prior to 
administration of investigational product (predose) on Day 1 
and prior to administration of investigational product or 
atorvastatin at the Week 16 Visit. 
12.1.2 
Relationship to 
Investigational 
Product or Study 
Medication 
 
If the relationship between a SAE and the atorvastatin is 
determined to be “definite,” “probable,” or “possible,” the 
event will be considered to be related to atorvastatin for the 
purpose of assessing expedited safety reporting and 
reporting to the manufacturer. 
12.1.4.1 Severity 
of Pruritus (as 
and AE) 
 
Since pruritus is a subjective symptom and the occurrence 
and magnitude of which are not readily measured by 
objective tools, clinical judgment needs to be applied in the 
management of each subject.  Managing OCA-related 
pruritus may help improve tolerance in those subjects who 
experience problematic pruritus and may otherwise 
discontinue from the study prematurely.  General guidance 
for the management of subjects experiencing significant 
pruritus includes: 
• 
Drug holiday:  A drug holiday is defined as an 
Investigator ‘prescribed’ complete interruption of 
dosing for 1 or more consecutive days (ie, non-daily 
dosing does not constitute a drug holiday).  For 
subjects with severe pruritus, instruct the subject to 
stop taking investigational product until the 
pruritus subsides to an acceptable level, at which 
time it should be restarted.  Details of drug holidays 
and/or nondaily dosing regimens should be recorded 
in the CRF.     
• 
Prescribe BAS.  Subjects taking BAS (including 
colestyramine and its derivatives, colestipol, 
colesevelam, or other sequestrants) should be 
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instructed to stagger their dosing of investigational 
product, ensuring at least 4 hours between doses of 
the BAS and investigational product.   
• 
Other therapies may be tried as deemed clinically 
appropriate. 
• 
Less frequent dosing of investigational product (eg, 
on alternate days) may be tried, after which subjects 
may return to their original daily dose as soon as 
tolerated.   
12.1.8.1 
Pregnancy and 
Follow-Up 
Pregnancies are not considered AEs in and of themselves; 
however, if a female study participant becomes pregnant while she 
is enrolled in the clinical study, she must discontinue treatment 
with investigational product and atorvastatin immediately (see 
Section 8.4.1.1) and the Sponsor must be notified within 24 hours 
of the Investigator’s learning of the pregnancy by completing the 
Pregnancy Report eCRF in the EDC system.  Entering the 
pregnancy report into the EDC system will automatically notify 
the Sponsor of the pregnancy.  The subject and neonate must be 
followed for outcome information and/or as considered 
appropriate by the Investigator and the Sponsor. 
Women who discontinue the study due to pregnancy may not re-
enroll in the study at any point, but should continue with the study 
visit schedule and must be followed by the Investigator through 
pregnancy outcome.  Similarly, if a subject’s pregnancy is 
terminated early (planned or unplanned), the subject will also be 
removed from the study. 
Completing the Pregnancy Report in the EDC is not a substitute 
for reporting an AE/SAE when an AE/SAE has occurred.  In the 
situation when an AE/SAE has occurred, the AE/SAE reporting 
procedures described in Section 17.1 must also be followed. 
Pregnancies are not considered AEs in and of themselves; 
however, if a female study participant becomes pregnant while 
she is enrolled in the clinical study, she must discontinue 
treatment with investigational product and atorvastatin 
immediately (see Section 8.4.1.1) and the Sponsor must be 
notified within 24 hours of the Investigator’s awareness of the 
pregnancy by completing the Pregnancy eCRF in the EDC 
system and downloading and completing the Pregnancy 
Report Form.  The Pregnancy Report Form must be emailed 
to sae@interceptpharma.com or faxed to +1-800-497-8521.  
The subject and neonate must be followed for outcome 
information and/or as considered appropriate by the Investigator 
and the Sponsor. 
Women who discontinue the study due to pregnancy may not re-
enroll in the study at any point, but should continue with the 
study visit schedule and must be followed by the Investigator 
through pregnancy outcome.  Similarly, if a subject’s pregnancy 
is terminated early (planned or unplanned), the subject will also 
be removed from the study. 
Completing the Pregnancy Report Form is not a substitute for 
reporting an AE/SAE if an AE/SAE has occurred related to or 
concurrent with the pregnancy.  In the situation when an 
AE/SAE has occurred, the AE/SAE reporting procedures 
described in Section 1.7.1 must also be followed. 
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12.2.4 
Electrocardiogra
m 
Investigative sites must retain a copy of all 12-lead ECGs 
evaluated by the Investigator or designee.  These ECGs must be 
clearly labeled with the subject’s initials, Subject ID number, date, 
and time.  Full instructions will be provided for forwarding the 12-
lead ECGs for central reading. 
Investigative sites must retain a copy of all 12-lead ECGs 
evaluated by the Investigator or designee.  These ECGs must be 
clearly labeled with the Subject ID number, date, and time.  Full 
instructions will be provided for forwarding the 12-lead ECGs 
for central reading. 
12.2.6 Laboratory 
Assessments 
Except for Screening, subjects will be instructed to attend each 
study visit in a fasted state, and subjects should remain fasted until 
their blood samples have been collected.   
Except for Screening Visit 1, subjects will be instructed to attend 
each study visit in a fasted state, and subjects should remain 
fasted until their blood samples have been collected.   
13.6.3.7 
Pharmacokinetic 
Analysis 
 
The PK Population will be used for analysis of PK parameters, 
which include plasma OCA (parent) and its conjugates (glyco-
OCA and tauro-OCA), total OCA, and potentially other 
conjugates or metabolites not yet identified.  PK analysis will be 
done using non-compartmental methods.   
The PK Population will be used for analysis of PK parameters, 
which include plasma OCA (parent) and its conjugates (glyco-
OCA and tauro-OCA), total OCA, OCA glucuronide and 
potentially other conjugates or metabolites not yet identified.  
PK analysis will be done using non-compartmental methods.   
13.7.5 
Adjudicated 
Cardiovascular 
Events 
 
Adjudicated cardiovascular events include core MACE 
(cardiovascular death, nonfatal myocardial infarction, and 
nonfatal stroke) and expanded MACE (unstable angina 
requiring hospitalization, transient ischemic attack, 
peripheral or coronary revascularization procedures, 
hospitalization for congestive heart failure).  Other events 
potentially related to adverse cardiovascular outcomes are 
defined in Appendix D and will be included in the 
Cardiovascular Adjudication Committee Charter for 
adjudication.  Undetermined cause of death will be classified 
as a cardiovascular death by the Cardiovascular 
Adjudication Committee. 
Summaries of adjudicated cardiovascular events will include 
the incidence of TEAEs and the incidence of serious TEAEs.  
All summaries of incidence will include the associated exact 
binomial 95% CI. 
13.9 Adjudication 
Committees 
• Cardiovascular Events Committee (CEC):  Adjudicates all 
suspected MACE 
• Cardiovascular Adjudication Committee (CAC):  
Adjudicates all suspected MACE, including all deaths 
16.4 Subject 
Confidentiality 
All information obtained during the conduct of the study with 
respect to the subject will be regarded as confidential and 
All information obtained during the conduct of the study with 
respect to the subject will be regarded as confidential and 
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and Data 
Protection 
confidentiality of all subjects will be maintained.  Monitors (eg, 
CRA, Medical Monitor), auditors and inspectors will require 
access to a subject’s medical notes for the purpose of source 
document verification but the subject’s confidentiality will be 
maintained at all times.  An agreement for disclosure of any such 
information will be obtained in writing and is included in the 
statement of informed consent.  The study data shall not be 
disclosed to a third party (with the exception of auditors and/or 
regulatory authorities) without the written consent of the Sponsor.  
All data shall be secured against unauthorized access. 
The Investigator will maintain a list of subject names and 
identifying information (eg, subjects’ hospital numbers, unique 
subject numbers).  This list will not be collected by the Sponsor. 
The written information sheet will explain that study data will be 
stored in a computer database, maintaining confidentiality in 
accordance with national data protection legislation.  All data 
computer processed by the Sponsor or designee will be identified 
by unique subject number/randomization code/subject initials/site 
number, only.   
confidentiality of all subjects will be maintained.  Monitors (eg, 
CRA, Medical Monitor), auditors and inspectors will require 
access to a subject’s medical notes for the purpose of source 
document verification but the subject’s confidentiality will be 
maintained at all times.  An agreement for disclosure of any such 
information will be obtained in writing and is included in the 
statement of informed consent.  The study data shall not be 
disclosed to a third party (with the exception of auditors and/or 
regulatory authorities) without the written consent of the 
Sponsor.  All reports and communications relating to 
subjects in this study that are disclosed to an authorized 
third party will identify subjects only by protocol and 
assigned number and will be shared in a secure manner.  All 
data shall be secured against unauthorized access. 
The Investigator will maintain a list of subject names and 
identifying information (eg, subjects’ hospital numbers, unique 
subject numbers).  This list will not be collected by the Sponsor. 
The written information sheet will explain that study data will be 
stored in a computer database, maintaining confidentiality in 
accordance with national data protection legislation.  All data 
computer processed by the Sponsor or designee will be 
identified by unique subject number/randomization code/ site 
number, only.   
19 List of 
References 
 
Beuers U, Gershwin ME, Gish RG, et al. Changing 
nomenclature for PBC: From ‘cirrhosis’ to ‘cholangitis’. Dig 
Liver Dis. 2015a;47(11):924-6. 
Beuers U, Gershwin ME, Gish RG, et al. Changing 
nomenclature for PBC: From ‘cirrhosis’ to ‘cholangitis’. 
Gastroenterology. 2015b;149(6):1627-9. 
Beuers U, Gershwin ME, Gish RG, et al. Changing 
nomenclature for PBC: From 'cirrhosis' to 'cholangitis'. 
Hepatology. 2015c;62(5):1620-2. 
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Appendix D 
Appendix D included Major Adverse Cardiovascular Event 
Definitions from Chapters 1 through 7 of  “Standardized 
Definitions for Cardiovascular and Stroke Endpoint Events in 
Clinical Trials,” dated August 20, 2014 
Appendix D was updated to add definitions from Chapters 8 
through 10 of “Standardized Definitions for Cardiovascular 
and Stroke Endpoint Events in Clinical Trials,” dated 
August 20, 2014 
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APPENDIX H. 747-209 PROTOCOL VERSION 4 SUMMARY OF CHANGES 
Protocol 747-209 was revised to include the following information: 
• Incorporation of the evaluation the bioanalytical concentrations of atorvastatin and its metabolites. 
• Updating the maximum percentage of subjects with stage 4 fibrosis from 20% to 30%. 
• Removing the obeticholic acid (OCA) glucuronide component of PK as that bioanalysis will be conducted in another 
study. 
• Additional clarifications.    
Summary of Changes 
The following revisions were made to the protocol in Protocol Version 4.  Revised and new text in Version 4 is indicated in bold 
font, and the text deleted from Protocol Version 3 is crossed out in the table below.  Minor/editorial changes are not listed 
individually in the summary table below. 
Section 
Original Text (Version 3) 
Revised Text (Version 4) 
Key Change 
Reasons / 
Justification for Change 
Study Personnel 
Contact Information 
Investigators are encouraged to call the NASH medical 
monitor hotline at +1 844 250 6396 or send an email to 
the NASH medical monitor at 
NASH209@interceptpharma.com with safety questions 
as these lines of contact are monitored 24 hours a day.  
The following individual medical monitors may also be 
contacted through the NASH medical monitor hotline 
and email address. 
Investigators are encouraged to call the PRA Medical 
Support Center phone number for the United 
States and Canada at +1 866 326 5053 or send an 
email to the NASH medical monitor at 
CONTROL@prahs.com with safety questions as 
these lines of contact are monitored 24 hours a day.   
The PRA Medical Support 
Center phone number and 
email address were updated. 
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Protocol 747-209  
Version 4:  19 Dec 2016 
Page 360 
 
Confidential and Proprietary 
Section 
Original Text (Version 3) 
Revised Text (Version 4) 
Key Change 
Reasons / 
Justification for Change 
Study Personnel 
Contact Information 
NASH 
Medical 
Monitor 
Hotline 
Email 
+1 844 250 6396  
 
NASH209@interceptpharma.com 
Deletion 
Removed the NASH Medical 
Monitor Hotline Email (no 
longer applicable). 
Study Personnel 
Contact Information 
Primary 
Medical 
Monitor 
Contact: 
 
Phone: 
Email 
Emad Basta, MD 
(Lead) Medical Monitor/Medical 
Expert 
PRA Health Sciences 
+1 866 326 5053 
CONTROL@PRAHS.com 
Primary Medical 
Monitor Contact: 
 
Phone: 
Email 
Emad Basta, MD 
(Lead) Medical Monitor/Medical 
Expert 
PRA Health Sciences 
+1 866 326 5053 
CONTROL@prahs.com 
Updated email address. 
Secondary 
Contact: 
Roya Hooshmand-Rad, MD PhD 
Executive Director, Medical Safety 
and Pharmacovigilance 
Intercept Pharmaceuticals, Inc. 
(Intercept) 
Secondary 
Contact: 
Tolga Baykal, MD, PhD 
Medical Director, Clinical 
Development 
Intercept Pharmaceuticals, Inc. 
(Intercept) 
Tolga Baykal was added as 
secondary contact. 
Mobile Phone: 
Email 
+1 858 880 6485 (Pacific time zone) 
rhooshmand-rad 
@interceptpharma.com 
Mobile Phone: 
Email 
+1 619 643 8886 (Pacific time 
zone) 
tolga.baykal@interceptpharma.c
om 
Synopsis 
Objectives: 
Exploratory 
Objectives 
6.3 Exploratory 
Objectives 
Insertion 
• 
To evaluate the bioanalytical concentrations of 
atorvastatin and its metabolites     
New exploratory objective for 
the determinations of the 
concentrations of atorvastatin 
and its metabolites. 
Synopsis 
Number of Subjects 
(Planned) 
 
Approximately 80 subjects with biopsy-confirmed 
NASH and evidence of liver fibrosis, but no hepatic 
decompensation, who meet eligibility criteria, will be 
randomized in a 1:1:1:1 ratio to 1 of 4 treatment 
groups.  A maximum of 20% of subjects will have 
stage 4 fibrosis. 
Approximately 80 subjects with biopsy-confirmed 
NASH and evidence of liver fibrosis, but no hepatic 
decompensation, who meet eligibility criteria, will be 
randomized in a 1:1:1:1 ratio to 1 of 4 treatment 
groups.  A maximum of 30% of subjects will have 
stage 4 fibrosis. 
The rapid rate of enrollment of 
subjects with stage 4 fibrosis 
allowed patients already in 
screening to be enrolled after 
the initial maximum of 20% 
was met (the overall number of 
subjects remains at ~ 80).   
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Confidential and Proprietary 
Section 
Original Text (Version 3) 
Revised Text (Version 4) 
Key Change 
Reasons / 
Justification for Change 
Synopsis 
Statistical Methods 
11.1, Efficacy  
Assessments 
Table 4, List of 
Planned Assessments 
OCA 
pharmacokinetics  
OCA, tauro-OCA, glyco-OCA, 
total OCA, OCA glucuronide, 
potentially other conjugates or 
metabolites not yet identified  
OCA 
pharmacokinetics  
OCA, tauro-OCA, glyco-OCA, 
total OCA, potentially other 
conjugates or metabolites not yet 
identified  
Removal of OCA glucuronide 
as that bioanalysis will be 
conducted in another study. 
Insertion 
Exploratory Endpoints 
Addition of the determination 
of the concentration of 
atorvastatin and its metabolites 
to characterize atorvastatin 
concentrations with and 
without OCA.  
Atorvastatin 
bioanalytical 
concentrations 
Atorvastatin and its 
metabolites   
Synopsis 
Analysis Populations 
13.1, Analysis Sets 
Pharmacokinetic Population: 
The PK Population will include all OCA subjects who 
consent to participate in the PK assessments and have 
at least one confirmed fasted analyzable sample.  
Subjects must have been fasting for approximately 8 
hours before the visit and must not have any major 
protocol deviations that potentially affect exposure 
levels.   
Pharmacokinetic Populations: 
The OCA PK Population will include all OCA 
subjects who consent to participate in the PK 
assessments and have at least one confirmed fasted 
analyzable sample.  Subjects must have been fasting 
for approximately 8 hours before the visit and must 
not have any major protocol deviations that 
potentially affect exposure levels.  The Atorvastatin 
PK Population will include all subjects who 
consent to participate in the PK assessments and 
have at least one confirmed fasted analyzable 
sample.   
Differentiation of OCA PK 
Population and incorporation 
of the Atorvastatin PK 
Population. 
7.1.2, Schedule of 
Study Procedures 
Table 1, Schedule of 
Study Procedures:  
Double-Blind Period 
s At selected investigational sites, subjects will have the 
option to provide blood samples for measurement of 
OCA PK.  PK samples will be collected within 30 
minutes prior to dosing and again at 0.5, 0.75, 1, 1.5, 2, 
2.5, 3, 4, 5, and 6 hours postdose.  Subjects should not 
drink additional water for 1 hour after taking the dose 
of investigational product and will remain fasted until 
the 1 hour sample is collected. 
s At selected investigational sites, subjects will have 
the option to provide blood samples for measurement 
of  PK for OCA (Day 1 and Week 16), and for 
atorvastatin (Week 16).  PK samples will be 
collected within 30 minutes prior to dosing and again 
at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours 
postdose.  Subjects should not drink additional water 
for 1 hour after taking the dose of investigational 
product and will remain fasted until the 1 hour sample 
is collected. 
Clarification on the PK 
sampling of OCA and 
incorporation of atorvastatin 
PK sampling. 
7.2,  Number of 
Subjects 
Approximately 80 subjects who meet the eligibility 
criteria, including biopsy-confirmed NASH and 
evidence of liver fibrosis, but no hepatic 
decompensation, will be included in this study.  A 
maximum of 20% of subjects will have stage 4 fibrosis. 
Approximately 80 subjects who meet the eligibility 
criteria, including biopsy-confirmed NASH and 
evidence of liver fibrosis, but no hepatic 
decompensation, will be included in this study.  A 
maximum of 30% of subjects will have stage 4 
fibrosis. 
The rapid rate of enrollment of 
subjects with stage 4 fibrosis 
allowed patients already in 
screening to be enrolled after 
the initial maximum of 20% 
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Protocol 747-209  
Version 4:  19 Dec 2016 
Page 362 
 
