Replicate Studies Evaluating the Effectiveness of Obeticholic Acid on Hepatic Real-World Outcomes in Patients With Primary Biliary Cholangitis
Conditions: Primary Biliary Cholangitis
Sponsor: Intercept Pharmaceuticals

Intercept 
Non-Interventional Study Protocol 747-404/405 
OBETICHOLIC ACID (OCA) 
Replicate Studies Evaluating the Effectiveness of Obeticholic Acid on Hepatic 
Real-World Outcom~ in Patients with Primary Biliary Cholangitis 
(HEROES PBC) 
Version 1.0: 24 January 2022 
ClinicalTrials.gov Identifier: NCT05292872 
Sponsor 
Intercept Pharmaceuticals, Inc. 
305 Madison Avenue 
Morristown, New Jersey 07960 
USA 
TEL: + 1 858 652 6800 
FAX: + 1 858 558 5961 
CONFIDENTIAL 
The info1mation contained herein is the property of Intercept Phaimaceuticals, Inc. and may not be 
reproduced, published, or disclosed to others without written authorization of Intercept Pha1maceuticals, 
Inc. 

Protocol 747-404/405 
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Pa _e2 
SPONSOR'S APPROVAL OF THE PROTOCOL 
Reviewed and Approved by: 
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Intercept Phaim aceuticals, Inc. 
Confidential and Proprietary 

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INVESTIGATOR’S AGREEMENT 
 
I have received and read the current version of the Investigator’s Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-404/405.  Having fully considered all the information 
available, I agree that it is ethically justifiable to conduct this study 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, study protocol 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 747-404/405 and in accordance 
with the elements of Good Clinical Practice (CPMP/ICH/135/95) and the Declaration of Helsinki 
relevant to observational research, and all regulatory requirements for protection of human 
subjects in 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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STUDY PERSONNEL CONTACT INFORMATION 
Sponsor Contact Information 
 
Primary Contact:   
 PhD 
 Global Medical Affairs 
Intercept Pharmaceuticals Inc. (Intercept) 
Telephone: 
 
Email: 
 
 
SAE Reporting Information 
SAE Fax: 
+1 800 497 8521 
ISAE Email: 
sae@interceptpharma.com 
 
Or if Not Available: 
Contact: 
 MD 
 Scientific Affairs 
Intercept 
Telephone: 
 
Email: 
 
 
 

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1. 
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:  
Replicate Studies Evaluating the Effectiveness of Obeticholic Acid on Hepatic Real-World Outcomes in Patients 
with Primary Biliary Cholangitis (HEROES PBC) 
Investigators and/or Study Center(s):  
Alexander Breskin (Target, University of North Carolina - Chapel Hill) 
M. Alan Brookhart (Target, Duke University) 
Michael Fried (Target) 
Bettina Hansen (University Health Network) 
Gideon Hirschfield (University Health Network) 
John Seeger (Optum) 
David Thompson (Syneos Health) 
Rajeshwari Punekar (Syneos Health) 
Studied Period (years):  
Estimated initial patient inclusion date 01 Jun 2015  
Estimated date last patient observation: 31 Dec 2021 
Phase of Development:   
Phase 4 
 
Objectives:  
Primary Objective 
To evaluate the effect of OCA treatment on time to the first occurrence of the composite endpoint of all-cause death, 
liver transplant, or hospitalization for hepatic decompensation in PBC patients in 2 data sources: Global PBC 
registry and Komodo Health claims database. 
Exploratory Objectives:  
To evaluate the effect of OCA treatment on time to the first occurrence of individual components of the composite 
endpoint (outlined below): 
• 
All-cause death  
• 
Liver transplant  
• 
Hospitalization for hepatic decompensation based on the first occurrence of: 
o 
Variceal bleed 
o 
Ascites (including hepatic hydrothorax and spontaneous bacterial peritonitis) 
o 
Hepatic encephalopathy   
Methodology:  
These are replicate, observational, retrospective cohort studies of patients with PBC who failed ursodeoxycholic 
acid (UDCA) treatment using 2 real-world data sources:  the Global PBC registry (Study 747-404) and the Komodo 
Health United States (US) claims database (Study 747-405).  All analyses will be conducted separately by data 
source (ie, not pooled).  The primary endpoint is time to first occurrence of all-cause death, liver transplant, or 
hospitalization for hepatic decompensation.  The analytic approach is a nested target trial emulation design. 

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The Komodo Health database contains administrative claims from >350 US payers, including commercial (63%); 
Medicaid (23%); Medicare (10%); dual eligible (<1%); and other (2%). Data are tokenized to allow for patient 
tracking across payers. Komodo Health claims will be linked through Datavant tokenization to Quest Diagnostics
and LabCorp laboratory data, the US National Death Index (NDI), and the Organ Transplant Network (OPTN) 
transplant registry for additional information and outcome verification. The database contains >100,000 patients 
with a PBC diagnostic code. The Global PBC registry includes >5,000 patients with PBC recruited from 17 liver 
centers across 8 countries in Europe and North America. It utilizes the CASTOR trial platform for electronic case 
report form (eCRF) collection of medical history, clinical events, and laboratory and treatment data.
All patients who meet diagnostic criteria for PBC in each database between 01 Jun 2015 and 31 Dec 2021 and who 
meet all eligibility criteria will be considered for these studies. The OCA treatment evaluation period will be from 
01 Jun 2016 (based on first country approval by Food and Drug Administration on 27 May 2016). The Komodo 
Health database is US-specific and the Global PBC registry includes the US and multiple other countries with later
approval dates. The Sponsor has applied the date of first global approval of 01 Jun 2016 for both studies. The first 
date of prescription of OCA after inadequate UDCA response (ALP>upper limit of normal [ULN] and/or total 
bilirubin [TB]>ULN after >270 days of treatment) or UDCA intolerance (discontinued UDCA after <90 days
despite ALP>ULN and/or TB>ULN) will be defined as the index date for OCA-treated PBC patients. The dates of 
evidence of inadequate UDCA response or UDCA intolerance during which OCA is not utilized will be used as an
index date for the non–OCA-treated comparator group. 
Each time a patient meets the UDCA inadequate response/intolerance definition or the definition of OCA initiation,
in addition to all other eligibility criteria, they will contribute an index to the study. Therefore, patients may 
contribute multiple control indices, and may contribute control indices before OCA initiation, but can contribute 
only one OCA initiation index. The non–OCA-treated patient indices will be weighted to have the same baseline 
covariate distribution as the OCA-treated patients at the time of OCA initiation, thus allowing for the estimation of 
the effect of treatment in the treated patients. The pre-index period is defined as 12 months prior to the index date, 
and follow-up is until the first occurrence of any component of the composite endpoint. Patients will be censored at 
dropout/disenrollment from the database, discontinuation of OCA (+90 days), initiation of fenofibrate or bezafibrate, 
initiation of OCA (for the non–OCA-treated patient -indices), unapproved OCA dose (>10 mg once daily [QD]) for 
those treated with OCA, or the end of the study period (31 Dec 2021), whichever comes first.
Schematic Diagram Studies 747-404/405:
Number of Patients (planned):
Komodo Health:  In the current Komodo Health database, there are 395 patients who meet all of the following
criteria for the OCA treatment group:
•
Meet PBC claims diagnostic criteria (1 inpatient or 2 outpatient claims)
•
Have evidence of UDCA failure
•
Have initiated OCA treatment

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There are 5916 patients who meet all of the following criteria for the control group (OCA-eligible but not currently 
OCA-treated) 
• 
Meet PBC claims diagnostic criteria (1 inpatient or 2 outpatient claims) 
• 
Have at least 270 days of UDCA use before elevated ALP and/or TB inclusive of up to 4 instances of elevation 
(inadequate response) or <90 days UDCA use despite elevated ALP and/or bilirubin (intolerant) 
• 
Have elevated ALP >ULN and/or TB >ULN 
 