Confidential and Proprietary 
Section 
Original Text (Version 3) 
Revised Text (Version 4) 
Key Change 
Reasons / 
Justification for Change 
was met (the overall number of 
subjects remains at ~ 80).   
9.7.13.1, Additional 
Week 16 Procedures 
for PK Subjects 
Following collection of the Week 16 fasted samples 
indicated above, subjects who are participating in the 
PK assessment will each receive a single dose of their 
assigned investigational product with water.  Serial 
blood samples will be obtained for measurement of 
OCA and its conjugates 30 minutes prior to dosing and 
at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose.   
Following collection of the Week 16 fasted samples 
indicated above, subjects who are participating in the 
PK assessment will each receive a single dose of their 
assigned double-blind investigational product with 
water.  Serial blood samples will be obtained for 
measurement of OCA and its conjugates, and 
atorvastatin and its metabolites, 30 minutes prior to 
dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 
hours postdose.   
Clarification of study phase. 
Incorporation of PK sampling 
for atorvastatin.  
11.2, 
Pharmacokinetic and 
Pharmacodynamic 
Assessments 
Parent OCA and its major conjugates (glyco-OCA and 
tauro-OCA), C4, and FGF-19 concentrations will be 
determined for OCA PK and FXR activity in 
OCA-treated subjects.   Samples will be obtained for 
possible assessment of conjugated and unconjugated 
bile acids. 
Parent OCA and its major conjugates (glyco-OCA and 
tauro-OCA), C4, and FGF-19 concentrations will be 
determined for OCA PK and FXR activity in 
OCA-treated subjects.  Concentrations of 
atorvastatin and its metabolites will be assessed in 
PK sampled subjects.  Samples will be obtained for 
possible assessment of conjugated and unconjugated 
bile acids. 
Addition of the determination 
of the concentration of 
atorvastatin and its 
metabolites.   
11.2.2, 
Pharmacokinetic 
Assessments 
Subjects who opt to participate in the PK assessment 
will provide blood samples for the measurement of 
OCA and its conjugates.  The first sample should be 
collected within 30 minutes prior to administration of 
investigational product (predose) on Day 1 and prior to 
administration of investigational product or atorvastatin 
at the Week 16 Visit.  Subjects will then receive a 
single dose of investigational product with 
approximately 240 mL of water.  Serial blood samples 
will be obtained for measurement of OCA and its 
conjugates at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 
hours postdose. 
Subjects who opt to participate in the PK assessment 
will provide blood samples for the measurement of 
OCA and its conjugates, and atorvastatin and its 
metabolites.  The first sample should be collected 
within 30 minutes prior to administration of 
investigational product (predose) on Day 1 and prior 
to administration of investigational product or 
atorvastatin at the Week 16 Visit.  Subjects will then 
receive a single dose of investigational product with 
approximately 240 mL of water.  Serial blood samples 
will be obtained for measurement of OCA and its 
conjugates, and atorvastatin and its metabolites, at 
0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose. 
Incorporation of atorvastatin 
PK and sampling. 
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Section 
Original Text (Version 3) 
Revised Text (Version 4) 
Key Change 
Reasons / 
Justification for Change 
12.1.4.1, Severity of 
Pruritus (as an AE) 
• Drug holiday:  A drug holiday is defined as an 
Investigator ‘prescribed’ complete interruption of 
dosing for 1 or more consecutive days (ie, non-daily 
dosing does not constitute a drug holiday).  For 
subjects with severe pruritus, instruct the subject to 
stop taking investigational product until the pruritus 
subsides to an acceptable level, at which time it should 
be restarted.  Details of drug holidays and/or nondaily 
dosing regimens should be recorded in the CRF.     
• Drug holiday:  A drug holiday is defined as an 
Investigator ‘prescribed’ complete interruption of 
dosing for 1 or more consecutive days (ie, non-daily 
dosing does not constitute a drug holiday).  Details of 
drug holidays and/or nondaily dosing regimens 
should be recorded in the CRF.  Per Section 8.4.1.1, 
subjects with pruritus ≥Grade 3 in severity and 
possibly, probably, or definitely related to 
investigational product must discontinue 
investigational product.     
Instructions for severity of 
pruritus were removed.  The 
instructions for the handling of 
≥Grade 3 in severity are 
provided. 
12.2.6, Laboratory 
Assessments 
Table 10, List of 
Laboratory Analytes 
to be Tested 
Subset of Subjects 
Subset of Subjects 
Removal of OCA glucuronide. 
Addition of atorvastatin and its 
metabolites.   
PK analytes 
OCA, tauro-OCA, glyco-OCA, OCA 
glucuronide and possible other 
conjugates or metabolites not yet 
identified 
PK analytes 
OCA, tauro-OCA, glyco-OCA,  
and possible other conjugates or 
metabolites not yet identified 
Atorvastatin and its metabolites 
a NMR-based panel will be used for (a) LDL, HDL, and 
VLDL cholesterol concentrations, particle sizes, and 
particle concentrations, and (b) ApoA1, ApoB, ApoE, 
ApoCII, ApoCIII and Lp(a) concentrations.  Serum 
chemistry panel will be used for LDL, HDL, VLDL, 
TG, and total cholesterol concentration. 
a NMR-based panel will be used for LDL, HDL, and 
VLDL cholesterol concentrations, particle sizes, 
and particle concentrations.  ApoA1, ApoB, ApoE, 
ApoCII, ApoCIII, Lp(a) and PCSK9 
concentrations will be measured using 
appropriate methods at central or specialty 
laboratories.  Serum chemistry panel will be used 
for LDL, HDL, VLDL, TG, and total cholesterol 
concentration. 
Clarification of methods to be 
used for the determination of 
ApoA1, ApoB, ApoE, ApoCII, 
ApoCIII, Lp(a), and PCSK9 
concentrations. 
13.6.3.7,
Pharmacokinetic 
Analysis 
The PK Population will be used for analysis of PK 
parameters, which include plasma OCA (parent) and its 
conjugates (glyco-OCA and tauro-OCA), total OCA, 
OCA glucuronide, and potentially other conjugates or 
metabolites not yet identified.  PK analysis will be done 
using non-compartmental methods.   
The values will be summarized by active treatment 
group using descriptive statistics.  Only samples that 
have a confirmed fasting of approximately 8 hours or 
more before their visit will be included in the analysis.   
Further details regarding specific parameters and 
methods will be described in the SAP. 
The PK Population will be used for analysis of PK 
parameters, which include plasma OCA (parent) and 
its conjugates (glyco-OCA and tauro-OCA), total 
OCA, atorvastatin and its metabolites, and 
potentially other analytes not yet identified.  PK 
analysis will be conducted using standard 
non-compartmental methodologies.   
For the analysis of OCA and its conjugates, values 
will be summarized by active treatment group using 
descriptive statistics.  Only samples that have a 
confirmed fasting of approximately 8 hours or more 
before their visit will be included in the analysis.   
Incorporation of clarifications 
for OCA and atorvastatin PK 
analysis. 
Page 363 of 364


Protocol 747-209  
Version 4:  19 Dec 2016 
Page 364 
 
Confidential and Proprietary 
Section 
Original Text (Version 3) 
Revised Text (Version 4) 
Key Change 
Reasons / 
Justification for Change 
Further details regarding the methods for 
calculating PK and the specific parameters to be 
reported will be described in the SAP. 
 
Page 364 of 364

SAP_001.pdf: 
Statistical Analysis Plan for Protocol 747-209 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Study 
Investigating the Effects of Obeticholic Acid and Atorvastatin Treatment on 
Lipoprotein Metabolism in Subjects with Nonalcoholic Steatohepatitis 
 The CONTROL Study 
Combination OCA aNd STatins for MonitoRing Of Lipids  
Protocol Version and Date: 
Version 4:  19 Dec 2016
Phase: 
Phase 2 
Methodology: 
Double-Blind, Randomized, Placebo-Controlled Study 
Prepared by: 
Courtney Van Biene 
Sponsor: 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA 92121 
Tel: 
858-652-6800 
Fax: 
858-558-5961 
Analysis Plan Date: 
20 Jun 2017 
Analysis Plan Version: 
2.0 




Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-209 
 
20 Jun 2017 
Confidential and Proprietary                                  Page 3 of 71 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2
LIST OF ABBREVIATIONS ..........................................................................................................7
1.
INTRODUCTION ......................................................................................................12
2.
STUDY OBJECTIVES ..............................................................................................12
3.
STUDY ENDPOINTS ................................................................................................13
3.1.
Primary Endpoints ......................................................................................................13
3.2.
Secondary Endpoints ..................................................................................................13
3.2.1.
Lipoprotein Metabolism Endpoints ............................................................................13
3.2.2.
Reverse Cholesterol Transport Endpoints ..................................................................13
3.2.3.
Safety and Tolerability Endpoints ..............................................................................13
3.3.
Exploratory Endpoints ................................................................................................14
3.3.1.
Liver Biochemistry and Markers of Liver Function ...................................................14
3.3.2.
Markers of Liver Inflammation ..................................................................................15
3.3.3.
Markers for Hepatic Apoptosis and Fibrosis ..............................................................15
3.3.4.
Glycemic Control ........................................................................................................15
3.3.5.
OCA Pharmacokinetics Endpoints .............................................................................15
3.3.6.
Atorvastatin Concentrations Endpoint ........................ Error! Bookmark not defined.
3.3.7.
Anthropometric Measures and Blood Pressure ..........................................................16
3.3.8.
Pharmacodynamics .....................................................................................................16
3.3.9.
Noninvasive Radiological Liver Fibrosis Measurements ...........................................16
3.3.10.
Cardiovascular Risk Scores ........................................................................................16
3.3.11.
Cardiovascular Markers of Risk .................................................................................17
4.
STUDY DESIGN AND PLAN ..................................................................................17
5.
DETERMINATION OF SAMPLE SIZE ...................................................................18
6.
GENERAL ANALYSIS CONSIDERATIONS .........................................................19
6.1.
Data Reporting ............................................................................................................19
6.2.
Data Analysis and Summaries ....................................................................................19
6.2.1.
Arithmetic Summaries ................................................................................................19
6.2.2.
Categorical Methods ...................................................................................................19
6.2.3.
Analysis of Covariance ...............................................................................................20
6.2.4.
Analysis of Covariance (Repeated Measures) ............................................................21


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-209 
 
20 Jun 2017 
Confidential and Proprietary                                  Page 4 of 71 
6.2.5.
Median and Confidence Interval Estimation Methods ...............................................21
6.2.6.
Dose Trend Methods ...................................................................................................21
6.2.7.
Geometric (Natural Log Transformed) Summaries ....................................................22
6.2.8.
Multiple Comparisons/Multiplicity ............................................................................22
6.2.9.
Subgroup Analyses .....................................................................................................22
6.3.
Data Handling .............................................................................................................22
6.3.1.
Baseline Values ..........................................................................................................22
6.3.2.
Missing Data ...............................................................................................................22
6.3.3.
Partial Dates ................................................................................................................22
6.3.4.
Data Conventions ........................................................................................................23
6.3.5.
Standard Calculations .................................................................................................24
6.3.6.
Cardiovascular Risk Scores Calculations ...................................................................25
6.3.7.
Fibrosis Scores Calculations .......................................................................................26
6.3.8.
Anomalous Concentration Handling ..........................................................................26
7.
ANALYSIS POPULATIONS ....................................................................................27
7.1.
Intent-to-Treat (ITT) Population .................................................................................27
7.2.
Safety Population ........................................................................................................27
7.3.
Efficacy Evaluable (EE) Population ...........................................................................27
7.4.
OCA Pharmacokinectic (PK) Population ...................................................................27
7.5.
Atorvastatin Pharmacokinetic (APK) Population ....... Error! Bookmark not defined.
8.
STUDY POPULATION .............................................................................................27
8.1.
Subject Disposition .....................................................................................................27
8.2.
Protocol Deviations ....................................................................................................28
8.3.
Demographic and Baseline Characteristics ................................................................28
8.4.
NASH Disease History ...............................................................................................30
8.5.
Alcohol Use Disorders Identification Test (AUDIT) .................................................30
8.6.
Tobacco Use ...............................................................................................................30
8.7.
Statin History ..............................................................................................................30
8.8.
Family Cardiovascular History ...................................................................................31
8.9.
General Medical History .............................................................................................31
8.10.
Prior and New Concomitant Medications ...................................................................31
9.
EFFICACY ANALYSES ...........................................................................................32


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Statistical Analysis Plan 
Protocol 747-209 
 
20 Jun 2017 
Confidential and Proprietary                                  Page 5 of 71 
9.1.
Primary Efficacy Analyses .........................................................................................32
9.2.
Secondary Efficacy Analyses .....................................................................................33
9.2.1.
Lipoprotein Metabolism .............................................................................................33
9.2.2.
Reverse Cholesterol Metabolism ................................................................................33
9.3.
Exploratory Efficacy Analyses ...................................................................................33
9.3.1.
Liver Biochemistry and Markers of Liver Function ...................................................33
9.3.2.
Markers of Liver Inflammation, Hepatic Apoptosis, and Fibrosis .............................34
9.3.3.
Glycemic Control ........................................................................................................34
9.3.4.
Noninvasive Radiological Liver Fibrosis Measurements ...........................................34
9.3.5.
Noninvasive Scores and NAFLD Liver Fibrosis Scores ............................................35
9.3.6.
Anthropometric Measures and Blood Pressure ..........................................................35
9.3.7.
Cardiovascular Risk Scores ........................................................................................35
9.3.8.
Cardiovascular Markers of Risk .................................................................................36
10.
EXPLORATORY PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSIS .................................................................................................................36
10.1.
Pharmacokinetic Measures .........................................................................................36
10.2.
Pharmacokinetic Data Handling .................................................................................36
10.2.1.
Missing Values ...........................................................................................................36
10.2.2.
Results Below Limit of Quantification (BLQ) ...........................................................36
10.2.3.
PK Sampling Times ....................................................................................................37
10.2.4.
Decision Paradigm for Reprocessing Samples ...........................................................37
10.2.5.
Anomalous Concentration Handling ..........................................................................37
10.2.6.
Representation of Mean Concentrations .....................................................................37
10.3.
Pharmacokinetic Analysis ..........................................................................................38
10.3.1.
Pharmacokinetic Methods ..........................................................................................38
10.3.2.
Reporting and Significant Figures ..............................................................................39
10.4.
Pharmacokinetic/Pharmacodynamic (PK/PD) Analyses ............................................39
10.5.
Bile Acid Pharmacodynamics .....................................................................................39
11.
SAFETY ANALYSES ...............................................................................................40
11.1.
Extent of Exposure .....................................................................................................41
11.1.1.
Investigational Product (OCA or Placebo) .................................................................41
11.1.2.
Atorvastatin .................................................................................................................41
11.2.
Adverse Events (AEs) .................................................................................................42


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Statistical Analysis Plan 
Protocol 747-209 
 
20 Jun 2017 
Confidential and Proprietary                                  Page 6 of 71 
11.3.
Adverse Events of Special Interest .............................................................................43
11.3.1.
Pruritus ........................................................................................................................44
11.3.2.
Hepatic Disorders .......................................................................................................45
11.3.3.
Dyslipidaemia .............................................................................................................45
11.3.4.
Myopathy ....................................................................................................................45
11.4.
Adjudicated Cardiovascular Events ............................................................................45
11.5.
On-Study Medical or Surgical Proecdures .................................................................46
11.6.
Clinical Laboratory Evaluations .................................................................................46
11.7.
Vital Signs ..................................................................................................................47
11.8.
Electrocardiograms (ECGs) ........................................................................................47
12.
CHANGES TO PROTOCOL-SPECIFIED ANALYSES AND ENDPOINTS .........47
13.
REFERENCES ...........................................................................................................49
APPENDIX A.
LIST OF TABLES, FIGURES, AND LISTINGS ............................................50
APPENDIX B.
DYSLIPIDEMIA PREFERRED TERMS AND ASSOCIATED 
CODES .......................................................................................................................60
APPENDIX C.
RHABDOMYOLYSIS AND MYOPATHY PREFERRED TERMS 
AND ASSOCIATED CODES ....................................................................................70
LIST OF TABLES 
Table 1:
Bile Acids and Their Sub-Components ......................................................................40
LIST OF FIGURES 
Figure 1:
Study Design Schematic .............................................................................................18


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Statistical Analysis Plan 
Protocol 747-209 
 
20 Jun 2017 
Confidential and Proprietary                                  Page 7 of 71 
LIST OF ABBREVIATIONS 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
Apo 
apolipoprotein 
ApoA1 
apolipoprotein A1  
ApoB 
apolipoprotein B 
ApoCII 
apolipoprotein CII 
ApoCIII 
apolipoprotein CIII 
ApoE 
apolipoprotein E 
APRI 
aspartate aminotransferase (AST) to platelet ratio index 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the concentration-time curve 
AUC0-6 
area under the concentration-time curve from hour 0 to last 
sampling time (hour 6) 
AUDIT 
Alcohol Use Disorders Identification Test 
BARD 
body mass index, aspartate aminotransferase to alanine 
aminotransferase ratio, and diabetes 
BLQ 
below the limit of quantitation 
BMI 
body mass index  
C4 
7α-hydroxy-4-cholesten-3-one 
CA 
cholic acid 
cAMP 
cyclic adenosine monophosphate 
CAP 
controlled attenuation parameter 
CDCA 
chenodeoxycholic acid 
CETP 
cholesterol ester transfer protein  
CI 
confidence interval 
CK-18-M30 
cytokeratin-18 neoepitope M30 
CK-18-M65 
cytokeratin-18 neoepitope M65 
cm 
centimeter(s) 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-209 
 
20 Jun 2017 
Confidential and Proprietary                                  Page 8 of 71 
Abbreviation or Specialist Term 
Explanation 
Cmax 
maximum plasma concentration  
CMH 
Cochran-Mantel-Haenszel 
CRN 
clinical research network 
CRP 
C-reactive protein 
CS 
clinically significant 
CSR 
clinical study report 
CTCAE 
common terminology criteria for adverse events 
CV 
coefficient of variation 
DB 
double-blind  
DCA 
deoxycholic acid 
DOB 
date of birth 
DOIC 
date of informed consent 
eCRF 
electronic case report form 
ECG 
Electrocardiogram 
EE 
efficacy evaluable 
Eq 
equivalents 
FGF-19 
fibroblast growth factor-19 
FIB-4 
Fibrosis-4  
FRS 
Framingham Risk Score 
FXR 
farnesoid X receptor 
G 
gram(s) 
GGT 
gamma-glutamyl transferase 
glyco-CA 
glycine 6α-ethyl cholic acid 
glyco-CDCA 
glycine 6α chenodeoxycholic acid 
glyco-DCA 
glycine 6α-ethyl deoxycholic acid 
glyco-LCA 
glycine 6α-ethyl lithocholic acid 
glyco-OCA 
glycine 6α-ethyl chenodeoxycholic acid 
glyco-UDCA 
glycine 6α-ethyl ursodeoxycholic acid 
H 
high/above the reference/normal range 
HbA1c 
hemoglobin-specific A1c fraction 
HDL 
high-density lipoprotein 
HDLc 
HDL cholesterol concentration 
HDLs 
HDL particle size 
HDLpc 
HDL particle concentration 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-209 
 
20 Jun 2017 
Confidential and Proprietary                                  Page 9 of 71 
Abbreviation or Specialist Term 
Explanation 
HOMA-β 
homeostatic model assessment – beta-cell function 
HOMA-IR 
homeostatic model assessment – insulin resistance 
hs-CRP 
high-sensitivity C-reactive protein 
In 
inch(es) 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IL-6 
interleukin-6 
INR 
International Normalized Ratio 
IQR 
interquartile range 
ITT 
intent-to-treat 
Kg 
kilogram(s) 
JT 
Joncheere-Terpstra 
KM 
Kaplan-Meier 
L 
low/below the reference/normal range 
Lb 
pound(s) 
LCA 
lithocholic acid 
LCAT 
lecithin-cholesterol acyltransferase 
LDL 
low-density lipoprotein 
LDLc 
LDL cholesterol concentration 
LDLs 
LDL particle size 
LDLpc 
LDL particle concentration 
LOCF 
last observation carried forward 
LLN 
lower limit(s) of normal 
LLOQ 
lower limit of quantification 
Lp(a) 
 
lipoprotein(a) 
LS 
least squares 
LTSE 
long-term safety extension  
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
milligram(s) 
mL 
milliliter 
mol 
mole(s) 
MW 
molecular weight 
NAFLD 
nonalcoholic fatty liver disease 


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Abbreviation or Specialist Term 
Explanation 
NAS 
nonalcoholic fatty liver disease activity score 
NASH 
nonalcoholic steatohepatitis 
ND 
not determined 
NFS 
nonalcoholic fatty liver disease fibrosis score 
ng 
nanogram 
NMR 
nuclear magnetic resonance 
NR 
not reported 
OCA 
obeticholic acid 
ODS 
output delivery system 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamic 
PK 
pharmacokinetic 
PP 
per protocol 
QT 
the time between the start of the Q wave and the end of the T wave
QTc 
corrected measure between Q wave and T wave (in heart’s electrical 
cycle) 
QTcB 
QT interval corrected by the Bazett’s formula 
QTcF 
QT interval corrected by the Fridericia’s formula 
RR 
time between two consecutive R waves 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SI 
International System of Units 
SMQ 
standardized MedDRA query 
SQRT 
square root 
tauro-CA 
taurine 6α-ethyl cholic acid 
tauro-CDCA 
taurine 6α chenodeoxycholic acid 
tauro-DCA 
taurine 6α-ethyl deoxycholic acid 
tauro-LCA 
taurine 6α-ethyl lithocholic acid 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
tauro-UDCA 
taurine 6α-ethyl ursodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach Cmax


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Abbreviation or Specialist Term 
Explanation 
TG 
triglycerides 
TNF-α 
tumor necrosis factor-alpha  
UDCA 
ursodeoxycholic acid 
ULN 
upper limit(s) of normal 
VLDL 
very low density lipoprotein 
VLDLc 
VLDL cholesterol concentration 
VLDLpc 
VLDL and chylomicron particle concentration 
VLDLs 
VLDL particle size 
WADD 
weighted average daily dose 
WHODDE 
World Health Organization Drug Dictionary Enhanced 


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1.
INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of the 
double-blind (DB) data collected within the scope of Intercept Pharmaceuticals, Inc. (henceforth 
referred to as Intercept or the Sponsor) for Protocol 747-209 (A Phase 2, Randomized, 
Double-Blind, Placebo-Controlled Clinical Study Investigating the Effects of Obeticholic Acid 
and Atorvastatin Treatment on Lipoprotein Metabolism in Subjects with Nonalcoholic 
Steatohepatitis).  The purpose of this statistical analysis plan (SAP) is to provide specific 
guidelines from which the analyses will proceed.  Any deviations from these guidelines will be 
documented in the clinical study report (CSR).  The scope of this plan includes the detailed 
specifications of the statistical analyses for the DB only.  A separate SAP will be written for the 
long-term safety extension (LTSE) phase of the study.  The analyses described in this plan are 
considered a priori, in that they have been defined prior to database lock of the DB.  Post hoc 
analyses will be labeled as such on the outputs and identified in the CSR.  Further details about 
study design and procedures can be found in the protocol. 
2.
STUDY OBJECTIVES 
The DB primary objective is to evaluate the effect of obeticholic acid (OCA) on low-density 
lipoprotein (LDL) metabolism in subjects with biopsy-confirmed nonalcoholic steatohepatitis 
(NASH) and to assess the ability of atorvastatin to modulate this effect. 
The DB secondary objectives are: 
x
To evaluate the safety and tolerability of OCA alone and in combination with 
atorvastatin therapy in subjects with biopsy-confirmed NASH. 
x
To evaluate the effect of OCA with and without atorvastatin therapy, on  

High-density lipoprotein (HDL), very low-density lipoprotein (VLDL), 
triglycerides (TG), total cholesterol, and apolipoprotein (Apo) concentrations 

Components of the reverse cholesterol transport pathway 
The DB exploratory objectives are: 
x
To evaluate the effect of OCA on: 

Liver biochemistry, inflammation, and apoptosis  

Markers of glucose metabolism including C-peptide, insulin, fasting plasma 
glucose, hemoglobin-specific A1c fraction (HbA1c), homeostatic model 
assessment – beta-cell function (HOMA-β), and homeostatic model assessment –
 insulin resistance (HOMA-IR) 

Anthropometric measures including height (measured at Screening Visit 1 only), 
weight, waist and hip circumference measurements, body mass index (BMI), and 
waist-to-hip ratio calculations 

Cardiovascular risk scores (eg, Framingham Risk Score [FRS] and Reynolds 
score) 


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x
To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of OCA and its 
conjugates 
x
To evaluate the bioanalytical concentrations of atorvastatin and its metabolites 
x
To evaluate improvement in noninvasive-radiological assessment of fibrosis via 
transient elastography (TE; at sites where available) 
3.
STUDY ENDPOINTS 
3.1.
Primary Endpoints 
The DB primary endpoints are change and percentage change from Baseline to Week 16 in LDL 
cholesterol concentration (LDLc), particle size (LDLs), and particle concentration (LDLpc).  
3.2.
Secondary Endpoints 
As defined in the protocol, the DB secondary endpoints are lipoprotein metabolism, reverse 
cholesterol transport, and safety and tolerability endpoints. 
3.2.1.
Lipoprotein Metabolism Endpoints 
The secondary parameters related to lipoprotein metabolism include HDL cholesterol 
concentration (HDLc), particle size (HDLs) and particle concentration (HDLpc); VLDL 
cholesterol concentration (VLDLc), particle size (VLDLs), and VLDL and chylomicrons particle 
concentration (VLDLpc); TG and total cholesterol concentrations; and apolipoprotein A1 
(ApoA1), apolipoprotein B (ApoB), apolipoprotein E (ApoE), apolipoprotein CII (ApoCII), 
apolipoprotein CIII (ApoCIII), lipoprotein(a) [Lp(a)], and  proprotein convertase subtilisin/kexin 
type 9 (PCSK9) enzyme level concentrations. 
For each of these parameters, the endpoints are: 
x
Observed values, change from Baseline, and percentage change from Baseline at each 
DB post-Baseline visit 
3.2.2.
Reverse Cholesterol Transport Endpoints 
The secondary parameters related to reverse cholesterol metabolism include pre-β1 HDL 
concentration, macrophage cholesterol efflux, lecithin-cholesterol acyltransferase (LCAT) 
activity, cholesterol ester transfer protein (CETP) activity. 
For each of these parameters, the endpoints are: 
x
Observed values, change from Baseline, and percentage change from Baseline at each 
DB post-Baseline visit 
3.2.3.
Safety and Tolerability Endpoints 
The DB safety and tolerability endpoints include the following: 
x
Extent of exposure to OCA and Atorvastatin  


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x
Incidence of Treatment-Emergent adverse events (TEAEs) 
x
Observed values and change from Baseline at each DB post-Baseline visit in 
quantitative clinical laboratory values for coagulation, hematology, and serum 
chemistry 
x
Shift tables (ie, low-normal-high at Baseline versus low-normal-high at each DB 
post-Baseline visit in a 3-by-3 contingency table) from Baseline to worst DB 
post-Baseline value, last DB post-Baseline value, and at each scheduled DB post-
Baseline visit for quantitative hematology, coagulation, and serum chemistry 
x
Observed values and change from Baseline at each DB post-Baseline visit in vital 
signs (ie, body temperature, sitting heart rate, and respiratory rate).  Note:  blood 
pressure (sitting) is described below in Section 3.3.6
x
Observed values at Baseline and each DB post-Baseline visit, and change from 
Baseline at each DB post-Baseline visit in electrocardiogram (ECG) parameters (time 
between 2 consecutive R waves [RR], heart rate, PR, QRS, the time from the start of 
the Q wave an T wave (in heart’s electrical cycle) (QT), QT interval corrected by 
Bazett’s formula (QTcB), and QT interval corrected by Fridericia’s formula (QTcF)) 
x
Categorical summaries of abnormal QTcF values (ie, > 450 msec, > 480 msec, and 
> 500 msec) and change from baseline values (> 30 msec and > 60 msec) 
3.3.
Exploratory Endpoints 
As defined in the protocol, the DB exploratory endpoints are liver biochemistry and markers of 
liver function, markers of liver inflammation, markers of hepatic apoptosis and fibrosis, 
glycemic control, OCA pharmacokinetics (PK), atorvastatin bioanalytical concentrations, 
anthropometric measures, pharmacodynamics (PD), noninvasive radiological liver fibrosis 
measurements, and cardiovascular risk scores. 
In addition, noninvasive scores of liver fibrosis including nonalcoholic fatty liver disease 
(NAFLD) fibrosis score (NFS) (Angulo 2007), fibrosis-4 (FIB-4) (Shah 2009), aspartate 
aminotransferase (AST) to platelet ratio index (APRI) (Calès 2009), and body mass index (BMI), 
AST to alanine aminotransferase (ALT) ratio, and diabetes (BARD) (Harrison 2008) will be 
computed based on Baseline characteristics and biochemistry values at scheduled visits.  
3.3.1.
Liver Biochemistry and Markers of Liver Function 
For the laboratory parameters albumin, alkaline phosphatase (ALP (isoenzymes)), ALT 
(isoenzymes), AST, total and direct bilirubin, gamma-glutamyl transferase (GGT), and INR 
(International Normalized Ratio), and platelets: 
x
Observed values, change from Baseline, and percentage change from Baseline at each 
DB post-Baseline visit 
x
Shift from Baseline to each DB post-Baseline visit 


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3.3.2.
Markers of Liver Inflammation 
For the laboratory parameters interleukin (IL-6), high-sensitivity C-reactive protein (hs-CRP), 
and tumor necrosis factor-alpha (TNF-α): 
x
Observed values, change from Baseline, and percentage change from Baseline at each 
DB post-Baseline visit 
3.3.3.
Markers for Hepatic Apoptosis and Fibrosis 
For the laboratory parameters cytokeratin-18 neoepitope M30 (CK-18-M30) and cytokeratin-18 
neoepitope M65 (CK-18-M65): 
x
Observed values, change from Baseline, and percentage change from Baseline at each 
DB post-Baseline visit 
For noninvasive scores of liver fibrosis NFS, FIB-4, and APRI: 
x
Observed values, change from Baseline, and percentage change from Baseline at each 
DB post-Baseline visit 
For noninvasive score of liver fibrosis BARD: 
x
Shift from Baseline to each DB post-Baseline visit 
3.3.4.
Glycemic Control 
For the laboratory parameters fasting glucose, fasting insulin, C-peptide, HbA1c, HOMA-β, and 
HOMA-IR. 
x
Observed values, change from Baseline, and percentage change from Baseline at each 
DB post-Baseline visit 
3.3.5.
OCA Pharmacokinetics Endpoints 
The OCA PK Population will be used for analysis of PK parameters, which include plasma OCA 
(parent) and its conjugates (glycine 6α-ethyl chenodeoxycholic acid [glyco-OCA] taurine 6α-
ethyl chenodeoxycholic acid [tauro-OCA]), total OCA, and potentially other conjugates or 
metabolites not yet identified.  PK analyses will utilize standard non-compartmental methods.   
PK parameter estimates will be summarized by active treatment group using descriptive 
statistics.  Only samples that have a confirmed fasting of at least 8 hours or more before their 
visit will be included in the analysis. 
x
The PK endpoints include the Day 1 and Week 16 plasma concentrations at all 
collection time points. Plasma PK parameters will include maximum plasma 
concentration [Cmax], time to reach Cmax [tmax], and area under the concentration-time 
curve from hour 0 to last sampling time (hour 6) [AUC0-6].  
x
OCA dose-normalized versions of Cmax, and AUC0-6 will be calculated for Day 1 and 
Week 16. 
x
Steady-state accumulation ratios based on Cmax (Rac Cmax) and AUC0-6 (Rac AUC0-6) 
will be calculated: 


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Rac Cmax = Week 16 Cmax/Day 1 Cmax
 
Rac AUC0-6 = Week 16 AUC0-6/Day 1 AUC0-6
x
Metabolite ratios based on Cmax (MRCmax) and AUC0-6 (MRAUC0-6) will be 
calculated: 
MR Cmax = (Cmax conjugate or metabolite / Cmax parent) x (molecular weight 
parent / molecular weight conjugate or metabolite) 
MR AUC0-6 = (AUC0-6 conjugate or metabolite / AUC0-6 parent) x (molecular 
weight parent / molecular weight conjugate or metabolite)
3.3.6.
Anthropometric Measures and Blood Pressure 
Anthropometric measures include height (measured and recorded only at Screening Visit 1), 
body weight, waist and hip circumference measurements, BMI, and waist-to-hip ratio 
calculations.  Blood pressure (sitting) will also be collected. 
x
Observed values, change from Baseline, and percentage change from Baseline at each 
DB post-Baseline visit 
3.3.7.
Pharmacodynamics 
For 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor-19 (FGF-19), conjugated 
and unconjugated endogenous bile acids, and total bile acids: 
x
Observed values and change from Baseline at each DB post-Baseline visit 
3.3.8.
Noninvasive Radiological Liver Fibrosis Measurements 
Noninvasive radiological methods to assess liver stiffness and steatosis will be conducted via 
transient elastography (TE) at selected centers where the devices are available.   
x
Observed liver stiffness values and change from Baseline at each DB post-Baseline 
visit 
x
Proportion of subjects with any reduction in liver stiffness value (kPa) at Week 16  
x
Observed controlled attenuation parameter (CAP) (dB/m) values and change from 
Baseline at each DB post-Baseline visit
x
Both liver stiffness and CAP values are median values based on number of valid 
measurements 
3.3.9.
Cardiovascular Risk Scores 
The cardiovascular risk scores include the Framingham Risk Score (FRS) and Reynolds score.  
Each score is derived from a subject’s age, sex, smoking status, total cholesterol and HDL levels, 
and other factors including family history, BMI, ethnicity, and medications.  Cardiovascular 
scores will be calculated at the time of data analysis.   
• 
Observed values, change from Baseline, and percentage change from Baseline at each 
DB post-Baseline visit 


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3.3.10.
Cardiovascular Markers of Risk 
The cardiovascular markers of risk scores include adiponectin, plasminogen activator inhibitor-
1(PAI-1), and B-type natriuretic peptide (BNP).   
x
Observed values, change from Baseline, and percentage change from Baseline at each 
DB post-Baseline visit 
4.
STUDY DESIGN AND PLAN 
This is a Phase 2, double-blind, randomized, placebo-controlled, multicenter study, evaluating 
the effects of OCA, and the subsequent addition of statin therapy, on lipoprotein metabolism in 
subjects with NASH with fibrosis stage 1 to 4, but no evidence of hepatic decompensation, in the 
DB phase, followed by an open-label LTSE phase to evaluate long term safety and efficacy. 
Approximately 80 subjects with histological evidence of definite or probable NASH, who meet 
all inclusion and none of the exclusion criteria will be enrolled in the study.  The histological 
evidence of definite or probable NASH will be based on the central read of a liver biopsy 
obtained no more than 1 year prior to randomization and a nonalcoholic fatty liver disease 
activity score (NAS) of 4 or greater.  Subjects not using statin therapy (ie, statin-free) and 
statin-treated subjects may be enrolled.  Statin-treated subjects will be required to stop statin 
treatment (after signing informed consent) for up to 5 weeks, including a 4-week statin washout 
period, prior to Randomization/Day 1. 
Subjects will have a screening period of up to 5 weeks prior to Randomization/Day 1.  At the 
Randomization (Day 1) Visit, subjects will be randomized in a 1:1:1:1 ratio to receive OCA 
5 mg, OCA 10 mg, OCA 25 mg, or placebo, orally, once daily, for 16 weeks.  Randomization 
will be stratified by the pre-randomization fasting serum LDLc (≤125 mg/dL or >125 mg/dL) 
and baseline fibrosis stage (stage 1, 2 or stage 3, 4). 
Subjects will attend on-site clinic visits at Weeks 2, 4, 8, 12, and 16 and will be contacted at 
Weeks 6, 10 and 14 to assess safety and treatment compliance.  At the Week 4 Visit, all subjects 
will initiate treatment with atorvastatin at a dose of 10 mg once daily.  At the Week 8 Visit, 
atorvastatin will be increased to 20 mg once daily (if 10 mg daily is tolerated), and continued for 
an additional 4 weeks.  After 4 weeks of treatment at 20 mg, the atorvastatin dose may be titrated 
(up or down) as clinically indicated.  The final visit during the DB phase will occur at Week 16, 
after which subjects may continue into the open-label LTSE.  
During the LTSE phase, all subjects will be treated with open-label OCA 10 mg or 25 mg.  
Subjects randomized to placebo or OCA 5 mg during the double-blind phase will be randomized 
in a 1:1 ratio to receive OCA 10 mg or OCA 25 mg upon entry into and throughout the LTSE 
phase.  Subjects randomized to OCA 10 mg or OCA 25 mg during the double-blind phase will 
continue on the same dose throughout the LTSE.  In the event of OCA-related tolerability 
concerns, the Investigator may refer to the Investigator’s Brochure (IB) for possible treatment 
options.  Subjects may continue, discontinue, or modify the atorvastatin therapy as clinically 
indicated.  The LTSE will continue for approximately 2 years.   


Intercept P
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6.
GENERAL ANALYSIS CONSIDERATIONS 
6.1.
Data Reporting 
The statistical analyses will be reported using summary tables, figures, and data listings.  All 
output will be incorporated into Microsoft Word rich text format (.rtf) files, sorted and labeled 
according to the ICH recommendations, and formatted to the appropriate page size(s).  
Laboratory units will be summarized and presented in the International System of Units (SI) and 
conventional units.  
Individual subject data obtained from the electronic case report forms (eCRFs), external 
laboratory data, and any derived data (such as change from Baseline and percent change from 
Baseline) will be presented in data listings by subject.  Data from all assessments, whether 
scheduled or unscheduled, will be listed by subject and visit.  Unscheduled visits and visits 
occurring more than one day outside protocol defined window will not be included in the table 
summaries, excluding transient elastography measurements 
The analyses described in this plan are considered a priori, in that they have been defined prior to 
database lock of the DB.  Post hoc analyses will be labeled as such on the outputs and identified 
in the CSR. 
Analyses and tabulations will be performed using SAS£ Version 9.3 or higher.  PK parameters 
will be estimated using Phoenix£ WinNonlin£ Version 6.3 or higher.  The following processes 
will be employed to validate statistical outputs: analysis datasets, summary tables, and data 
listings will be verified through independent programming; graphical displays will be compared 
against supporting summary tables; and all outputs will undergo a senior-level statistical review.  
The process includes confirmation that statistically valid methods have been implemented and 
that all data manipulations and calculations are appropriate and accurate.  Checks will be made to 
ensure accuracy, adherence to this SAP, consistency within tables, and agreement between tables 
and their corresponding data listings.  Upon completion of validation/verification and quality 
review procedures, all documentation will be collected and filed in the study master file by the 
project statistician or designee. 
6.2.
Data Analysis and Summaries 
Data distribution characteristics will determine which analysis methods are most appropriate.  If 
methods do not allow for parametric modeling assumptions to be met, then non-parametric 
methods will be implemented.   
6.2.1.
Arithmetic Summaries 
Continuous variables will be summarized with means, standard deviations (SDs), standard errors 
(SEMs) of the mean, medians, interquartile ranges (IQRs), minimums, and maximums.        
6.2.2.
Categorical Methods 
Categorical variables will be summarized by counts and percentage of subjects in corresponding 
categories.  Percentages will be based on the number of non-missing assessments unless 
otherwise specified.  


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6.2.3.
Analysis of Covariance  
Analysis of covariance (ANCOVA) will be performed to provide least squares (LS) mean 
estimates and 95% confidence intervals (CIs) of the change and percentage change from 
Baseline at each DB post-Baseline visit.  Model covariates will include the randomization 
stratification values (ie, pre-randomization fasted serum LDLc [≤125 mg/dL or >125 mg/dL] and 
baseline fibrosis stage [stage 1, 2 or stage 3, 4]) and the Baseline value of the parameter being 
evaluated.  The primary analysis will exclude the treatment by visit interaction term.  
Example SAS code for the primary analysis is as follows: 
ODS graphics on; 
proc mixed data=ADEFF noclprint plots=residualpanel; 
 
  by visit; 
class ldlcon fbstg trt; 
model change=Baseline ldlcon fbstg trt / ddfm=kr;  
 
lsmeans trt / cl diff alpha=0.05; 
 
title1 "Linear Mixed Effects Model Based Estimates of XXXX Means by Visit";  
title2 " Fixed Effects for Visit, Randomization Strata and Baseline as Covariates"; 
run; 
ODS graphics off; 
quit; 


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6.2.4.
Analysis of Covariance (Repeated Measures) 
Analysis of covariance (ANCOVA) with repeated measures will be performed to provide LS 
mean estimates and 95% CIs of the change and percentage change from Baseline at each DB 
post-Baseline visit.  Model covariates will include the randomization stratification values (ie, 
pre-randomization fasted serum LDLc [≤125 mg/dL or >125 mg/dL] and baseline fibrosis stage 
[stage 1, 2 or stage 3, 4]) and the Baseline value of the parameter being evaluated.  This will 
include the treatment by visit interaction term.  Example SAS code for the secondary analysis is 
as follows: 
ODS graphics on; 
proc mixed data=ADEFF noclprint plots=residualpanel; 
 
class subjid week ldlcon fbstg trt; 
 
model change=trt week trt*week ldlcon fbstg Baseline/ ddfm=kr; 
            repeated week / subject=subjid type=un; 
 
lsmeans trt*week / cl diff alpha=0.05; 
 
title1 "Linear Mixed Effects Model Based Estimates of XXXX Means by Visit"; 
 
title2 " Fixed Effects for Visit, Randomization Strata and Baseline as Covariates, and  
Treatment by Visit Interaction"; 
run; 
ODS graphics off; 
quit; 
6.2.5.
Median and Confidence Interval Estimation Methods 
Hodges Lehmann estimation will be used to provide estimators of the median and 95% CIs for 
the median. 
6.2.6.
Dose Trend Methods 
The Joncheere-Terpstra (JT) approach will be used to provide an estimate of relationship 
between change in LDLc from DB Baseline to Week 16 and dose level. 
Example SAS code as follows:  
ODS graphics on; 
proc freq data=ldlchg; 
Tables trt*chg/out=jtpval jt; 
Title1 “Jonckheere-Terpstra Trend Test for Continuous Data”; 
Run; 
ODS graphics off; 


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6.2.7.
Geometric (Natural Log Transformed) Summaries  
To calculate a geometric mean and corresponding 95% CI, the following steps are used: 
x
Transform the data by taking natural logarithms (loge) 
x
Calculate the mean and 95% CI of the loge-transformed data 
x
Exponentiate the mean and the lower and upper CIs back to the original scale to 
obtain the geometric mean and corresponding 95% CI 
6.2.8.
Multiple Comparisons/Multiplicity 
As this is a descriptive study, no formal adjustments for multiple comparisons are being made.  
Therefore, CIs and p-values will be interpreted as purely descriptive. 
6.2.9.
Subgroup Analyses 
The following subgroups will be assessed for some specific endpoints as noted.   
Diabetes status (Yes/No) – defined as subjects with any condition in the Endocrine/Metabolic 
body system and medical term is coded to ‘Type 2 diabetes melitus’. 
Antihypertensive medication use (Yes/No) – Anatomical Therapeutic Chemical (ATC) codes 
starting with ‘C02’; for blood pressure endpoints. 
Prior statin medication use (Yes/No) – collected on eCRF Statin Use History; for lipoprotein 
evaluations. 
If less than 10% of the ITT population subjects are not included in a subgroup, the subgroup 
analysis will not be performed.   
6.3.
Data Handling 
6.3.1.
Baseline Values 
Baseline values are defined as the last value (using fasting blood sample values for lipoprotein 
and plasma glucose) prior to administration of investigational product on Day 1 (predose). 
6.3.2.
Missing Data 
Primary analysis of efficacy endpoints will utilize observed data only; missing values will not be 
imputed.  A sensitivity analysis using a last observation carried forward (LOCF) approach may 
be considered.  If performed, the LOCF imputation will replace any missing value from a DB 
post-Baseline visit with the last available non-missing value from a DB post-Baseline visit. 
6.3.3.
Partial Dates 
If only a partial date is available and is required for a calculation, the following standards will be 
applied: 
x
Diagnosis date (eg, NASH diagnosis date) 

For missing day only: Day will be imputed as the first day of the month (ie, 01). 