The Komodo Health database has not yet been linked to LabCorp laboratory database.  It is anticipated that the 
number of patients in each group will approximately double with the availability of LabCorp data. 
Global PBC registry:  The Global PBC registry data are currently being refreshed.  A previous analysis identified 
344 patients who had initiated OCA.  Among the >5000 patients not treated with OCA, it is anticipated that >2200 
will meet criteria for UDCA failure and for inclusion in the control group (Corpechot 2008, Kumagi 2010). 
Diagnosis and Main Criteria for Inclusion:  
The treatment group will be patients with PBC with a history of inadequate response or intolerance to UDCA who 
initiated OCA in the study window.  The control group will be PBC patients with a history of inadequate response or 
intolerance to UDCA who were eligible but not treated with OCA (or off-label fibrates) in the study window.  
Key Inclusion Criteria 
A patient who meets all of the following criteria for a given index date is eligible for inclusion: 
• 
Definite or probable PBC diagnosis 
o 
Global PBC registry (consistent with American Association for the Study of Liver Diseases [AASLD] and 
the European Association for the Study of the Liver [EASL] practice guidelines; Lindor 2009, 
EASL 2009): presence of ≥2 of the following 3 diagnostic factors: 
▪ 
History of elevated ALP levels for at least 6 months 
▪ 
Positive antimitochondrial antibody (AMA) titer  
▪ 
Liver biopsy finding consistent with PBC 
o 
Komodo Health claims data: one of the following (Meyers 2010):  
▪ 
≥1 inpatient claim with a PBC admission diagnosis at any position (ie, primary, secondary 
diagnosis, etc.)  
▪ 
≥2 outpatient claims with a PBC diagnosis on separate days 
• 
Inadequate response or intolerant to UDCA (see definitions below) 
• 
Age ≥18 years at the index date 
• 
Continuous enrollment and evaluable data for at least 12 months before the index date (inclusive) 
Key Exclusion Criteria:  
A patient who meets any of the following criteria for a given index date is not eligible for inclusion: 
• 
History or presence of the following concomitant liver diseases before the index date (inclusive), including: 
o 
Acute or chronic hepatitis C virus infection  
o 
Acute or chronic hepatitis B infection 
o 
Primary sclerosing cholangitis  
o 
Active alcoholic liver disease  
o 
Hepatocellular carcinoma  
o 
Hepatorenal syndrome  
o 
Hepatopulmonary syndrome 
o 
Portopulmonary syndrome 
o 
Nonalcoholic steatohepatitis (NASH) 
• 
History of non-skin malignancy or melanoma before the index date (inclusive) 
• 
History of HIV before the index date (inclusive) 
• 
Medical conditions that may cause non-hepatic increases in ALP such as: 
o 
Paget's disease during the 12-month period before the index date (inclusive) 
o 
Fractures within 3 months before the index date (inclusive) 

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• 
Patients with laboratory values indicative of hepatic decompensation or significant hepatobiliary injury before 
the index date (inclusive) 
o 
TB >3 mg/dL 
o 
ALP >10x ULN 
o 
ALT and/or AST >10x ULN 
• 
History of liver transplant before the index date (inclusive) 
• 
Evidence of OCA, fenofibrate, or bezafibrate use before the index date (inclusive)   
• 
History or presence of any of the following hepatic decompensating events before the index date (inclusive): 
o 
Variceal bleeding 
o 
Ascites 
o 
Hepatic hydrothorax 
o 
Spontaneous bacterial peritonitis 
O 
Hepatic encephalopathy 
Definitions: 
• 
UDCA failure:  
o 
Inadequate response requires both of the following: 
− 
At least 1 measure of ALP>ULN and/or TB>ULN 
− 
>270 days of UDCA treatment prior to ALP and/or TB elevation 
o 
Intolerant: 
− 
A maximum of 90 days of UDCA use with ALP>ULN and/or TB >ULN 
Group Assignments: 
o 
Treatment group (OCA-treated): ≥1 prescription or medical claim for OCA at or after UDCA failure date.  
The first date will be the one index date. 
o 
Control Group (Non-OCA-treated but eligible for OCA): Each date corresponding to evidence of a patient 
meeting the definition of UDCA inadequate response or intolerance in which the patient meets the inclusion and 
exclusion criteria and does not initiate OCA will be an index date for the non–OCA-treated patient group.  
Patients may contribute indices to this group before they initiate OCA, but not after OCA index. 
Study medication, Dosage and Mode of Administration:  
OCA tablet, 5 mg to 10 mg, once daily, oral administration 
Patients may down titrate to <5 mg daily, but are censored if dose exceeds 10 mg per day.  
Study drug is not provided nor administered by the Sponsor but is recorded by either administrative claim or registry 
CRF. 
Duration of treatment will range from 1 to 67 months 
Reference Therapy, Dosage and Mode of Administration:  
Not applicable 
Data Sources 
The data source for each analysis will include one of the following: 
1. Komodo Health US administrative claims database linked to the following: 
• 
Laboratory measures (Quest Diagnostics and LabCorp) 
• 
National Death Index (US NDI) 
• 
National transplant registry (OPTN registry) 
Or 
2. Global PBC registry 

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Criteria for Evaluation: 
Primary Outcome: 
As-treated time to the first event of the composite endpoint of all-cause death, liver transplant, or hospitalization for 
hepatic decompensation, whichever occurs first. 
Exploratory Outcomes: 
As-treated time to the first occurrence of individual components of the composite endpoint: 
• 
All-cause death 
• 
Liver transplant 
• 
Hepatic decompensation requiring hospitalization assessed through claims or registry CRF and defined as first 
occurrence of:  
o 
Variceal bleed 
o 
Ascites (including hepatic hydrothorax and spontaneous bacterial peritonitis) 
o 
Hepatic encephalopathy   
Exposure Variable: 
The exposure variable is the use of OCA initiated at the index date. 
Covariates:  
The following covariates/control variables will be assessed in the pre-index period, utilizing the value closest to 
the index date: 
• 
Age at index date 
• 
Sex 
• 
Most recent liver biochemistry levels (TB, ALP, ALT, AST) 
• 
Most recent platelet counts  
• 
Time (in months) since UDCA failure 
• 
Clinical evidence of portal hypertension (platelets <150,000 and/or non-bleeding varices) 
• 
Cirrhosis  
• 
Most recent Charlson Comorbidity Index Score  
• 
Insurance type at index date (Komodo Health only) 
Statistical Methods: 
Analysis Populations   
The statistical analysis of the HEROES PBC studies will follow a nested randomized trial emulation approach 
(Hernán 2008, Danaei 2013) using a treatment decision design to identify index events (Brookhart 2015).  Due to 
the lack of randomization, non-randomized observational studies will instead be conducted, with the goal of 
mimicking the hypothetical randomized trial as closely as possible.  All patients will be evaluated over time from the 
start of the study period to identify evidence of inadequate treatment response to UDCA.  Each date of inadequate 
response identified in the data will be considered a treatment decision point, and that date will be considered an 
index date, with a corresponding record created in the analytic data for that patient index.  Each patient can 
contribute multiple index dates and thus patient indices, corresponding to each date they have a treatment decision 
point, and therefore each patient may contribute person-time to multiple patient index records.  
It is likely that OCA-treated and non–OCA-treated patient indices will differ on confounding variables, ie, variables 
that influence both treatment and outcome.  To address differences in the covariate distribution between treatment 
groups, the Sponsor will first conduct descriptive analyses on all baseline variables (demographics, clinical 
characteristics, and treatment history) for the OCA-treated and non–OCA-treated groups at index.  Standardized 
mortality/morbidity ratio (SMR) weights then will be used to create a pseudo-population of non–OCA-treated 
indices with the same covariate distribution as the OCA-treated patients at the time of OCA initiation (Sato 2003), 
and unweighted and weighted standardized mean differences will be computed.  
Primary Analysis: 
The objective of the primary analysis is to estimate the as-treated effect of OCA treatment versus non–OCA-based 
treatment on the composite endpoint of all-cause death, liver transplant, or decompensation requiring 
hospitalization.  The primary analysis outcome will be assessed with the hazard ratio comparing the hazard of the 
first event of the composite endpoint among the OCA-treated patients and standardized morbidity ratio-weighted 