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
For missing day and month: Day and month will be imputed as the first day of the 
year (ie, 01 January). 
x
Start dates (eg, AE onset date or start date of medication) 

For missing start day only: Day will be imputed as the first day of the month 
(ie, 01) with the following exception:  if the partial date falls in the same month 
and year as the date being used in the calculation (eg, first dose date, informed 
consent date), then the partial date will be imputed to equal the date being used 
for the calculation. 

For missing start day and month: Day and month will be imputed as the first day 
of the year (ie, 01 January) with the following exception:  if the partial date falls 
in the same year as the date being used in the calculation (eg, first dose date, 
informed consent date), then the partial date will be imputed to equal the date 
being used for the calculation. 

For missing start day, month, and year: Date will be imputed to the date being 
used in the calculation (eg., first dose date, informed consent date).   

Imputed start dates must be prior to the stop date. 
x
Stop dates (eg, AE resolution date or stop date of medication) 

For missing stop day only: Day will be imputed as the last day of the month 
(ie, 28, 29, 30, or 31). 

For missing stop day and month: Day and month will be imputed as the last day 
of the year (ie, 31 December). 

For missing stop day, year, and month: Date will be imputed as date of 
completion or discontinuation in the DB phase.   

Imputed dates should not extend beyond the date of completion or discontinuation 
of the DB phase. 

Imputed stop dates must be on or after the start date. 
6.3.4.
Data Conventions 
Unless otherwise specified, in summary tables of continuous variables, the minimum and 
maximum values will be displayed to the same number of decimal places as the raw data, the 
mean, median, and IQR will be presented to 1 extra decimal place compared to the raw data, and 
the SD, SEM, LS Mean, and CIs will be displayed to 2 extra decimal places compared to the raw 
data.  Coefficient of variation will be displayed with one decimal place.   
The concentration versus time data as reported by the respective bioanalytical laboratory should 
be used without rounding for all analyses.  The bioanalytical generated tables should not be 
reported to any greater accuracy than that of the concentration data.  Default significant figures 
used for bioanalytical tables is three significant figures, with exception to time related parameters 
which will be reported as two decimal places. 


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Rounding will only occur after all calculations have been incorporated.  For tables where 
rounding is required, rounding will be done to the nearest round-off unit; for example, when 
rounding to the nearest integer, values ≥XX.5 will be rounded up to XX + 1 (eg, 97.5 will round 
up to 98), whereas values <XX.5 will be rounded down to XX (eg, 97.4 will round down to 97).  
Percentages based on frequency counts will be based on available data, and denominators will 
generally exclude missing values unless some form of imputation is defined or a ‘missing’ 
category is presented.  For frequency counts of categorical variables, categories with zero counts 
will be displayed for the sake of completeness.  For example, if none of the subjects discontinue 
due to “lost to follow-up,” this reason will be included in the table with a count of zero.  
Percentages based on frequency counts will be presented as a whole number (no decimal places), 
and values less than 1% will be presented as “<1%.”  Values less than 100% but that round up 
from 99.5% to 100% will be presented as “>99%.” 
6.3.5.
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
x
Days: A duration expressed in days between one date (date1) and another later date 
(date2) will be calculated using the following formulas: 
duration in days = date2 – date1 + 1, where date2 ≥ date1 
duration in days = date2 – date1, where date2 < date1 
x
Months: A duration expressed in months is calculated as the number of days divided 
by 365.25 / 12. 
x
Years: A duration expressed in years between one date (date1) and another date 
(date2) is calculated using the following formulas: 
duration in years = (date2 – date1 + 1)/365.25, where date2 ≥ date1 
duration in years = (date2 – date1)/365.25, where date2 < date1 
x
Age: Age is calculated as the number of years from the date of birth (DOB) to the 
specified date, eg, date of informed consent (DOIC).  If the month of DOIC < month 
of DOB or the month of DOIC=DOB and the day of DOIC < day of DOB, then the 
following formula is used: 
age (years) = year of DOIC – year of DOB – 1 
Otherwise, the following formula is used: 
age (years) = year of DOIC – year of DOB 
x
Height: Height measured in inches (in) are converted to centimeters (cm) using the 
following formula:  
height (cm) = height (in) × 2.54 
x
Weight: Weight measured in pounds (lb) are converted to kilograms (kg) using the 
following formula: 
weight (kg) = weight (lb) / 2.2046 


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x
Temperature: Temperature measured in degrees Fahrenheit are converted to degrees 
Celsius using the following formula:  
temp (degrees Celsius) = 5 / 9 × (temp [degrees Fahrenheit] – 32) 
x
Body Mass Index (BMI): BMI is calculated using height (cm) and weight (kg) using 
the following formula: 
BMI (kg/m2) = weight (kg) / ([height (cm)/100]2) 
x
Change from Baseline: Change from Baseline is calculated as:  
change from Baseline = post-Baseline value – Baseline value 
x
Percentage Change from Baseline: Percentage change from Baseline is calculated 
as:  
percentage change from Baseline = 100 u ([post-Baseline value – Baseline value] 
/ Baseline value)  
x
Geometric Mean: In order to calculate a geometric mean and corresponding 95% CI, 
the following steps are used: 

Transform the data by taking natural logarithms (loge) 

Calculate the mean and 95% CI of the loge-transformed data 

Exponentiate the mean and the lower and upper CIs back to the original scale in 
order to obtain the geometric mean and corresponding 95% CI. 
The geometric coefficient of variation (geometric CV%) is calculated as   
100 u sqrt(eSD^2-1) where SD is the SD of the loge-transformed data.  
x
Coefficient of Variation - The coefficient of variation (CV%) will be calculated as 
the ratio of the standard deviation to the arithmetic mean using the following formula: 
6.3.6.
Cardiovascular Risk Scores Calculations 
Cardiovascular risk scores (ie, FRS and Reynolds) will be calculated at the time of data analysis 
using data collected via the Baseline Tobacco Use, Family Cardiovascular History eCRFs, and 
the central laboratory data.  The calculations are as follows: 
FRS: 
The 10-year cardiovascular disease risk (%) for women = [1 −  0.95012exp(B - 26.1931)] × 100%, 
where 
B = 2.32888 × natural logarithm (age) + 1.20904 × natural logarithm (total cholesterol) – 
0.70833 × natural logarithm (high-density lipoprotein cholesterol) + 2.76157 × natural logarithm 
(systolic blood pressure if not treated) + 2.82263 × natural logarithm (systolic blood pressure if 
treated) + 0.52873 (if current smoker) + 0.69154 (if diabetic)  


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The 10-year cardiovascular disease risk (%) for men = [1 − 0.88936exp(B - 23.9802)] × 100%, where
B = 3.06117 × natural logarithm (age) + 1.2370 × natural logarithm (total cholesterol) – 0.93263 
× natural logarithm (high-density lipoprotein cholesterol) + 1.93303 × natural logarithm (systolic 
blood pressure if not treated) + 1.99881 × natural logarithm (systolic blood pressure if treated) + 
0.65451 (if current smoker) + 0.57367 (if diabetic) [Framingham Heart Study 2016]. 
Reynolds Score: 
The 10-year cardiovascular disease risk (%) for women = [1 − 0.98634(exp (B − 22.325)] × 100%, 
where 
B = 0.0799 × age + 3.137 × natural logarithm (systolic blood pressure) + 0.180 × natural 
logarithm (high-sensitivity C-reactive protein) + 1.382 × natural logarithm (total cholesterol) 
−1.172 × natural logarithm (high-density lipoprotein cholesterol) + 0.134 × hemoglobin A1c (%) 
(if diabetic) + 0.818 (if current smoker) + 0.438 (if family history of premature myocardial 
infarction) [Ridker, 2007]. 
The 10-year cardiovascular disease risk (%) for men = [1 − 0.8990 exp (B − 33.097)] × 100%, where  
B = 4.385 × natural logarithm(age) + 2.607 × natural logarithm(systolic blood pressure) + 0.963 
×natural logarithm(total cholesterol) − 0.772 × natural logarithm(high-density lipoprotein 
cholesterol) + 0.405 (if current smoker) + 0.102 × natural logarithm(high-sensitivity C-reactive 
protein) + 0.541 (if parental history of premature myocardial infarction) [Ridker, 2008]. 
6.3.7.
Fibrosis Scores Calculations 
Fibrosis scores (ie, NFS and APRI) will be calculated at the time of data analysis using data 
collected via the Medical History eCRF and the central laboratory data.  The calculations are as 
follows: 
NFS = -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × impaired fasting 
glucose(fasting glucose ≥110 mg/dL) / diabetes (yes = 1, no = 0) +  0.99 × AST/ALT ratio – 
0.013 × platelets (×109/L) – 0.66 × albumin (g/dL) 
APRI = ((AST(IU/L)/AST upper limit of normal)/ platelets (x109/L)) x 100 
FIB-4 = (Age (years) x AST(IU/L))/(Platelets(x109/L) x sqrt(ALT(IU/L))) 
BARD score is calculated by designating 0 to 2 points to the following parameters: BMI ≥ 28 
kg/m2 = 1 point, BMI < 28 kg/m2 = 0 point; AST/ALT ratio ≥ 0.8 = 2 points, AST/ALT ratio 
< 0.8 = 0 point; freshly recognized or preexisting diabetes mellitus type 2 = 1 point.  A total of 2 
to 4 points indicates significant fibrosis. 
6.3.8.
Anomalous Concentration Handling  
Anomalous concentration values are those that, after verification of bioanalytical validity, are 
grossly inconsistent with the known or expected pharmacokinetic behavior of the drug.  If an 
entire profile appears inconsistent with those of other subjects or previous periods, then the 
clinical pharmacologist/pharmacometrician will use her/his discretion regarding the handling of 
this data.  The rationale will be documented within the CSR.  Any such anomalous concentration 
data will also be identified in the relevant tables or as a stand-alone table of the CSR. 


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7.
ANALYSIS POPULATIONS 
7.1.
Randomized Population  
7.2.
Intent-to-Treat (ITT) Population 
All randomized subjects who receive any amount of investigational product within the DB phase 
will be included in the ITT Population.  Treatment assignment will be based on the randomized 
treatment allocation.   
7.3.
Safety Population 
The Safety Population will include all subjects who receive any amount of investigational 
product within the DB phase.  Treatment assignment will be based on the actual treatment 
received. 
7.4.
Efficacy Evaluable (EE) Population 
All subjects who complete the DB phase according to the indicated doses of investigational 
product and atorvastatin without any major protocol deviations that potentially affect the efficacy 
of the study drug will be included in the EE Population, which is the primary population used for 
efficacy analyses.  If greater than 20% of the ITT Population subjects have such deviations as 
determined prior to database lock of the DB (see Section 8.2), then all efficacy analyses and 
selected other summaries will be repeated using the ITT Population. 
7.5.
OCA Pharmacokinetic (PK) Population 
The PK Population will include all OCA treated subjects who consent to participate in the PK 
assessments and have at least one confirmed fasted OCA concentration.  Subjects must have 
been fasting for at least 8 hours prior to dosing and must not have any major protocol deviations 
that potentially affect exposure levels.     
8.
STUDY POPULATION 
8.1.
Subject Disposition 
Subject disposition information will be summarized and listed for all subjects.  Summaries will 
include the following: the number of subjects randomized, the number of subjects in each 
analysis population, the number of subjects at each study site, the number of subjects completing 
the DB phase (Week 16) and each scheduled visit (Week 2, 4, 8, and 12), the primary reason for 
discontinuation from the DB phase, and the number of subjects enrolling in the LTSE.  A subject 
will be considered as completing the DB phase if the subject has non-missing assessment of LDL 
metabolism at all scheduled visits (Weeks 2, 3, 4, 12, and 16).  Percentages will be based on the 
ITT Population. 
The reasons for discontinuation of investigational product (OCA/PBO) and discontinuation of 
study atorvastatin will be summarized in a similar manner.   


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8.2.
Protocol Deviations 
Protocol deviations for missed visits, missed assessments, out of window visits or assessments, 
and violations of inclusion/exclusion criteria will be determined based on available data.  The 
clinical research associates will collect all other protocol deviations.  Major protocol deviations 
identified during the DB phase that could potentially affect the conclusions of the study or result 
in a subject’s removal from an analysis population will be classified as such prior to database 
lock of the DB phase.  Major protocol deviations will be summarized by deviation category and 
treatment group.  All protocol deviations and their classifications will be presented in a listing.  
Subjects with protocol deviations that result in a subject’s removal from the ITT, Safety, EE, or 
PK Populations will be flagged in a listing. 
8.3.
Demographic and Baseline Characteristics 
Demographic variables will include the following:  
x
Age at informed consent 
x
Age at informed consent categorized as < 65 years and ≥ 65 years  
x
Sex 
x
Race/ethnicity 
Other Baseline characteristics will include the following:  
x
Weight (kg)  
x
Height (cm) at Screening visit 
x
BMI (kg/m2) 
x
BMI categorized as < 30 kg/m2 and ≥ 30 kg/m2
x
Liver fibrosis stage using NASH Clinical Research Network (CRN) scoring criteria 
categorized as Stage 1a, 1b, 1c, 2, 3, 4 
x
Liver fibrosis stage using NASH CRN scoring criteria categorized as Stage 1, 2 and 
Stage 3, 4 
x
Liver fibrosis stage using modified Ishak scoring criteria categorized as Stage 1, 2, 3, 
4, 5, 6 
x
NAFLD Activity Score (NAS) and its components categorized as:  

Steatosis:  0, 1, 2, 3 

Hepatocellular Ballooning: 0, 1, 2 

Lobular Inflammation: 0, 1, 2, 3 
x
NAS categorized as < 6 and ≥ 6 total points 
x
Diabetes status: Yes, No (defined as subjects with any condition in the 
Endocrine/Metabolic body system and medical term containing “diabetes type II” or 


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similar derivative, as collected on the eCRF Medical History; if unable to determine 
what type of diabetes, set diabetes status to yes)  
x
Concomitant medication use (ongoing on Day 1.  If it cannot be determined whether 
the medication was ongoing at the Day 1 visit due to a partial start or stop date, then it 
will be counted as ongoing.) 

Vitamin E (ATC codes = ‘A11HA’ and Trade name = ‘E VITAMIN’) 

TZD (ATC codes starting with ‘A10BG’) 

Antidiabetic medication (ATC codes starting with ‘A10’) 

Antihypertension medication (ATC codes starting with ‘C02’)   
x
Screening fasted serum LDL cholesterol concentration categorized as ≤ and 
> 125 mg/dL 
x
Screemomg HDL cholesterol concentration (mg/dL) categorized as ≥ lower limit of 
normal (LLN), < LLN 
x
Baseline liver function test results as a continuous variable and categorized as follows 
by the LLN and the upper limit of normal (ULN) unless otherwise specified: 

ALT: ≤ 40 U/L, > 40 U/L and ≤ ULN, > ULN 

AST: ≤ 40 U/L, > 40 U/L and ≤ ULN, > ULN 

Direct Bilirubin: ≤ ULN, > ULN 

Total Bilirubin: ≤ ULN, > ULN 

Platelets: ≥ LLN, < LLN 
Arithmetic summary statistics as described in Section 6.2.1 will be presented for age, weight, 
height, BMI, and key liver function tests.  Frequency counts and percentages will be presented 
for age groups, sex, race/ethnicity, BMI categories, liver fibrosis stage categories, NAS, 
concomitant medication use, diabetes status, LDL and HDL cholesterol categories, and key liver 
function test categories.  Race and ethnicity will be summarized as follows: 
x
Race 

American Indian or Alaska Native 

Asian 

Black or African American 

Native Hawaiian or Other Pacific Islander 

White 
x
Ethnicity 

Hispanic or Latino 

Not Hispanic or Latino 


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
Not reported 

Unknown 
Demographic and Baseline characteristics will be summarized for the ITT, Safety, PK, and EE 
Populations (if warranted).  All demographic and Baseline characteristics will be presented in 
data listings. 
8.4.
NASH Disease History 
Baseline NASH disease characteristics will be summarized using data collected from the 
Medical History eCRF.  Assessments include the following: 
x
Age at NASH diagnosis 
x
Age at NASH diagnosis categorized as < 50 years and ≥ 50 years  
x
Duration of NASH in years at time of informed consent 
x
Duration of NASH categorized as ≤ median years and > median years 
x
Method of confirmation for NASH diagnosis categorized as liver biopsy, elevated 
liver enzymes, non-invasive imaging, or other. 
Arithmetic summary statistics as described in Section 6.2.1 will be presented for the age at 
NASH diagnosis and the duration of NASH.  All other categorical NASH disease characteristics 
will be summarized using frequency counts and percentages.  NASH disease history will be 
summarized for the ITT Population and, if warranted, the EE Population.  NASH disease history 
will be presented in a data listing. 
8.5.
Alcohol Use Disorders Identification Test (AUDIT) 
Baseline, Day 1, Week 16, and Early Termination/End of Study AUDIT scores will be 
summarized using arithmetic summary statistics as described in Section 6.2.1 and presented in a 
data listing. 
8.6.
Tobacco Use 
Arithmetic summary statistics as described in Section 6.2.1 will be presented for duration of use 
(among former and current users) and amount of daily cigarette, cigar, smokeless tobacco 
(amount of pinches), pipe (amount of pipefuls), and other tobacco use (among former and current 
users) at Screening.  Frequency counts and percentages will be presented for tobacco use 
(Yes/No) and frequency of use for each type of tobacco (among former and current users).  
Tobacco use data will be presented in a data listing. 
8.7.
Statin History 
Baseline statin history use characteristics will be summarized using data collected from the 
Statin History Use eCRF.  Assessments include the following: 
x
Statin use (Yes/No) 
x
Name of statin used 


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x
Last statin medication dose 
x
Duration of statin use (years) 
x
Primary reason statin stopped 
All categorical statin history will be summarized using frequency counts and percentages.  
Overall statin use will be summarized using the ITT Population as the denominator.  The other 
characteristics will be summarized for each statin used with the number of subjects using the 
corresponding statin as the denominator.  The continuous characteristics for each statin will be 
summarized using arithmetic summary statistics as described in Section 6.2.1.  Subjects may 
have used more than 1 statin.  All statin use history data will be listed (including comments). 
8.8.
Family Cardiovascular History 
Baseline family cardiovascular history will be summarized using data collected from the Family 
Cardiovascular History (First Degree) eCRF.  Assessments include the following: 
x
Family history of myocardial infarction, angina or dyslipidemia? (Yes/No)  
x
Person with event (father, mother, brother, sister, other - specify) 
x
Myocardial infarction (Yes/No) and age at time of event (categorical) 
x
Angina (Yes/No) and age at time of event (categorical) 
x
Dyslipidemia (Yes/No) 
All categorical family cardiovascular history will be summarized using frequency counts and 
percentages for the ITT Population.  Subjects may have more than one family member and type 
of event recorded.  All family cardiovascular history data will be listed. 
8.9.
General Medical History 
Verbatim medical history terms on eCRFs will be mapped to preferred terms and system organ 
classes using the Medical Dictionary for Regulatory Activities (MedDRA; version 18.1).  
Frequency counts and percentages of the number of subjects reporting an abnormal Baseline 
medical history will be summarized by MedDRA system organ class and preferred term using 
the ITT Population.   
Summaries that are displayed by system organ class and preferred term will be ordered by 
descending order of incidence for all OCA treated subjects of system organ class and by 
preferred term within each system organ class.  
Medical History data will be presented in a data listing. 
8.10.
Prior and New Concomitant Medications 
Verbatim terms on eCRFs will be mapped to ATC class and preferred term using the World 
Health Organization Drug Dictionary Enhanced (WHODDE; WHO-DDE-B2 Dec2015).  
Pretreatment medications are those medications with start and stop dates prior to the first dose of 
investigational product in the DB phase.  Prior concomitant medications are those medications 
started prior to, and continued after, the first OCA dose in the DB phase.  New concomitant 


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medications are those medications that were started after the first OCA dose in the DB phase.  If 
it cannot be determined whether the medication was a new concomitant medication due to a 
partial start or stop date or if the medication is taken on the same date as the first OCA dose in 
the DB phase, then it will be counted as a new concomitant medication. 
Pretreatment medications will be presented in listings only.  Prior and new concomitant 
medications will be summarized by World Health Organization ATC class and preferred term 
using the ITT Population.  New concomitant medications will be summarized separately.  These 
summaries will present the number and percentage of subjects using each medication.  Subjects 
may have more than 1 medication per ATC class and preferred name.  A subject is counted once 
when 1 or more medications is reported at the ATC class or preferred term level.  Each summary 
table will be ordered by descending order of incidence, for all OCA-treated subjects, of ATC 
class and preferred term within each ATC class. 
Prior and new concomitant medications will be presented in a data listing. 
9.
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will be based on the EE Population.   Analyses on 
the ITT Population will only be performed if greater than 20% of ITT subjects are excluded in 
the EE Population.  All analyses are to be carried out on observed data, as there are no 
imputations planned.  The efficacy data are a result of the centralized, specialized nuclear 
magnetic resonance (NMR) lipoprotein assay and the central laboratory serum chemistry.  All 
analyses of lipoprotein metabolism will include fasted samples only.  For all lipoprotein 
concentration values, the serum chemistry panel results will be used.  For particle size and 
particle concentration, the NMR lipoprotein assay results will be used.  Sensitivity analysis may 
be performed with the NMR lipoprotein concentration results.   
9.1.
Primary Efficacy Analyses 
The primary efficacy analysis, changes in LDLc, LDLs, and LDLpc at Week 16 (end of DB) 
from Baseline will be summarized by treatment group, using the EE Population.   
The observed values, change from Baseline, and percentage change from Baseline will be 
summarized by treatment group and visit using arithmetic summary statistics as described in 
Section 6.2.1.  
In order to provide estimates of the change from Baseline and corresponding 95% CI, the 
ANCOVA methods described in Section 6.2.3 will be applied with change from Baseline as the 
dependent variable, including treatment group, and randomization stratification factor as fixed 
effects and Baseline as a covariate.  The same analysis will be carried out using percentage 
change from Baseline as the dependent variable.  Model fit will be assessed in order to determine 
the validity of the estimates.  Estimates of LS means, SEs, and 95% CIs will be presented by 
treatment group.  
The comparison of LDLc, LDLs, and LDLpc change from baseline and percentage change from 
baseline values between each active treatment group and placebo group at each DB post-
Baseline visit will be performed as exploratory analyses.  Estimates of the LS mean difference 


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between each active treatment group and placebo group, the SE of the difference, and 95% CI of 
the difference will be presented. 
The relationship of OCA dose level and changes in LDLc will be explored using the 
Jonckheere-Terpstra (JT) test.  
Sensitivity analysis for the primary efficacy analysis will be performed using the ITT Population 
using both the ANCOVA methods described in Section 6.2.3 and the ANCOVA with repeated 
measures methods described in Section 6.2.4.   
9.2.
Secondary Efficacy Analyses 
The secondary efficacy parameters will be analyzed in the same manner as the primary efficacy 
variables.  Descriptive statistics will be generated and will include change from Baseline, 
percentage change from Baseline at each DB post-Baseline visit, and estimates of LS means, 
SEs, and 95% CIs presented by treatment group. 
9.2.1.
Lipoprotein Metabolism 
The secondary parameters related to lipoprotein metabolism include HDLc, HDLs, HDLpc, 
VLDLc, VLDLs, VLDLpc, TG, and total cholesterol concentrations; and ApoA1, ApoB, ApoE, 
ApoCII, ApoCIII, Lp(a), and PCSK9 concentrations.     
9.2.2.
Reverse Cholesterol Metabolism 
The secondary parameters related to reverse cholesterol metabolism include pre-β1 HDL 
concentration, macrophage cholesterol efflux, LCAT activity, and CETP activity.   
9.3.
Exploratory Efficacy Analyses 
9.3.1.
Liver Biochemistry and Markers of Liver Function 
The following laboratory parameters will be summarized by treatment group:  albumin, ALP, 
ALT (isoenzymes), AST, direct bilirubin, GGT, INR, total bilirubin, and platelets. 
Analyses of observed laboratory values will be carried out using a repeated measures ANCOVA 
model with change from Baseline as the dependent variable, including treatment group, and 
randomization stratification factors as fixed effects and Baseline as a covariate as described in 
Section 6.2.3.  The same analysis will be carried out using percentage change from Baseline as 
the dependent variable. 
Arithmetic summary statistics as described in Section 6.2.1 will be used to summarize the 
laboratory values by treatment group and visit.  The results, change from baseline, and 
percentage change from baseline, as well as estimates of LS means, SEs, and 95% CIs, will be 
presented by treatment group.  Estimates of the mean difference between each active treatment 
group and placebo group, the SE of the difference, and 95% CI of the difference will be 
presented. 


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9.3.2.
Markers of Liver Inflammation, Hepatic Apoptosis, and Fibrosis 
Markers of liver inflammation, hepatic apoptosis and/or fibrosis include IL-6, hs-CRP, TNF-α, 
CK-18-M30, and CK-18-M65.  These biomarkers will be summarized by treatment group using 
arithmetic summary statistics as described in Section 6.2.1 at Baseline and at each DB post-
Baseline visit.  The absolute and percentage change from Baseline will be analyzed using the 
Wilcoxon Rank Sum Test to compare active treatment groups and placebo.  The median 
differences and 95% CI of the median differences between treatment groups will be constructed 
using a Hodges-Lehmann estimate as described in Section 6.2.5 .  The protocol specifies the Sign 
Test may be used when the median differences between treatments are not symmetrical around 
the median. The median differences between treatments will always be symmetrical, therefore, 
the Sign Test will not be used. 
9.3.3.
Glycemic Control 
Glycemic control measures include fasting glucose, fasting insulin, C-peptide, HbA1c, 
HOMA-β, and HOMA-IR.  These measures will be summarized using arithmetic summary 
statistics as described in Section 6.2.1 at Baseline and at each DB post-Baseline visit by 
treatment group.  The change from Baseline will also be summarized.  Baseline is defined as the 
last fasting assessment prior to the administration time of the first OCA dose.  Treatment groups 
will be compared using an ANCOVA model with change from Baseline as the dependent 
variable, including treatment group, and randomization stratification factors as fixed effects and 
Baseline as a covariate as described in Section 6.2.3.  The same analysis will be carried out using 
percentage change from Baseline as the dependent variable.  Estimates of LS means, SEs, and 
95% CIs will be presented by treatment group.  Estimates of the mean difference between each 
active treatment group and placebo group, the SE of the difference, and 95% CI of the difference 
will be presented.  The distribution of glycemic control measures will be evaluated for normality 
assumptions.  If normality assumptions are violated, non-parametric methods, such as a rank 
ANCOVA model, will be used. 
Subgroup analyses will also be presented by diabetes status, excluding the randomization 
stratification factors from the ANCOVA model. 
9.3.4.
Noninvasive Radiological Liver Fibrosis Measurements 
Noninvasive radiological methods to assess liver stiffness and steatosis via TE will be conducted 
at selected centers where the devices are available.  Liver stiffness values (kPa) and CAP (dB/m) 
values (based on available data) will be summarized by treatment group using arithmetic 
summary statistics as described in Section 6.2.1 at Baseline and at each DB post-Baseline visit.  
Treatment groups will be compared using a ANCOVA model at each visit with change from 
Baseline as the dependent variable, including treatment group and Baseline fibrosis stage based 
on NASH CRN criteria, and randomization stratification factors as fixed effects and Baseline as 
a covariate.   
The proportion of fibrosis improvement based on liver stiffness value will be summarized using 
arithmetic summary statistics as described in Section 6.2.1 by treatment group at Week 16 of the 
DB phase.  Fibrosis improvement is defined as any reduction in liver stiffness value.  Treatment 
groups will be compared using a Cochran–Mantel–Haenszel (CMH) test stratified by the 


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Baseline fibrosis stage based on NASH CRN criteria and randomization strata.  Missing values 
will be considered a nonresponse. 
The correlation of Baseline liver stiffness value with baseline fibrosis stage based on NASH 
CRN criteria (Stage 1, 2 or 3, 4) and modified Ishak scoring criteria (Stage 1, 2, 3, 4, 5, 6) based 
on biopsy will also be assessed using Spearman’s rank correlation coefficient.  Arithmetic 
summary statistics of Baseline liver stiffness by each fibrosis stage scoring will be presented.  A 
box and whisker plot of the data also will be produced.  The correlation analysis and 
corresponding plot will be performed using the ITT population. 
9.3.5.
Noninvasive Scores and NAFLD Liver Fibrosis Scores 
Noninvasive scores of liver fibrosis including FIB-4, APRI, and NFS will be summarized with 
descriptive statistics at Baseline and each DB post-Baseline visit.  In addition, change and 
percentage change will be summarized and analyzed using the Wilcoxon Rank Sum Test to 
compare treatment groups.  The median differences and 95% CI of the median differences 
between treatment groups will be constructed using Hodges-Lehmann estimate.   
In addition, BARD score shift changes from Baseline to each DB post-Baseline visit will be 
summarized by treatment group.  
9.3.6.
Anthropometric Measures and Blood Pressure 
Anthropometric measures (ie, body weight, waist and hip circumference measurements, BMI, 
and waist-to-hip ratio calculations) and blood pressure will be summarized using arithmetic 
summary statistics as described in Section 6.2.1 at Baseline and at each DB post-Baseline visit.  
Change and percentage change from baseline will also be summarized in the same manner.  Re-
tests or unscheduled visit results after the first OCA dose administration time will not be 
summarized but will be included in the data listings.   
Treatment groups will be compared using an ANCOVA model with change from Baseline as the 
dependent variable, including treatment group, and randomization stratification factors as fixed 
effects and baseline as a covariate.  The same analysis will be carried out using percentage 
change from Baseline as the dependent variable.  Estimates of LS means, SEs, and 95% CIs will 
be presented by treatment group.  Estimates of the mean difference between each active 
treatment group and placebo group, the SE of the difference, and 95% CI of the difference will 
be presented. 
Subgroup analyses will also be presented by diabetes status, excluding the randomization 
stratification factors from the ANCOVA model.  Subgroup analyses of blood pressure will also 
be presented by use of antihypertensive medications. 
9.3.7.
Cardiovascular Risk Scores 
Cardiovascular risk scores including FRS and Reynolds scores will be calculated at the time of 
data analysis using the formulas in Section 6.3.6.  These scores will be summarized by treatment 
group and sex using arithmetic summary statistics as described in Section 6.2.1 at Baseline and 
at each DB post-Baseline visit.  The change and percentage change from Baseline will also be 
summarized. 


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9.3.8.
Cardiovascular Markers of Risk 
Cardiovascular markers of risk including adiponectin, PAI-1, and BNP will be summarized by 
treatment using arithmetic summary statistics as described in Section 6.2.1 at Baseline and at 
each DB post-Baseline visit.  The change and percentage change from Baseline will also be 
summarized. 
While the protocol states PAI-1 and BNP will be stored for future analysis, it was later 
determined the samples would not maintain stability for future analysis, and thus were assayed 
for analysis.   
10.
EXPLORATORY PHARMACOKINETIC AND 
PHARMACODYNAMIC ANALYSIS 
Total OCA will be calculated as the micromolar concentration sum of unconjugated OCA, glyco-
OCA, and tauro-OCA.  Concentrations will be converted from ng/mL units to micromolar units 
as follows:  concentration (µM) = concentration (ng/mL) / molecular weight (MW).  The MW 
weights for OCA are as follows:  unconjugated OCA = 420.6 g/mol, glyco-OCA = 477.7 g/mol, 
and tauro-OCA = 527.8 g/mol.  Total OCA in micromolar units can be converted to mass 
equivalents of OCA as follows: concentration (ng/mL) = concentration (µM) * 420.6. The PK 
Population will be used in the analyses of OCA PK (Day 1 and Week 16).  
Further population PK/PD analyses may be conducted utilizing a separate appropriate plan to 
describe analysis methods.  The methods and results would be included in a separate report. 
10.1.
Pharmacokinetic Measures 
At selected investigational sites, subjects will have the option to provide blood samples for 
measurement of OCA concentrations.  On Day 1 and Week 16, PK samples will be collected 
within 30 minutes prior to dosing (predose) and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours 
postdose.  Subjects should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until the 1-hour sample is collected. 
10.2.
Pharmacokinetic Data Handling 
10.2.1.
Missing Values 
The lack of concentration values or dosing information due to failure to collect the sample or 
dosing information, a lost or compromised sample or due to the subject’s early termination from 
the study may be termed “missing” in the dataset. If a missing value occurs for the time point 
prior to the first study drug administration, the value is set to zero. Otherwise, no imputation of 
missing values will be performed.  
10.2.2.
Results Below Limit of Quantification (BLQ) 
For the purposes of PK parameter estimation, the following rules for BLQ results will be 
followed: 
x
BLQ values that occur prior to the first quantifiable concentration will be set to zero 


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x
BLQ values occurring between two quantifiable values will be set to the lower limit 
of quantification (LLOQ) divided by 2 
x
BLQ values occurring after the last quantifiable value will be set to missing 
10.2.3.
PK Sampling Times 
Actual (rather than nominal) PK sample collection times will be used for the purposes of PK 
parameter estimation. 
10.2.4.
Decision Paradigm for Reprocessing Samples 
The PK sample reprocessing paradigm will be detailed in the bioanalytical report. Intercept 
Clinical Pharmacology may issue a request for sample reprocessing if an observed concentration 
represents an unexplained, significant deviation from temporal consistency with the prior and 
following samples in the affected subject’s concentration-time profile.  Reprocessing will only 
take place if sufficient sample volume exists. 
10.2.5.
Anomalous Concentration Handling 
Anomalous concentration values are those that, after verification of bioanalytical validity, are 
grossly inconsistent with the known or expected pharmacokinetics behavior of the drug. The 
clinical pharmacologist will use his/her discretion regarding the handling of this data. The 
rationale will be documented within the study report. Any such anomalous concentrations data 
will be documented in the clinical study report. 
10.2.6.
Representation of Mean Concentrations 
All values reported as below the limit of quantitation (BLQ) will be replaced with zero for mean 
representation in figures.  In the tables presenting summary statistics of concentration-time 
series, the total number of values (n) and the number of values that are BLQ will be presented to 
allow appropriate interpretation of the data.  
If missing observations at a nominal time point exceed 50% of the observations collected at that 
nominal time point, summary statistics for the time point will not be calculated.  
If the mean concentration value is less than the LLOQ, then the mean concentration value will be 
set to BLQ in tables and missing in graphics. 
The central tendency and dispersion of OCA (and its conjugates and metabolite) 
concentration-time data will be graphically represented as the Mean (optional +/- SD) by 
nominal time point in linear scale and semi-log scale by visit.  Median by nominal time point 
representations may also be presented if deemed appropriate. 
PK samples that have a significant time deviation from the planned sampling time will be 
considered as “missing” for the calculation of concentration summary statistics at that nominal 
time point.  Acceptable PK sampling time windows are defined in the table below: 
Nominal PK Sampling Time  
Acceptable Sampling Window 


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Pre-dose 
Within 30 minutes prior to dosing 
0.5 h, 0.75 h 
+/- 5 minutes relative to nominal 
1 h 
+/- 10 minutes relative to nominal 
1.5h,  2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h 
+/- 15 minutes relative to nominal 
Only samples from subjects with confirmed fasting of ≥ 8 hours prior to dosing will be included 
in summaries.  Individual subject plasma concentrations, including derived concentrations for 
total OCA, will be listed by analyte and formulation and summarized with descriptive statistics 
on Day 1 and on Week 16 by treatment group as defined in Section 6.2.1 and Section 6.2.7, 
including geometric coefficient of variation (CV%).   
10.3.
Pharmacokinetic Analysis  
10.3.1.
Pharmacokinetic Methods 
PK parameters for OCA and its conjugates, and total OCA will be determined using standard 
non-compartmental methods.  Pharmacokinetics will be summarized in tabular and graphical 
forms.  The primary PK parameter estimations in this study are:  
For both Day 1 and Week 16: 
x
Cmax (ng/mL):  Maximum observed concentration obtained by inspection of the data.  
If all observations are below the limit of quantification (BLQ), Cmax will be reported 
as zero.  
x
tmax (h):  First time at which Cmax is observed and is obtained by inspection of the 
data.  If all observations are BLQ, tmax will be reported as not determined (ND). 
x
AUC0-6 (hr*ng/mL): Area under the concentration versus time curve from zero time 
until the last sampling time (hour 6).  

The linear interpolation rule should be used for estimation of area under the 
concentration-time curve (AUC).  

Where the clinical pharmacologist identifies that another method is more 
appropriate, the reason for this decision should be documented.  

A minimum of 4 measurable values are required for AUC calculation 

For last sampling times >6 hours, AUC0-6 will be interpolated. For last sampling 
times from 5.75 to 6 hours, AUClast will be reported for AUC0-6. For last sampling 
times <5.75 hours, AUC0-6 will not be reported.  
x
Dose-normalized versions of Cmax and AUC0-6 will be calculated for Day 1 and Week 
16. 


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x
Metabolite ratios based on Cmax (MRCmax) and AUC0-6 (MRAUC0-6) will be 
calculated: 
MR Cmax = (Cmax conjugate or metabolite / Cmax parent) x (molecular weight parent / 
molecular weight conjugate or metabolite) 
MR AUC0-6 = (AUC0-6 conjugate or metabolite / AUC0-6 parent) x (molecular weight 
parent / molecular weight conjugate or metabolite)
Accumulation [only for OCA and its conjugates]: 
x
Steady-state accumulation ratios based on Cmax (Rac Cmax) and AUC0-6 (Rac AUC0-6) 
will be calculated: 
  
Rac Cmax = Week 16 Cmax/Day 1 Cmax
 
 
Rac AUC0-6 = Week 16 AUC0-6/Day 1 AUC0-6
Additional parameters may be calculated in order to further characterize PK, if deemed 
necessary. 
10.3.2.
Reporting and Significant Figures 
The concentration data as reported by the respective bioanalytical group should be used without 
rounding for all analysis.  The non-compartmental parameters should not be reported to any 
greater accuracy than that of the concentration data.  Default significant figures used for 
reporting in text and tables of the study report is 3 significant figures, except for time related 
parameters (h) and for geometric least squares mean ratios.  Time related parameters (h) which 
will be presented with 2 decimal places.  Geometric least squares ratios will be presented with 2 
decimal places.  
In the instance where the full parameters set (as defined in the analysis plan) cannot be 
estimated, the parameters that can be estimated will be reported.  The term “NR” (not reported) 
may be used to denote that a value cannot be reported for a particular profile. 
10.4.
Pharmacokinetic/Pharmacodynamic (PK/PD) Analyses 
The PK population will be used for all PK analyses.  The ITT population will be used for all PD 
analyses.  Using the PK population, scatter plots of the Week 16 actual values and change from 
Baseline in LDL cholesterol, particle size, and particle concentration, C4, FGF-19, and hs-CRP 
will be created versus total OCA plasma AUC0-6 and Cmax.  Additional PK/PD correlations may 
be identified and reported as deemed appropriate. 
10.5.
Bile Acid Pharmacodynamics 
Analysis of conjugated and unconjugated bile acids may be undertaken per the protocol. 
Bile acids include the following:  total bile acids, UDCA (unconjugated-UDCA, glyco-UDCA, 
tauro-UDCA), chenodeoxycholic acid (CDCA) (unconjugated-CDCA, glyco-CDCA, 
tauro-CDCA), lithocholic acid (LCA) (unconjugated-LCA, glyco-LCA, tauro-LCA), cholic acid 
(CA) (unconjugated-CA, glyco-CA, tauro-CA), and deoxycholic acid (DCA) 
(unconjugated-DCA, glyco-DCA, tauro-DCA).   


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The bile acid assay comprises 15 sub-component bile acid concentrations that will be used to 
create totals of the individual bile acid concentrations.  Bile acid concentrations will be 
converted from ng/mL units to micromolar units (µM) as follows:  Concentration (µM) = 
Concentration (ng/mL) / molecular weight (MW).  Bile acids totals should be summed on a 
molar basis (eg µM).  The MWs of the bile acids and their conjugates are presented in Table 1.  
For each bile acid, the assay will provide 3 subcomponent values that will need to be summed to 
produce the total bile acid value, as shown below in Table 1.  As an example, the total UDCA 
concentration would be the sum of the glyco-, tauro-, and parent molecules. 
Table 1: 
Bile Acids and Their Sub-Components 
Derived  
Sub-components (molecular weight) 
Total UDCA 
Glyco-UDCA 
(449.6 g/mol) 
Tauro-UDCA 
(499.7 g/mol) 
UDCA 
(392.6 g/mol) 
Total CDCA 
Glyco-CDCA 
(449.6 g/mol) 
Tauro-CDCA 
(499.7 g/mol) 
CDCA 
(392.6 g/mol)  
Total DCA 
Glyco-DCA 
(449.6 g/mol) 
Tauro-DCA 
(499.7 g/mol) 
DCA 
(392.6 g/mol) 
Total CA 
Glyco-CA 
(465.6 g/mol) 
Tauro-CA 
(515.7 g/mol) 
CA 
(408.6 g/mol) 
Total LCA 
Glyco-LCA 
(433.6 g/mol) 
Tauro-LCA 
(483.7 g/mol) 
LCA 
(376.6 g/mol) 
Individual total bile acids are derived as the sum of all bile acids (total UDCA, total CDCA, total 
DCA, total CA, and total LCA). 
Total endogenous bile acids are derived as the sum of all bile acids, excluding all forms of OCA 
and UDCA. 
Proportions of each bile acid are derived as the individual bile acid total divided by total bile 
acids (eg, total UDCA/total bile acids). 
The ITT population will be used to summarize the total bile acid concentrations.  The total bile 
acids, total endogenous bile acids, individual bile acid totals, and each of the bile acid 
proportions will be summarized by treatment group using descriptive statistics.  BLQ values will 
be treated as one-half the lower limit of quantification [(LLOQ/2)].  For total UDCA and total 
endogenous bile acid, the change from Baseline concentrations within each treatment group will 
be compared using a paired t-test.  Only samples from subjects that have a confirmed fasting 
(based on eCRF) of approximately 8 hours or more prior to the subject’s visit will be included in 
the analysis.   
11.
SAFETY ANALYSES 
All safety analyses will be based on the Safety Population.  The AE, vital signs, clinical 
laboratory evaluations, and ECG analyses are defined as secondary endpoints per the protocol.  
The anthropometric measures, blood pressure, and cardiovascular risk scores are defined as 
exploratory efficacy endpoints per the protocol. 