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non–OCA-treated PBC patient indices.  The hazard ratio will be estimated using a Cox proportional hazards model.  
The nonparametric bootstrap will be used to estimate the standard error of the estimate, which will then be used to 
generate 95% CI for the hazard ratio and to perform a test of the hypothesis that the hazard ratio is equal to the null 
value of 1. 
Exploratory Analysis: 
The exploratory objectives are to estimate the effect of OCA treatment versus non-OCA treatment on each 
component of the composite endpoint (all-cause death, liver transplant, or hepatic decompensation).  The 
exploratory analysis outcomes will be assessed with the subdistribution hazard ratio comparing the hazard of the 
first event of each element of the composite endpoint, separately, among the OCA-treated patients and standardized 
morbidity ratio-weighted non–OCA-treated PBC patient indices.  For the endpoint of liver transplant, death will be 
treated as a competing event.  For the endpoint of hepatic decompensation, death and liver transplant will be treated 
as competing events.  The subdistribution hazard ratio will be estimated using a Fine-Gray proportional 
subdistribution hazards model.  The nonparametric bootstrap will be used to estimate the standard error of the 
estimates, which will then be used to calculate 95% CI for the hazard ratio and perform a test of the hypothesis that 
the hazard ratio is equal to the null value of 1. 
Sample Size Justification:  
Using the expected sample size in the 2 populations, the Sponsor computed power to detect treatment effects 
(relative hazards) of varying sizes, estimated using Cox proportional hazards regression.  Computations are based on 
the formulae of Schoenfeld 1983.  To account for confounding control due to the application of IP weights, the 
Sponsor inflated the variance from the Schoenfeld formula using factors derived by Shook-Sa 2020.  It was 
conservatively assumed just one control observation per patient.  In the Komodo Health data, a preliminary 
investigation found that approximately 395 patients who meet entry criteria initiate OCA and that 5916 patients will 
contribute at least one record to the control group (UDCA nonresponders).  In the Global PBC registry, the Sponsor 
expects to have 344 patients meeting entry criteria who initiate OCA, and 2200 who contribute at least one 
observation to the control group.  Power in both cohorts was computed for relative hazards ranging from 0.5 to 0.9 
with an alpha level of 0.05.  The Sponsor considered baseline event rates during follow-up from 5% to 15% and 
variance inflation corresponding to mild confounding (VIF=1.05), moderate confounding (VIF=1.5), and strong 
confounding (VIF=2.0).  In each study, power was plotted under these assumptions against a reference line of 80% 
power under moderate confounding (VIF=1.5). 
Under mild confounding, both studies will be well-powered to detect an HR of 0.5.  For moderate confounding, the 
Komodo Health study will be adequately powered to detect HR of 0.5 for event rates >6%.  The Global PBC 
registry will be adequately powered to detect event rates >8%.  Under strong confounding, the Komodo Health 
study will be adequately powered to detect HR of 0.5 for event rates >9%.  The Global PBC registry will be 
adequately powered to detect event rates >11%.  Power decreases for more moderate HRs.  None of the studies 
under even the most favorable assumptions will be able to detect HRs of 0.9.  The Sponsor notes that the 
assumptions made here are conservative; in particular, it is expected that many more than one control observation 
and that the addition of lab data from LabCorp to will substantially increase the size of both treatment groups in the 
Komodo Health study. 
Subgroup Analyses: 
The entire analysis will be repeated separately by patient race (Komodo Health only), age (categorical), sex, region, 
presence/absence of cirrhosis, and pre-/post-COVID.  Because race is not completely captured in either database, 
these analyses will only include those with non-missing values for race. 
 
Sensitivity Analyses: 
• 
An analysis will be conducted in the Komodo database to assess the performance of a claims-based PBC 
definition with AMA test results as the gold standard. 
• 
Quantitative bias analysis to quantify the sensitivity of the estimate to violations of the assumption of no 
unmeasured confounding.  
 