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11.1.
Extent of Exposure 
11.1.1.
Investigational Product (OCA or Placebo) 
Subjects may change their OCA or placebo dosing regimen while on treatment during the DB if 
deemed necessary by the Investigator.  The duration of investigational product exposure at DB 
will be calculated as follows: 
x
Exposure to investigational product = {[(Date of last investigational product dose –
Date of 1st investigational product dose) +1] 
Total investigational product (mg) exposed to subject will be calculated by adding the doses 
taken by a subject during the study and will be summarized using descriptive statistics. 
Subject’s overall compliance (%) with investigational product will be calculated as follows: 
x
(# of investigational product tablets consumed during study / # of investigational 
product tablets expected to be consumed during study) u 100 
where # of investigational product tablets consumed during study = # of days on treatment based 
– any missed doses, and # of investigational product tables expected to be consumed during 
study is the total # of days on study drug based on treatment start and stop dates, excluding drug 
holidays 
Subject compliance with investigational product will be summarized by treatment group using 
descriptive statistics.  Percent compliance will be summarized separately for subjects who 
completed the study versus those who withdrew early so as to distinguish between those subjects 
who were compliant throughout the entirety of the study versus those who were compliant until 
they withdrew from the study.   
Additional summaries will present the number and percentage of subjects with any drug 
interruption and drug discontinuation. Denominators for calculating percentages will be based on 
the number of subjects who received at least one dose in the treatment group summarized. 
All exposure data will be presented in a by-subject data listing. 
11.1.2.
Atorvastatin 
The weighted average daily dose (WADD) of atorvastatin, the study medication, will be 
calculated as: 
WADD
(dose × number of days at specified dose)
all doses
For example, for a subject on 10 mg atorvastatin for 6 weeks and 20 mg atorvastatin for 6 weeks 
without any days off atorvastatin, WADD would be calculated as: 
WADD = [(10 mg × 42 days) + (20 mg × 42 days)]/ (84 days) = 15 mg 
The WADD will also be categorized as ≤ 12 mg atorvastatin, > 12 mg to 20 mg atorvastatin, 
>20 mg atorvastatin. 
Subject’s overall compliance (%) with study medication will be calculated as follows: 


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x
(# of study medication tablets consumed during study / # of study medication tablets 
expected to be consumed during study) u 100 
Subject compliance with atorvastatin will be summarized by treatment group using descriptive 
statistics.  Percent compliance will be summarized separately for subjects who completed the 
study versus those who withdrew early so as to distinguish between those subjects who were 
compliant throughout the entirety of the study versus those who were compliant until they 
withdrew from the study. 
Additional summaries will present the number and percentage of subjects with any drug 
interruption and drug discontinuation. Denominators for calculating percentages will be based on 
the number of subjects who received at least one dose in the treatment group summarized. 
All exposure data will be presented in a by-subject data listing. 
11.2.
Adverse Events (AEs) 
AE data will be collected from the time that signed informed consent is obtained until the subject 
fully completes her/his study participation of the study.   
Pre-treatment AEs and treatment-emergent adverse events (TEAEs) will be summarized.  TEAEs 
are defined as any AEs that newly appear, increase in frequency, or worsen in severity following 
initiation of investigational product.  If it cannot be determined whether the AE is Treatment-
Emergent due to a partial onset date, then it will be counted as treatment-emergent.  Verbatim 
terms on eCRFs will be mapped to preferred terms and system organ classes using MedDRA 
(version 18.1).  
Summaries that are displayed by system organ class and preferred terms will be ordered by 
descending order of incidence, for all OCA-treated patients, of system organ class and by 
preferred terms within each system organ class.  Summaries of the following types will be 
presented by treatment group: 
x
Overall summary of TEAEs 
x
Subject incidence of pre-treatment AEs and the total number of entries by MedDRA 
system organ class and preferred term 
x
Subject incidence of TEAEs and the total number of entries by MedDRA system 
organ class and preferred term     
x
Subject incidence of drug-related TEAEs by MedDRA system organ class and 
preferred term.  Related AEs are those with relationships reported as “Definite,” 
“Probable,” “Possible,” or with a missing relationship.  This analysis will be 
performed for relationship to investigational product and to atorvastatin. 
x
Subject incidence of liver biopsy-related TEAEs by MedDRA system organ class and 
preferred term.  Related AEs are those with relationships reported as “Definite” or 
AEs with a missing relationship.   
x
Subject incidence of serious TEAEs by MedDRA system organ class and preferred 
term  


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x
Subject incidence of TEAEs leading to investigational product withdrawal by 
MedDRA system organ class and preferred term   
x
Subject incidence of TEAEs leading to study medication withdrawal by MedDRA 
system organ class and preferred term 
x
Subject incidence of TEAEs leading to study discontinuation by MedDRA system 
organ class and preferred term   
x
Subject incidence of TEAEs leading the investigational product withdrawal, study 
medication withdrawal, or study discontinuation by MedDRA system organ class and 
preferred term 
x
Subject incidence of TEAEs by MedDRA system organ class, preferred term, and 
maximum severity will be presented.  At each level of subject summarization, a 
subject is classified according to the maximum severity if the subject reported one or 
more events.  AEs with missing severity will be considered severe for this summary. 
The summaries above will be repeated presenting only preferred term ordered by descending 
order of incidence, for all OCA treated subjects, excluding system organ class.   
In addition, other than Follow-up TEAEs, these summaries will be repeated for the time period 
up to Week 4, to evaluate the effects of OCA alone and in combination with atorvastatin.  These 
analyses will include TEAEs with date of onset prior to the start of atorvastatin. 
The following listings will be presented by subject: 
x
All AEs  
x
Serious AEs (subset of the AEs where serious is marked as “Yes”) 
x
Death information will be provided in a separate listing, should any deaths occur 
x
AE’s leading to withdrawal of investigational product 
x
AEs leading to withdrawal of study medication 
x
AEs leading to Study Discontinuation 
11.3.
Adverse Events of Special Interest  
Adverse events of special interest (AESI) are pruritus, hepatic disorders, dyslipidaemia, and 
myopathy.  For each of these AESI, subject incidence of TEAEs and the total number of entries 
by MedDRA system organ class and preferred term will be presented.  In addition, for each 
AESI, the time to first onset and time to most severe event will be summarized using descriptive 
statistics. 
x
Time to first onset of AESI event 

The time to the onset of the first event will be calculated by date of onset of first 
event – date of first dose of investigational product + 1. 

Subjects without AESI events will be censored at the date of completion or early 
termination. 


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x
Time to start of most severe of AESI event 

The time to the onset of the most severe event will be calculated by date of onset 
of most severe event – date of first dose of investigational product + 1. 

Subjects without AESI events will be censored at the date of study completion or 
early termination. 
11.3.1.
Pruritus  
Treatment-emergent pruritus, defined as any preferred term that contains “Prur,” will be 
summarized separately by the MedDRA SOC, treatment group, and PT as a subset of all TEAEs.   
An analysis of treatment-emergent pruritus event days per subject years on study will be 
performed.  The days at each severity grade, including the total days of event, and the percent of 
event days on study at each severity grade, including the total, will be summarized.     
In order to explore the relationship between pruritus and the investigational product, the 
following time-to-event analyses will be performed: 
x
Total duration of treatment-emergent pruritus 

Duration of each treatment-emergent pruritus event will be calculated as end date 
– start date +1.  For events that are ongoing at Week 16, the Week 16 date will be 
used as the end date.  The sum of each event will be summed for an overall by-
patient duration during the DB phase. 
x
Time to first onset of treatment-emergent pruritus  

The time to the start of the first episode will be calculated by date of onset of first 
episode – date of first dose of investigational product + 1. 

Subjects who never report an AE of pruritus will be censored at the date of 
completion or discontinuation. 
x
Time to onset of the most severe treatment-emergent pruritus 

The time to the start of the most severe pruritus will be calculated by date of onset 
of the most severe pruritus – date of first dose of investigational product + 1. 

Subjects who never report a severe AE of pruritus will be censored at the date of 
study completion or discontinuation. 
x
Time to resolution of the most severe treatment-emergent pruritus event  

The time to resolution of the most severe event of treatment-emergent pruritus 
will be calculated by date of resolution of the most severe event of treatment-
emergent pruritus – start date of the most severe event of treatment-emergent 
pruritus + 1.   

Subjects whose most severe event of treatment-emergent pruritus is ongoing will 
be censored at the date of study completion or discontinuation.  For subjects that 
are lost to follow-up, the last contact date will be used. 

Only subjects that report a pruritus event are included in this analysis. 


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
For subjects reporting multiple events at the most severe level, the event with the 
longest duration will be used. 

Separate summaries will be presented for those who discontinue due to pruritus. 
The analysis of time-to-event will include the number of subjects with the event (first onset, most 
severe), the number of subjects without the event (censored), descriptive statistics of total 
duration of pruritus, descriptive statistics of time for those with an event, and range in days for 
all subjects.  Kaplan-Meier (KM) estimates will be calculated by treatment group.  The quartiles, 
including the median time-to-event and their respective 2-sided 95% CIs, will be presented.  KM 
estimates will be plotted as a “survival curve” for each treatment group, with the number at risk 
identified.  The comparison of OCA to placebo will be summarized using a log-rank test 
stratified by randomization strata factors.   
11.3.2.
Hepatic Disorders  
Hepatic disorders are defined as events included in the Hepatic Disorders Standardized MedDRA 
query (SMQ), excluding the following sub-SMQs: Congenital, familial, neonatal and genetic 
disorders of the liver; Hepatitis, non-infectious; Liver infections; and Pregnancy-related hepatic 
disorders.  See Appendix B for a list of the preferred terms and their associated codes. 
11.3.3.
Dyslipidaemia  
AE lipid profile changes, defined in the Dyslipidaemia SMQ, will be reported.  See Appendix C
for a list of the preferred terms and their associated codes. 
11.3.4.
Myopathy 
Myopathy is defined as any condition in the Rhabdomyolysis and Myopathy SMQs.  See 
Appendix D  for a list of the preferred terms and their associated codes. 
11.4.
Adjudicated Cardiovascular Events 
All suspected cardiovascular events that occur after administration of the first dose of 
investigational product will be reviewed and adjudicated by the Cardiovascular Adjudication 
Committee according to criteria defined in their charter.  Events adjudicated by the committee 
will be included in the cardiovascular event analysis. 
Summaries that are displayed by system organ class and preferred terms will be ordered by 
descending order of incidence, for all OCA-treated patients, of system organ class and by 
preferred terms within each system organ class.  All summaries of incidence will include the 
associated exact binomial 95% CI.  Summaries of the following types will be presented by 
treatment group: 
x
Subject incidence of adjudicated cardiovascular events and the total number of entries 
by MedDRA system organ class and preferred term     
In order to explore the relationship between adjudicated cardiovascular events and the 
investigational product, the following time-to-event analyses will be performed: 
x
Time to first onset of adjudicated cardiovascular event 


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
The time to the start of the first event will be calculated by date of onset of first 
event – date of first dose of investigational product + 1. 

Subjects without adjudicated events will be censored at the date of completion or 
early termination. 
x
Time to onset of most severe adjudicated cardiovascular event 

The time to the onset of most severe event will be calculated by date of onset of 
most severe event – date of first dose of investigational product + 1. 

Subjects without adjudicated events will be censored at the date of completion or 
early termination. 
The incidence and time-to-event analysis for adjudicated cardiovascular events will be repeated 
for suspected cardiovascular events.   
11.5.
On-Study Medical or Surgical Procedures 
 On-study medical or surgical procedure data will be collected from the time that signed 
informed consent is obtained until the subject fully completes her/his study participation of the 
study.  Verbatim procedure terms on eCRFs will be mapped to preferred terms and system organ 
classes using MedDRA (version 18.1).   
All on-study medical or surgical procedure data will be presented in a by-subject data listing.   
11.6.
Clinical Laboratory Evaluations 
Clinical laboratory evaluations during the DB are assessed at the central laboratory.  The central 
laboratory reference/normal ranges will be used in determining whether a subject’s value is 
above (H) or below (L) the reference/normal range.  A listing of available laboratory 
reference/normal ranges for each laboratory parameter will be provided including age, sex, and 
values with units.   
Quantitative hematology, coagulation, and serum chemistry laboratory parameters will be 
summarized by treatment group in SI and conventional units using arithmetic summary statistics 
as described in Section 6.2.1 at Baseline and at each scheduled DB post-Baseline visit.  Change 
from Baseline will also be summarized in the same manner.  Re-tests or unscheduled visit results 
after first dose of investigational product in the DB will not be summarized but will be included 
in the data listings.  Re-tests or unscheduled visit results prior to the administration time of the 
first dose in the DB will be included in the calculation of Baseline.  
For laboratory test results that are below the quantifiable limits: 
Imputed laboratory result = (numeric portion of the result) × 0.9. 
For laboratory test results that are above the quantifiable limits: 
Imputed laboratory result = (numeric portion of the result) × 1.1. 
In addition, shift tables (ie, low-normal-high at Baseline versus low-normal-high at DB post-
Baseline visit in a 3-by-3 contingency table) from Baseline to worst value, last value, and at each 


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Statistical Analysis Plan 
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Confidential and Proprietary                                  Page 47 of 71 
scheduled DB post-Baseline visit will be provided for hematology, coagulation, and serum 
chemistry by treatment group. Worst post-Baseline value is defined as the most abnormal value.   
Urinalysis results will not be summarized but will be provided in a data listing. 
Listings of all laboratory values will flag values outside of the normal range as high (H) or low 
(L) and indicate whether or not a value is clinically significant (CS), based on Investigator 
judgment. 
11.7.
Vital Signs 
Vital signs (body temperature, sitting heart rate, and respiratory rate) will be summarized using 
arithmetic summary statistics as described in Section 6.2.1 at Baseline and at each DB post-
Baseline visit.  Change from Baseline will also be summarized in the same manner.  Re-tests or 
unscheduled visit results prior to the administration time of the first dose in the DB will be 
included in the calculation of Baseline.  Re-tests or unscheduled visit results after the first OCA 
dose administration time will not be summarized but will be included in the data listings.  
11.8.
Electrocardiograms (ECGs) 
The ECG data analysis will be conducted based on methodology recommended in the 
International Conference on Harmonization (ICH) E14 guideline, The Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs.   
Baseline is defined as the mean of all available evaluations prior to treatment.  Arithmetic 
summary statistics as described in Section 6.2.1 will be used to summarize ECG parameters 
(heart rate, RR, PR, QRS, QT, QTcB and QTcF) at Baseline and at each DB post-Baseline visit 
will be summarized by treatment group; absolute change from Baseline will also be summarized.   
A categorical summary of abnormal QTcF values will be presented by treatment group.  The 
number of subjects with values of > 450 msec, > 480 msec, and > 500 msec at each visit will be 
presented and the number of subjects with change from Baseline values of > 30 msec and 
> 60 msec will also be presented.   
Overall interpretation of results for ECGs and the Investigator interpretation of results are 
collected as normal, abnormal not clinically significant, and abnormal clinically significant.  
Subjects whose result shifts from normal to abnormal will be listed separately including 
description of the abnormality and any associated comments. 
12.
CHANGES TO PROTOCOL-SPECIFIED ANALYSES AND 
ENDPOINTS 
There has been one change between the protocol-defined statistical analyses and those presented 
in this statistical analysis plan.  The bioanalytical atorvastatin concentration results did not pass 
incurred sample reanalysis testing.  Therefore, pharmacokinetic analysis of atorvastatin will not 
be performed.   
The non-invasive fibrosis scores were not specified in the protocol.  However, the fibrosis score 
components are from protocol-defined data points, and thus, the addition of the scores does not 
change how the data was collected, nor how the data points are defined.   


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Statistical Analysis Plan 
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Confidential and Proprietary 
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13.
REFERENCES
Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, Enders F, Saksena S, Burt 
AD, Bida JP, Lindor K, Sanderson SO, Lenzi M, Adams LA, Kench J, Therneau, Day CP.  The 
NAFLD fibrosis score: A Noninvasive System That Identifies Liver Fibrosis in Patients with 
NAFLD.   Hepatology. 2007; Apr;45(4):846-56. 
Calès P, Lainé F, Boursier J, et al. Comparison of blood tests for liver fibrosis specific or not to 
NAFLD.  J Hepatol. 2009;50(1):165-73. 
Framingham Heart Study.  Framingham Heart Study: A Project of the National Heart, Lung, and 
Blood Institute and Boston University; c2016.  Available from: 
https://www.framinghamheartstudy.org/risk-functions/cardiovascular-disease/10-year-risk.php. 
Harrison SA, Oliver D, Arnold HL, et al. Development and validation of a simple NAFLD 
clinical scoring system for identifying patients without advanced disease.  Gut. 
2008;57(10):1441-7. 
Ridker PM, Buring JE, Rifai N, et al. Development and validation of improved algorithms for 
the assessment of global cardiovascular risk in women: the Reynolds Risk Score.  JAMA. 
2007;297(6):611-619.  
Ridker PM, Paynter NP, Rifai N, et al. C-reactive protein and parental history improve global 
cardiovascular risk prediction: the Reynolds Risk Score for men. Circulation. 2008;118:2243-
2251. 
Shah AG, Lydecker A, Murray K, et al. Comparison of noninvasive markers of fibrosis in 
patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(10):1104-12. 


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APPENDIX A. LIST OF TABLES, FIGURES, AND LISTINGS 
List of Tables 
Table Number
Population
Table Title
14.1 
Demographic Data 
14.1.1 
All 
Randomized 
Subjects 
Summary of Analysis Populations  
14.1.2.1 
All 
Randomized 
Subjects 
Summary of Subject Disposition  
14.1.2.2 
ITT 
Summary of Investigational Product Discontinuation  
14.1.2.3 
ITT 
Summary of Study Medication Discontinuation  
14.1.3 
ITT 
Summary of Subject Protocol Deviations  
14.1.4.1 
ITT 
Summary of Demographics and Baseline Characteristics 
14.1.4.2 
PK 
Summary of Demographics and Baseline Characteristics 
14.1.4.3 
EE 
Summary of Demographics and Baseline Characteristics (only  
produced if > 20% of ITT subjects are excluded from EE population) 
14.1.5.1 
ITT 
Summary of NASH Disease History 
14.1.5.2 
EE 
Summary of NASH Disease History 
14.1.6 
ITT 
Summary of Tobacco Use Score 
14.1.7 
ITT 
Summary of Statin History 
14.1.8 
ITT 
Summary of Family Cardiovascular History 
14.1.9 
ITT 
Summary of Abnormal Medical History at Baseline 
14.2 
Efficacy Data 
14.2.1.1.1 
EE 
Summary of LDL Cholesterol Concentration – SI Units 
14.2.1.1.2 
EE 
Summary of LDL Cholesterol Concentration  – CV Units 
14.2.1.1.3 
EE 
Summary of LDL Cholesterol Particle Size and Particle Concentration 
14.2.1.2.1 
ITT 
Summary of LDL Cholesterol Concentration – SI Units 
14.2.1.2.2 
ITT 
Summary of LDL Cholesterol Concentration  – CV Units 
14.2.1.2.3 
ITT 
Summary of LDL Cholesterol Particle Size and Particle Concentration 
14.2.1.3.1 
ITT 
Summary of LDL Cholesterol Concentration – SI Units (MMRM) 
14.2.1.3.2 
ITT 
Summary of LDL Cholesterol Concentration  – CV Units (MMRM) 
14.2.1.3.3 
ITT 
Summary of LDL Cholesterol Particle Size and Particle Concentration 
(MMRM) 
14.2.1.4.1 
ITT 
Summary of Change in LDL Choleterol Concentration and Relationship 
to Treatment – CV Units 
14.2.1.4.2 
ITT 
Summary of Change in LDL Choleterol Concentration and Relationship 
to Treatment – SI Units 
14.2.2.1.1 
EE 
Summary of HDL Cholesterol Concentration  – SI Units 
14.2.2.1.2 
EE 
Summary of HDL Cholesterol Concentration – CV Units 
14.2.2.1.3 
EE 
Summary of HDL Cholesterol Particle Size and Particle Concentration  


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Confidential and Proprietary 
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Table Number
Population
Table Title
14.2.2.2.1 
ITT 
Summary of HDL Cholesterol Concentration – SI Units (MMRM) 
14.2.2.2.2 
ITT 
Summary of HDL Cholesterol Concentration  – CV Units (MMRM) 
14.2.2.2.3 
ITT 
Summary of HDL Cholesterol Particle Size and Particle Concentration 
(MMRM) 
14.2.3.1.1 
EE 
Summary of V:DL Cholesterol Concentration  – SI Units 
14.2.3.1.2 
EE 
Summary of VLDL Cholesterol Concentration – CV Units 
14.2.3.1.3 
EE 
Summary of VLDL Cholesterol Particle Size and Particle Concentration 
14.2.3.2.1 
ITT 
Summary of VLDL Cholesterol Concentration – SI Units (MMRM) 
14.2.3.2.2 
ITT 
Summary of VLDL Cholesterol Concentration  – CV Units (MMRM) 
14.2.3.2.3 
Summary of VLDL Cholesterol Particle Size and Particle Concentration 
(MMRM) 
14.2.4.1 
EE 
Summary of Total Cholesterol and Triglyceride Concentrations – SI 
Units 
14.2.4.2 
EE 
Summary of Total Cholesterol and Triglyceride Concentrations – CV 
Units 
14.2.5 
EE 
Summary of ApoA1, ApoB, ApoE, ApoCII, ApoCIII and Lp(a) 
Concentrations   
14.2.6 
EE 
Summary of Reverse Cholesterol Metabolism 
14.2.7 
EE 
Summary of Liver Biochemistry and Markers of Liver Function 
14.2.8 
EE 
Summary of Liver Inflammation, Hepatic Apoptosis, and Fibrosis  
14.2.9.1 
EE 
Summary of Glycemic Control  
14.2.9.2 
EE 
Summary of Glycemic Control by Diabetes Status  
14.2.10 
EE 
Summary of Liver Stiffness Measurements via Transient Elastography  
14.2.11 
EE 
Summary of Liver Fibrosis Improvement via Transient Elastography 
14.2.12.1 
EE 
Summary of Correlation Between Liver Stiffness via Transient 
Elastography and Liver Biopsy NASH CRN Criteria 
14.2.12.2 
EE 
Summary of Correlation Between Liver Stiffness via Transient Liver 
Elastography and Liver Biopsy Modified Ishak Scoring Criteria    
14.2.13.1 
EE 
Summary of FIB-4 Score 
14.2.13.2 
EE 
Summary of APRI Score 
14.2.13.3 
EE  
Summary of NFS Score 
14.2.13.4 
EE 
BARD Score Shift from Baseline 
14.2.14.1 
EE 
Summary of Anthropometric Measures and Blood Pressure 
14.2.14.2 
EE 
Summary of Anthropometric Measures and Blood Pressure by Diabetes 
Status  
14.2.14.3 
EE 
Summary of Blood Pressure by Antihypertensive Use 
14.2.15.1 
EE 
Summary of Cardiovascular Risk Scores  
14.2.15.2.1 
EE 
Summary of Cardiovascular Markers of Risk – SI Units 
14.2.15.2.2 
EE 
Summary of Cardiovascular Markers of Risk – CV Units 
14.2.16.1 
PK 
Summary of Plasma Concentrations for OCA, Glyco-OCA, Tauro-
OCA, and Total OCA by Treatment and Visit 
14.2.16.2 
PK 
Summary of PK Parameters for OCA, Glyco-OCA, Tauro-OCA, and 
Total OCA by Treatment and Visit 


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Table Number
Population
Table Title
14.2.17.1 
APK 
Summary of Week 16 Plasma Concentrations for Atorvastatin, 2OH-
Atorvastatin, and 4OH-Atorvastatin by Treatment 
14.2.17.2 
APK 
Summary of Week 16 PK Parameters for Atorvastatin, 2OH-
Atorvastatin, and 4OH-Atorvastatin by Treatment 
14.2.18.1 
ITT 
Summary of Total Bile Acids and Total Endogenous Bile Acids 
14.2.18.2 
ITT 
Summary of Bile Acids and Bile Acid Sub-components 
14.2.18.3 
ITT 
Summary of Bile Acid Proportions 
14.3 
Safety Data 
14.3.1 
Safety 
Summary of Investigational Product Exposure 
14.3.2 
Safety 
Summary of Atorvastatin Exposure 
14.3.3.1 
Safety 
Summary of Prior and New Concomitant Medications 
14.3.3.2 
Safety 
Summary of New Concomitant Medications 
14.3.1 
Displays of Adverse Events 
14.3.1.1.1 
Safety 
Overall Summary of Treatment-Emergent Adverse Events 
14.3.1.1.2 
Safety 
Overall Summary of Treatment-Emergent Adverse Events Up to Week 
4 
14.3.1.2.1 
Safety 
Summary of Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
14.3.1.2.2 
Safety 
Summary of Treatment-Emergent Adverse Events by Preferred Term 
14.3.1.2.3 
Safety 
Summary of Treatment-Emergent Adverse Events Up to Week 4 by 
System Organ Class and Preferred Term 
14.3.1.2.4 
Safety 
Summary of Treatment-Emergent Adverse Events Up to Week 4 by 
Preferred Term 
14.3.1.3.1 
Safety 
Summary of Investigational product-related Treatment-Emergent 
Adverse Events by System Organ Class and Preferred Term 
14.3.1.3.2 
Safety 
Summary of Investigational product-related Treatment-Emergent 
Adverse Events by Preferred Term 
14.3.1.3.3 
Safety 
Summary of Investigational product-related Treatment-Emergent 
Adverse Events Up to Week 4 by System Organ Class and Preferred 
Term 
14.3.1.3.4 
Safety 
Summary of Investigational product-related Treatment-Emergent 
Adverse Events Up to Week 4 by Preferred Term 
14.3.1.4.1 
Safety 
Summary of Study Medication-related Treatment-Emergent Adverse 
Events by System Organ Class and Preferred Term 
14.3.1.4.2 
Safety 
Summary of Study Medication-related Treatment-Emergent Adverse 
Events by Preferred Term 
14.3.1.5.1 
Safety 
Summary of Liver biopsy-related Treatment-Emergent Adverse Events 
by System Organ Class and Preferred Term 
14.3.1.5.2 
Safety 
Summary of Liver biopsy-related Treatment-Emergent Adverse Events 
by Preferred Term 
14.3.1.6.1 
Safety 
Summary of Treatment-Emergent Serious Adverse Events by System 
Organ Class and Preferred Term 
14.3.1.6.2 
Safety 
Summary of Treatment-Emergent Serious Adverse Events by Preferred 
Term 
14.3.1.6.3 
Safety 
Summary of Treatment-Emergent Serious Adverse Events Up to Week 
4 by System Organ Class and Preferred Term 


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Confidential and Proprietary                                  Page 53 of 71 
Table Number
Population
Table Title
14.3.1.6.4 
Safety 
Summary of Treatment-Emergent Serious Adverse Events Up to Week 
4 by Preferred Term 
14.3.1.7.1 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to 
Investigational Product Withdrawal, Study Medication Withdrawal, or 
Study Discontinuation by System Organ Class and Preferred Term 
14.3.1.7.2 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to 
Investigational Product Withdrawal, Study Medication Withdrawal, or 
Study Discontinuation by Preferred Term 
14.3.1.8.1 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to 
Investigational Product Withdrawal by System Organ Class and
Preferred Term 
14.3.1.8.2 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to 
Investigational Product Withdrawal by Preferred Term
14.3.1.8.3 
Safety 
Summary of Treatment-Emergent Adverse Events Up to Week 4 
Leading to Investigational Product Withdrawal by System Organ Class 
and Preferred Term 
14.3.1.8.4 
Safety 
Summary of Treatment-Emergent Adverse Events Up to Week 4 
Leading to Investigational Product Withdrawal by Preferred Term 
14.3.1.9.1 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to Study 
Discontinuation by System Organ Class and Preferred Term 
14.3.1.9.2 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to Study 
Discontinuation by Preferred Term 
14.3.1.9.3 
Safety 
Summary of Treatment-Emergent Adverse Events Up to Week 4 
Leading to Study Discontinuation by System Organ Class and Preferred 
Term 
14.3.1.9.4 
Safety 
Summary of Treatment-Emergent Adverse Events Up to Week 4 
Leading to Study Discontinuation by Preferred Term 
14.3.1.10.1 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to Study 
Medication Withdrawal by System Organ Class and Preferred Term
14.3.1.10.2 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to Study 
Medication Withdrawal by Preferred Term
14.3.1.11.1 
Safety 
Summary of Treatment-Emergent Adverse Events by Maximum 
Severity, System Organ Class, and Preferred Term 
14.3.1.11.2 
Safety 
Summary of Treatment-Emergent Adverse Events by Maximum 
Severity and Preferred Term 
14.3.1.11.3 
Safety 
Summary of Treatment-Emergent Adverse Events Up to Week 4 by 
Maximum Severity, System Organ Class, and Preferred Term 
14.3.1.11.4 
Safety 
Summary of Treatment-Emergent Adverse Events Up to Week 4 by 
Maximum Severity and Preferred Term 
14.3.1.12.1 
Safety
Summary of Pre-Treatment Adverse Events by System Organ Class and 
Preferred Term 
14.3.1.12.2 
Safety
Summary of Pre-Treatment Adverse Events by Preferred Term 
14.3.1.13.1 
Safety
Summary of Pre-Treatment Serious Adverse Events by System Organ 
Class and Preferred Term 
14.3.1.13.2 
Safety
Summary of Pre-Treatment Serious Adverse Events by Preferred Term 
14.3.1.14.1 
Safety
Summary of Pruritus Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 


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Table Number
Population
Table Title
14.3.1.14.2 
Safety
Summary of Pruritus Treatment-Emergent Adverse Events by Preferred 
Term 
14.3.1.14.3 
Safety 
Time to Onset of First Treatment-Emergent Pruritus 
14.3.1.14.4 
Safety  
Time to Onset of Most Severe Treatment-Emergent Pruritus 
14.3.1.14.5 
Safety  
Time to Resolution of Most Severe Treatment-Emergent Pruritus 
14.3.1.14.6 
Safety 
Treatment-Emergent Pruritus Event Days 
14.3.1.15.1 
Safety
Summary of Treatment-Emergent Hepatic Disorder Adverse Events by 
System Organ Class and Preferred Term 
14.3.1.15.2 
Safety
Summary of Treatment-Emergent Hepatic Disorder Adverse Events by 
Preferred Term 
14.3.1.15.3 
Safety 
Time to Onset of First Treatment-Emergent Hepatic Disorder 
14.3.1.15.4 
Safety  
Time to Onset of Most Severe Treatment-Emergent Hepatic Disorder 
14.3.1.16.1 
Safety
Summary of Treatment-Emergent Dyslipidaemia Adverse Events by 
System Organ Class and Preferred Term 
14.3.1.16.2 
Safety
Summary of Treatment-Emergent Dyslipidaemia Adverse Events by 
Preferred Term 
14.3.1.16.3 
Safety  
Time to Onset of First Treatment-Emergent Dyslipidaemia  
14.3.1.16.4 
Safety  
Time to Onset of Most Severe Treatment-Emergent Dyslipidaemia 
14.3.1.17.1 
Safety
Summary of Treatment-Emergent Myopathy Adverse Events by System 
Organ Class and Preferred Term 
14.3.1.17.2 
Safety
Summary of Treatment-Emergent Myopathy Adverse Events by 
Preferred Term 
14.3.1.17.3 
Safety 
Time to Onset of First Treatment-Emergent Myopathy 
14.3.1.17.4 
Safety  
Time to Onset of Most Severe Treatment-Emergent Myopathy 
14.3.1.18.1 
Safety
Summary of Treatment-Emergent Adjudicated Cardiovascular 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
14.3.1.18.2 
Safety  
Summary of Treatment-Emergent Suspected Cardiovascular Treatment-
Emergent Adverse Events by System Organ Class and Preferred Term 
14.3.1.18.3 
Safety
Time to Onset of First Treatment-Emergent Adjudicated Cardiovascular 
Event 
14.3.1.18.4 
Safety 
Time to Onset of First Treatment-Emergent Suspected Cardiovascular 
Event 
14.3.4 
Clinical Laboratory Evaluations 
14.3.4.1.1 
Safety 
Summary of Hematology and Coagulation – SI Units 
14.3.4.1.2 
Safety  
Summary of Hematology and Coagulation – CV Units 
14.3.4.2.1 
Safety 
Hematology and Coagulation Shift Analysis – SI Units 
14.3.4.2.2 
Safety 
Hematology and Coagulation Shift Analysis – CV Units 
14.3.4.3.1 
Safety 
Summary of Serum Chemistry – SI Units 
14.3.4.3.2 
Safety  
Summary of Serum Chemistry – CV Units 
14.3.4.4.1 
Safety 
Serum Chemistry Shift Analysis – SI Units 
14.3.4.4.2 
Safety 
Serum Chemistry Shift Analysis – CV Units 
14.3.4.5.1 
Safety 
Summary of Vital Signs  
14.3.4.5.2 
Safety 
Summary of Blood Pressure by Use of Antihypertensive Medications  


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Confidential and Proprietary                                  Page 55 of 71 
Table Number
Population
Table Title
14.3.4.6 
Safety 
Summary of Electrocardiogram Parameters  
14.3.4.7 
Safety 
Summary of Electrocardiogram Parameter Subgroups  
14.3.4.8 
Safety  
Summary of Alcohol Use Disorders Identification Test (AUDIT) Score 
List of Figures 
Figure Number 
Population 
Figure Title 
14.2 
Efficacy Data 
14.2.1.1 
ITT 
Baseline Liver Stiffness Measurements versus Baseline NASH CRN 
Liver Biopsy Stage 
14.2.1.2 
ITT 
Baseline Liver Stiffness Measurements versus Baseline Modified Ishak 
Liver Biopsy Stage 
14.2.1.1 
PK 
Individual Plasma Concentration of Unconjugated OCA Over Time  
14.2.1.2 
PK 
Individual Plasma Concentration of Glyco-OCA Over Time  
14.2.1.3 
PK 
Individual Plasma Concentration of Tauro-OCA Over Time  
14.2.1.4 
PK 
Individual Plasma Concentration of Total OCA Over Time  
14.2.2.1 
PK 
Mean (SD) Plasma Concentration of Unconjugated OCA Over Time by 
Dose (linear and semi-log plots) 
14.2.2.2 
PK 
Mean (SD) Plasma Concentration of Glyco-OCA Over Time by Dose 
(linear and semi-log plots) 
14.2.2.3 
PK 
Mean (SD) Plasma Concentration of Tauro-OCA Over Time by Dose 
(linear and semi-log plots) 
14.2.2.4 
PK 
Mean (SD) Plasma Concentration of Total OCA Over Time by Dose 
(linear and semi-log plots) 
14.2.3.1 
PK 
Boxplots of AUC0-6 and Cmax versus Dose for OCA, Glyco-OCA, 
Tauro-OCA, and Total OCA by Visit (Day 1 and Week 16)
14.2.4.1.1 
PK 
Scatter Plot of Week 16 LDL Cholesterol Concentration versus Total 
OCA AUC0-6 – SI Units 
14.2.4.1.2 
PK 
Scatter Plot of Week 16 LDL Cholesterol Concentration versus Total 
OCA AUC0-6 – CV Units 
14.2.4.2.1 
PK 
Scatter Plot of Week 16 Change from Baseline in LDL Cholesterol 
versus Total OCA AUC0-6 – SI Units 
14.2.4.2.2 
PK 
Scatter Plot of Week 16 Change from Baseline in LDL Cholesterol 
versus Total OCA AUC0-6 – CV Units 
14.2.4.3.1 
PK 
Scatter Plot of Week 16 LDL Particle Size versus Total OCA AUC0-6
14.2.4.3.2 
PK 
Scatter Plot of Week 16 Change from Baseline in LDL Particle Size 
versus Total OCA AUC0-6
14.2.4.4.1 
PK 
Scatter Plot of Week 16 LDL Particle Concentration versus Total OCA 
AUC0-6
14.2.4.4.2 
PK 
Scatter Plot of Week 16 Change from Baseline in LDL Particle 
Concentration versus Total OCA AUC0-6
14.2.4.5.1 
PK 
Scatter Plot of Week 16 FGF-19 versus Total OCA AUC0-6
14.2.4.5.2 
PK 
Scatter Plot of Week 16 Change from Baseline in FGF-19 versus Total 
OCA AUC0-6
14.2.4.6.1 
PK 
Scatter Plot of Week 16 C4 versus Total OCA AUC0-6


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Figure Number 
Population 
Figure Title 
14.2 
Efficacy Data 
14.2.4.6.2 
PK 
Scatter Plot of Week 16 Change from Baseline in C4 versus Total OCA 
AUC0-6
14.2.4.7.1 
PK 
Scatter Plot of Week 16 CRP versus Total OCA AUC0-6
14.2.4.7.2 
PK 
Scatter Plot of Week 16 Change from Baseline in CRP versus Total 
OCA AUC0-6
14.2.4.8.1.1 
PK 
Scatter Plot of Week 16 LDL Cholesterol Concentration versus Total 
OCA Cmax – SI Units 
14.2.4.8.1.2 
PK 
Scatter Plot of Week 16 LDL Cholesterol Concentration versus Total 
OCA Cmax – CV Units 
14.2.4.8.2.1 
PK 
Scatter Plot of Week 16 Change from Baseline in LDL Cholesterol 
Concentration versus Total OCA Cmax – SI Units 
14.2.4.8.2.2 
PK 
Scatter Plot of Week 16 Change from Baseline in LDL Cholesterol 
Concentration versus Total OCA Cmax – CV Units 
14.2.4.9.1 
PK 
Scatter Plot of Week 16 LDL Particle Size versus OCA Cmax
14.2.4.9.2 
PK 
Scatter Plot of Week 16 Change from Baseline in LDL Particle Size 
versus Total OCA Cmax
14.2.4.10.1 
PK 
Scatter Plot of Week 16 LDL Particle Concentration versus Total OCA 
Cmax
14.2.4.10.2 
PK 
Scatter Plot of Week 16 Change from Baseline in LDL Particle 
Concentration versus Total OCA Cmax
14.2.4.11.1 
PK 
Scatter Plot of Week 16 C4 versus Total OCA Cmax
14.2.4.11.2 
PK 
Scatter Plot of Week 16 Change from Baseline in C4 versus Total OCA 
Cmax
14.2.4.12.1 
PK 
Scatter Plot of Week 16 FGF-19 versus Total OCA Cmax
14.2.4.12.2 
PK 
Scatter Plot of Week 16 Change from Baseline in FGF-19 versus Total 
OCA Cmax
14.2.4.13.1 
PK 
Scatter Plot of Week 16 CRP versus Total OCA Cmax
14.2.4.13.2 
PK 
Scatter Plot of Week 16 Change from Baseline in CRP versus Total 
OCA Cmax
List of Data Listings 
Listing Number 
Listing Title 
16.2
Subject Data Listings 
16.2.1 
Discontinued subjects 
16.2.1.1 
Analysis Populations  
16.2.1.2 
Subject Disposition 
16.2.2 
Protocol deviations 
16.2.2.1 
Protocol Deviations 
16.2.2.2.1 
Inclusion and Exclusion Criteria Findings 
16.2.2.2.2 
Liver Biopsy Eligibility 
16.2.4 
Demographic data
16.2.4.1 
Demographics  
16.2.4.2 
NASH Disease History 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 57 of 71 
Listing Number 
Listing Title 
16.2.4.3 
Alcohol Use Disorders Identification Test (AUDIT) 
16.2.4.4 
Tobacco Use 
16.2.4.5 
Statin History 
16.2.4.6 
Family Cardiovascular History 
16.2.4.7 
Medical History 
16.2.4.8 
Historical Procedures 
16.2.5
Compliance and/or drug concentration data
16.2.5.1 
Investigational Product Accountability 
16.2.5.2 
Investigational Product Exposure 
16.2.5.3 
Study Medication Accountability 
16.2.5.4 
Study Medication Exposure 
16.2.5.5 
Prior and New Concomitant Medications 
16.2.5.6.1 
Plasma Concentration Collection 
16.2.5.6.2 
Plasma Concentration Data for OCA, Glyco-OCA, Tauro-OCA, and Total OCA 
16.2.5.6.3 
PK Parameters for OCA, Glyco-OCA, Tauro-OCA, and Total OCA 
16.2.5.8.1 
Bile Acids and Bile Acid Subcomponents: UDCA, Glyco-UDCA, Tauro-UDCA, and 
Total UDCA 
16.2.5.8.2 
Bile Acids and Bile Acid Subcomponents: CDCA, Glyco-CDCA, Tauro-CDCA, and 
Total CDCA 
16.2.5.8.3 
Bile Acids and Bile Acid Subcomponents: DCA, Glyco-DCA, Tauro-DCA, and Total 
DCA 
16.2.5.8.4 
Bile Acids and Bile Acid Subcomponents: CA, Glyco-CA, Tauro-CA, and Total CA 
16.2.5.8.5 
Bile Acids and Bile Acid Subcomponents: LCA, Glyco-LCA, Tauro-LCA, and Total 
LCA 
16.2.5.8.6 
Total Bile Acids and Total Endogenous Bile Acids 
16.2.6 
Individual efficacy response data
16.2.6.1.1 
Lipoprotein Serum Concentration – SI Units 
16.2.6.1.2 
Lipoprotein Serum Concentration – CV Units 
16.2.6.2 
Lipoprotein Particle Concentration and Size 
16.2.6.3.1 
ApoA1, ApoB, ApoA1/ApoB Ratio, ApoE, and Lp(a) Concentrations – SI Units 
16.2.6.3.2 
ApoA1, ApoB, ApoA1/ApoB Ratio, ApoE, and Lp(a) Concentrations – CV Units 
16.2.6.4 
Reverse Cholesterol Transport  
16.2.6.5.1 
Liver Biochemistry and Markers of Liver Function – SI Units 
16.2.6.5.2 
Liver Biochemistry and Markers of Liver Function – CV Units 
16.2.6.6 
Markers of Liver inflammation, Hepatic Apoptosis and Fibrosis 
16.2.6.7.1 
Markers of Glycemic Control – SI Units 
16.2.6.7.2 
Markers of Glycemic Control – CV Units 
16.2.6.8.1 
Markers of Cardiovascular Risk – SI Units 
16.2.6.8.2 
Markers of Cardiovascular Risk – CV Units 
16.2.6.9.1 
Nuclear Magnetic Resonance Lipoprotein Concentrations – SI Units 
16.2.6.9.2 
Nuclear Magnetic Resonance Lipoprotein Concentrations – CV Units 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-209 
 
20 Jun 2017 
Confidential and Proprietary                                  Page 58 of 71 
Listing Number 
Listing Title 
16.2.6.10 
Transient Elastography 
16.2.6.11 
Fibrosis-4 Score 
16.2.6.12 
APRI Score 
16.2.6.13 
BARD Score 
16.2.6.14 
NSF Score 
16.2.7 
Adverse events listings
16.2.7.1 
Adverse Events 
16.2.7.2 
Serious Adverse Events 
16.2.7.3 
Severe Adverse Events 
16.2.7.4 
Adverse Events Related to Investigational Product 
16.2.7.5 
Adverse Events Related to Study Medication 
16.2.7.6 
Adverse Events Related to Liver Biopsy 
16.2.7.7 
Adverse Events Leading to Investigational Product Withdrawal or Study 
Discontinuation 
16.2.7.8 
Adverse Events Leading to Death 
16.2.7.9 
Adjudicated Adverse Events 
16.2.7.10 
Adverse Events of Pruritus 
16.2.7.11 
Derived Time to Treatment-Emergent Pruritus Endpoints 
16.2.7.12 
Derived Time to Treatment-Emergent Adverse Events of Special Interest 
16.2.8
Listing of individual laboratory measurements by subject, when required by 
regulatory authorities
16.2.8.1.1 
Hematology and Coagulation – SI Units 
16.2.8.1.2 
Hematology and Coagulation – CV Units 
16.2.8.2.1 
Serum Chemistry – SI Units 
16.2.8.2.2 
Serum Chemistry – CV Units 
16.2.8.3 
Urinalysis 
16.2.8.4 
Laboratory Sample Collection 
16.2.8.5.1 
Laboratory Reference/Normal Ranges – SI Units 
16.2.8.5.2 
Laboratory Reference/Normal Ranges – CV Units 
16.2.9 
Additional Safety Listings 
16.2.9.1 
Vital Signs 
16.2.9.2 
Anthropometric Measures 
16.2.9.3.1 
12-lead Electrocardiograms (ECGs)  
16.2.9.3.2 
12-lead Electrocardiograms (ECGs) Central Reading Results  
16.2.9.4.1 
Cardiovascular Risk Scores – Framingham Risk Score 
16.2.9.4.2 
Cardiovascular Risk Scores – Reynolds Score 
16.2.9.5 
On-Study Medical or Surgical Procedure 
16.2.9.6 
Pregnancy Test Results 
16.2.9.7 
Subject Visit Information 
16.2.9.8 
Comments 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 59 of 71 
Intentionally Left Blank


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-209 
 
20 Jun 2017 
Confidential and Proprietary                                  Page 60 of 71 
APPENDIX B. HEPATIC DISORDER PREFERRED TERMS AND 
ASSOCIATED CODES 
Preferred Term 
Code 
5'nucleotidase increased 
10000028 
Acquired antithrombin III deficiency 
10074561 
Acquired protein S deficiency 
10068370 
Acute hepatic failure 
10000804 
Acute yellow liver atrophy 
10070815 
Alanine aminotransferase abnormal 
10001547 
Alanine aminotransferase increased 
10001551 
Alcoholic liver disease 
10001627 
Ammonia abnormal 
10001942 
Ammonia increased 
10001946 
Anorectal varices 
10068924 
Anorectal varices haemorrhage 
10068925 
Antithrombin III decreased 
10049547 
Ascites 
10003445 
Aspartate aminotransferase abnormal 
10003477 
Aspartate aminotransferase increased 
10003481 
Asterixis 
10003547 
Bacterascites 
10068547 
Benign hepatic neoplasm 
10004269 
Bile output abnormal 
10051344 
Bile output decreased 
10051343 
Biliary ascites 
10074150 
Biliary cirrhosis 
10004659 
Biliary cirrhosis primary 
10004661 
Biliary fibrosis 
10004664 
Bilirubin conjugated abnormal 
10067718 
Bilirubin conjugated increased 
10004685 
Bilirubin excretion disorder 
10061009 
Biopsy liver abnormal 
10004792 
Blood alkaline phosphatase abnormal 
10059571 
Blood alkaline phosphatase increased 
10059570 
Blood bilirubin abnormal 
10058477 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 61 of 71 
Preferred Term 
Code 
Blood bilirubin increased 
10005364 
Blood bilirubin unconjugated increased 
10005370 
Blood cholinesterase abnormal 
10005429 
Blood cholinesterase decreased 
10005430 
Blood fibrinogen abnormal 
10005518 
Blood fibrinogen decreased 
10005520 
Blood thrombin abnormal 
10005818 
Blood thrombin decreased 
10005820 
Blood thromboplastin abnormal 
10005824 
Blood thromboplastin decreased 
10005826 
Bromosulphthalein test abnormal 
10006408 
Child-Pugh-Turcotte score abnormal 
10077020 
Child-Pugh-Turcotte score increased 
10068287 
Cholaemia 
10048611 
Cholestasis 
10008635 
Cholestatic liver injury 
10067969 
Cholestatic pruritus 
10064190 
Chronic hepatic failure 
10057573 
Cirrhosis alcoholic 
10009208 
Coagulation factor decreased 
10009736 
Coagulation factor IX level abnormal 
10061770 
Coagulation factor IX level decreased 
10009746 
Coagulation factor V level abnormal 
10061771 
Coagulation factor V level decreased 
10009754 
Coagulation factor VII level abnormal 
10061772 
Coagulation factor VII level decreased 
10009761 
Coagulation factor X level abnormal 
10061774 
Coagulation factor X level decreased 
10009775 
Coma hepatic 
10010075 
Computerised tomogram liver 
10076215 
Cryptogenic cirrhosis 
10063075 
Deficiency of bile secretion 
10071634 
Diabetic hepatopathy 
10071265 
Drug-induced liver injury 
10072268 
Duodenal varices 
10051010 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 62 of 71 
Preferred Term 
Code 
Fatty liver alcoholic 
10016262 
Focal nodular hyperplasia 
10052285 
Foetor hepaticus 
10052554 
Galactose elimination capacity test abnormal 
10059710 
Galactose elimination capacity test decreased 
10059712 
Gallbladder varices 
10072319 
Gamma-glutamyltransferase abnormal 
10017688 
Gamma-glutamyltransferase increased 
10017693 
Gastric variceal injection 
10076237 
Gastric variceal ligation 
10076238 
Gastric varices 
10051012 
Gastric varices haemorrhage 
10057572 
Glutamate dehydrogenase increased 
10049483 
Guanase increased 
10051333 
Haemangioma of liver 
10018821 
Haemorrhagic ascites 
10059766 
Haemorrhagic hepatic cyst 
10067796 
Hepaplastin abnormal 
10019621 
Hepaplastin decreased 
10019622 
Hepatectomy 
10061997 
Hepatic adenoma 
10019629 
Hepatic angiosarcoma 
10067388 
Hepatic artery flow decreased 
10068997 
Hepatic atrophy 
10019637 
Hepatic calcification 
10065274 
Hepatic cancer 
10073069 
Hepatic cancer metastatic 
10055110 
Hepatic cancer recurrent 
10073070 
Hepatic cancer stage I 
10059318 
Hepatic cancer stage II 
10059319 
Hepatic cancer stage III 
10059324 
Hepatic cancer stage IV 
10059325 
Hepatic cirrhosis 
10019641 
Hepatic congestion 
10019645 
Hepatic cyst 
10019646 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 63 of 71 
Preferred Term 
Code 
Hepatic cyst ruptured 
10053973 
Hepatic encephalopathy 
10019660 
Hepatic encephalopathy prophylaxis 
10066599 
Hepatic enzyme abnormal 
10062685 
Hepatic enzyme decreased 
10060794 
Hepatic enzyme increased 
10060795 
Hepatic failure 
10019663 
Hepatic fibrosis 
10019668 
Hepatic fibrosis marker abnormal 
10074084 
Hepatic fibrosis marker increased 
10074413 
Hepatic function abnormal 
10019670 
Hepatic haemangioma rupture 
10054885 
Hepatic hydrothorax 
10067365 
Hepatic hypertrophy 
10076254 
Hepatic infiltration eosinophilic 
10064668 
Hepatic lesion 
10061998 
Hepatic mass 
10057110 
Hepatic necrosis 
10019692 
Hepatic neoplasm 
10019695 
Hepatic pain 
10019705 
Hepatic sequestration 
10066244 
Hepatic steato-fibrosis 
10077215 
Hepatic steatosis 
10019708 
Hepatic vascular resistance increased 
10068358 
Hepatitis alcoholic 
10019728 
Hepatitis cholestatic 
10019754 
Hepatitis fulminant 
10019772 
Hepatobiliary cancer 
10073073 
Hepatobiliary cancer in situ 
10073074 
Hepatobiliary disease 
10062000 
Hepatobiliary neoplasm 
10061203 
Hepatobiliary scan abnormal 
10066195 
Hepatoblastoma 
10062001 
Hepatoblastoma recurrent 
10019823 
Hepatocellular carcinoma 
10073071 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 64 of 71 
Preferred Term 
Code 
Hepatocellular foamy cell syndrome 
10053244 
Hepatocellular injury 
10019837 
Hepatomegaly 
10019842 
Hepatopulmonary syndrome 
10052274 
Hepatorenal failure 
10019845 
Hepatorenal syndrome 
10019846 
Hepatosplenomegaly 
10019847 
Hepatotoxicity 
10019851 
Hyperammonaemia 
10020575 
Hyperbilirubinaemia 
10020578 
Hypercholia 
10051924 
Hyperfibrinolysis 
10074737 
Hypertransaminasaemia 
10068237 
Hypoalbuminaemia 
10020942 
Hypocoagulable state 
10020973 
Hypofibrinogenaemia 
10051125 
Hypoprothrombinaemia 
10021085 
Hypothrombinaemia 
10058517 
Hypothromboplastinaemia 
10058518 
Icterus index increased 
10021209 
International normalised ratio abnormal 
10022592 
International normalised ratio increased 
10022595 
Intestinal varices 
10071502 
Intrahepatic portal hepatic venous fistula 
10072629 
Jaundice 
10023126 
Jaundice cholestatic 
10023129 
Jaundice hepatocellular 
10023136 
Kayser-Fleischer ring 
10023321 
Leucine aminopeptidase increased 
10024275 
Liver ablation 
10074766 
Liver and small intestine transplant 
10052280 
Liver carcinoma ruptured 
10050842 
Liver dialysis 
10076640 
Liver disorder 
10024670 
Liver function test abnormal 
10024690 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 65 of 71 
Preferred Term 
Code 
Liver induration 
10052550 
Liver injury 
10067125 
Liver iron concentration abnormal 
10074352 
Liver iron concentration increased 
10074354 
Liver operation 
10062040 
Liver palpable 
10075895 
Liver scan abnormal 
10061947 
Liver tenderness 
10024712 
Liver transplant 
10024714 
Lupoid hepatic cirrhosis 
10025129 
Minimal hepatic encephalopathy 
10076204 
Mitochondrial aspartate aminotransferase increased 
10064712 
Mixed hepatocellular cholangiocarcinoma 
10027761 
Mixed liver injury 
10066758 
Molar ratio of total branched-chain amino acid to tyrosine 
10066869 
Nodular regenerative hyperplasia 
10051081 
Non-alcoholic steatohepatitis 
10053219 
Ocular icterus 
10058117 
Oedema due to hepatic disease 
10049631 
Oesophageal varices haemorrhage 
10030210 
Parenteral nutrition associated liver disease 
10074151 
Perihepatic discomfort 
10054125 
Peripancreatic varices 
10073215 
Periportal oedema 
10068821 
Peritoneal fluid protein abnormal 
10069000 
Peritoneal fluid protein decreased 
10068999 
Peritoneal fluid protein increased 
10068998 
Peritoneovenous shunt 
10052716 
Pneumobilia 
10066004 
Portal fibrosis 
10074726 
Portal hypertension 
10036200 
Portal hypertensive enteropathy 
10068923 
Portal hypertensive gastropathy 
10050897 
Portal shunt 
10036204 
Portal vein cavernous transformation 
10073979 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 66 of 71 
Preferred Term 
Code 
Portal vein dilatation 
10073209 
Portal vein flow decreased 
10067337 
Portal vein pressure increased 
10064936 
Portopulmonary hypertension 
10067281 
Protein C decreased 
10037005 
Protein S abnormal 
10051736 
Protein S decreased 
10051120 
Prothrombin level abnormal 
10037048 
Prothrombin level decreased 
10037050 
Prothrombin time abnormal 
10037057 
Prothrombin time prolonged 
10037063 
Prothrombin time ratio abnormal 
10061918 
Prothrombin time ratio increased 
10037068 
Renal and liver transplant 
10052279 
Retinol binding protein decreased 
10048473 
Retrograde portal vein flow 
10067338 
Reye's syndrome 
10039012 
Reynold's syndrome 
10070953 
Small-for-size liver syndrome 
10069380 
Spider naevus 
10041519 
Splenic varices 
10067823 
Splenic varices haemorrhage 
10068662 
Spontaneous intrahepatic portosystemic venous shunt 
10076239 
Steatohepatitis 
10076331 
Stomal varices 
10075186 
Subacute hepatic failure 
10056956 
Thrombin time abnormal 
10051319 
Thrombin time prolonged 
10051390 
Total bile acids increased 
10064558 
Transaminases abnormal 
10062688 
Transaminases increased 
10054889 
Ultrasound liver abnormal 
10045428 
Urine bilirubin increased 
10050792 
Urobilinogen urine decreased 
10070480 
Urobilinogen urine increased 
10070479 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 67 of 71 
Preferred Term 
Code 
Varices oesophageal 
10056091 
Varicose veins of abdominal wall 
10072284 
X-ray hepatobiliary abnormal 
10056536 
Yellow skin 
10048245 
Zieve syndrome 
10048255 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 68 of 71 
APPENDIX C. DYSLIPIDEMIA PREFERRED TERMS AND 
ASSOCIATED CODES 
Preferred Term 
Code 
Acquired lipoatrophic diabetes 
10073667 
Acquired mixed hyperlipidaemia 
10071236 
Apolipoprotein B/Apolipoprotein A-1 ratio increased 
10065516 
Autoimmune hyperlipidaemia 
10071577 
Blood cholesterol abnormal 
10005423 
Blood cholesterol decreased 
10005424 
Blood cholesterol esterase increased 
10071304 
Blood cholesterol increased 
10005425 
Blood triglycerides abnormal 
10005837 
Blood triglycerides decreased 
10005838 
Blood triglycerides increased 
10005839 
Diabetic dyslipidaemia 
10070901 
Dyslipidaemia 
10058108 
Familial hypertriglyceridaemia 
10059183 
Fat overload syndrome 
10074028 
High density lipoprotein abnormal 
10020051 
High density lipoprotein decreased 
10020060 
High density lipoprotein increased 
10020061 
Hypercholesterolaemia 
10020603 
Hyperlipidaemia 
10062060 
Hypertriglyceridaemia 
10020869 
Hypo HDL cholesterolaemia 
10068961 
Hypotriglyceridaemia 
10021128 
Intermediate density lipoprotein decreased 
10064237 
Intermediate density lipoprotein increased 
10064236 
LDL/HDL ratio decreased 
10052338 
LDL/HDL ratio increased 
10049030 
Lipid metabolism disorder 
10061227 
Lipids abnormal 
10024588 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 69 of 71 
Preferred Term 
Code 
Lipids decreased 
10024591 
Lipids increased 
10024592 
Lipoprotein (a) abnormal 
10054023 
Lipoprotein (a) decreased 
10054021 
Lipoprotein (a) increased 
10054009 
Low density lipoprotein abnormal 
10024901 
Low density lipoprotein decreased 
10024909 
Low density lipoprotein increased 
10024910 
Non-high-density lipoprotein cholesterol decreased 
10064235 
Non-high-density lipoprotein cholesterol increased 
10063967 
Remnant hyperlipidaemia 
10038316 
Remnant-like lipoprotein particles increased 
10073041 
Total cholesterol/HDL ratio abnormal 
10058633 
Total cholesterol/HDL ratio decreased 
10058631 
Total cholesterol/HDL ratio increased 
10058630 
Type I hyperlipidaemia 
10060749 
Type II hyperlipidaemia 
10045254 
Type IIa hyperlipidaemia 
10045261 
Type IIb hyperlipidaemia 
10045263 
Type III hyperlipidaemia 
10060751 
Type IV hyperlipidaemia 
10060753 
Type V hyperlipidaemia 
10060755 
Very low density lipoprotein abnormal 
10047352 
Very low density lipoprotein decreased 
10047360 
Very low density lipoprotein increased 
10047361 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 70 of 71 
APPENDIX D. RHABDOMYOLYSIS AND MYOPATHY PREFERRED 
TERMS AND ASSOCIATED CODES 
Preferred Term 
Code 
Muscle necrosis 
10028320 
Myoglobin blood increased 
10028625 
Myoglobin blood present 
10059888 
Myoglobin urine present 
10028631 
Myoglobinaemia 
10058735 
Myoglobinuria 
10028629 
Myopathy 
10028641 
Myopathy toxic 
10028648 
Necrotising myositis 
10074769 
Rhabdomyolysis 
10039020 
Acute kidney injury 
10069339 
Anuria 
10002847 
Biopsy muscle abnormal 
10004803 
Blood calcium decreased 
10005395 
Blood creatine phosphokinase abnormal 
10005468 
Blood creatine phosphokinase increased 
10005470 
Blood creatine phosphokinase MM increased 
10005477 
Blood creatinine abnormal 
10005481 
Blood creatinine increased 
10005483 
Chromaturia 
10008796 
Chronic kidney disease 
10064848 
Compartment syndrome 
10010121 
Creatinine renal clearance abnormal 
10068447 
Creatinine renal clearance decreased 
10011372 
Diaphragm muscle weakness 
10012708 
Electromyogram abnormal 
10014431 
Glomerular filtration rate abnormal 
10018356 
Glomerular filtration rate decreased 
10018358 
Hypercreatininaemia 
10062747 


Intercept Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 747-209 
20 Jun 2017 
Confidential and Proprietary 
 Page 71 of 71 
Preferred Term 
Code 
Hypocalcaemia 
10020947 
Muscle disorder 
10028300 
Muscle enzyme increased 
10057945 
Muscle fatigue 
10049565 
Muscle haemorrhage 
10028309 
Muscle rupture 
10028331 
Muscular weakness 
10028372 
Musculoskeletal discomfort 
10053156 
Musculoskeletal disorder 
10048592 
Musculoskeletal pain 
10028391 
Myalgia 
10028411 
Myalgia intercostal 
10028413 
Myositis 
10028653 
Oliguria 
10030302 
Renal failure 
10038435 
Renal impairment 
10062237 
Renal tubular necrosis 
10038540 
Tendon discomfort 
10074599