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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
SYNOPSIS ................................................................................................................... 5 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ............... 11 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................. 14 
4. 
INTRODUCTION ...................................................................................................... 16 
4.1. 
Overview of Disease State and OCA .......................................................................... 16 
4.2. 
Mechanism of Action of OCA .................................................................................... 16 
4.3. 
Nonclinical Experience with OCA ............................................................................. 17 
4.4. 
Clinical Experience with Obeticholic Acid ................................................................ 17 
4.5. 
Rationale for Study Design and Dose for OCA .......................................................... 19 
4.5.1. 
Rationale for Study Design ......................................................................................... 19 
4.5.2. 
Rationale for Dose ...................................................................................................... 19 
4.5.3. 
Rationale for Control Group ....................................................................................... 19 
4.6. 
Summary of Safety with OCA .................................................................................... 19 
4.6.1. 
Clinical Trial Exposure and Safety Experience .......................................................... 19 
4.6.2. 
Known and Potential Risks of OCA ........................................................................... 20 
5. 
STUDY OBJECTIVES AND PURPOSE .................................................................. 22 
5.1. 
Pri1nary Objective ....................................................................................................... 22 
5.2. 
Exploratory Objectives ............................................................................................... 22 
6. 
INVESTIGATIONAL PLAN ..................................................................................... 22 
6.1. 
Overall Design ............................................................................................................ 22 
6.1.1. 
Design Diagram .......................................................................................................... 23 
6.2. 
Number of Patients ..................................................................................................... 23 
7. 
SELECTION OF PATIENTS ..................................................................................... 24 
7 .1. 
Study Population ......................................................................................................... 24 
7.1.1. 
Definition ofUDCA Failure ....................................................................................... 24 
7.2. 
Inclusion Criteria ........................................................................................................ 25 
7.3. 
Exclusion Criteria ....................................................................................................... 25 
7.4. 
Group Assignrnents .................................................................................................... 26 
7.5. 
Study Product, Dosage and Mode of Administration ................................................. 27 
Confidential and Proprieta1y 

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7.6.
Study Period ................................................................................................................27
8.
ASSESSMENT OF EFFICACY ................................................................................27
8.1.
Primary Outcomes/Endpoints .....................................................................................27
8.2.
Exploratory Outcomes ................................................................................................29
8.3.
Exposure Variable ......................................................................................................29
9.
ASSESSMENT OF SAFETY .....................................................................................29
10.
STATISTICAL METHODS .......................................................................................29
10.1.
Analysis Populations and Blinding .............................................................................29
10.1.1.
Analysis Populations ..................................................................................................29
10.1.2.
Blinding ......................................................................................................................32
10.2.
Estimation of Effect Size ............................................................................................32
10.3.
Hypotheses ..................................................................................................................33
10.3.1.
Primary Hypothesis ....................................................................................................33
10.4.
Determination of Sample Size ....................................................................................33
10.5.
Primary Efficacy Analysis ..........................................................................................34
10.6.
Exploratory Analyses ..................................................................................................35
10.7.
Handling of Dropouts or Missing Data ......................................................................35
10.8.
Subgroup Analyses .....................................................................................................35
10.9.
Sensitivity Analyses ....................................................................................................35
10.10.
Assessment of Claims-based PBC Definition ............................................................36
10.11.
Clean Room Committee .............................................................................................36
11.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................37
12.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................38
12.1.
Data Collection and Transfer ......................................................................................38
12.1.1.
Komodo Health ...........................................................................................................38
12.1.2.
Global PBC Registry ..................................................................................................38
12.1.3.
National Death Index ..................................................................................................39
12.1.4.
Quest Diagnostics .......................................................................................................39
12.1.5.
LabCorp ......................................................................................................................39
12.1.6.
OPTN Transplant Registry .........................................................................................39
12.2.
Data De-identification ................................................................................................40
12.2.1.
Global PBC Registry ..................................................................................................40

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12.2.2. 
Komodo Health ...........................................................................................................40 
12.3. 
Data Linkages .............................................................................................................41 
12.4. 
Data Harmonization ....................................................................................................42 
12.4.1. 
Komodo Health and National Death Index ................................................................42 
12.4.2. 
Komodo Health and OPTN Liver Transplant .............................................................42 
12.4.3. 
Komodo Health Hospitalization for Hepatic Decompensation ..................................42 
12.4.4. 
Quest Diagnostics and LabCorp .................................................................................43 
12.4.5. 
Cirrhosis ......................................................................................................................44 
12.5. 
Characterization of Missing Data ...............................................................................46 
12.6. 
Data Management and Analysis SOPs .......................................................................46 
12.7. 
Audits and Inspections ................................................................................................46 
12.8. 
Quality Control and Quality Assurance ......................................................................46 
12.9. 
Data Retention and Archiving Study Documents .......................................................46 
13.
PROTECTION OF HUMAN SUBJECTS .................................................................47 
14.
ADVERSE EVENT REPORTING ............................................................................47 
15.
PUBLICATION POLICY ..........................................................................................47 
16.
LIST OF REFERENCES ............................................................................................49 
APPENDIX A. LIST OF INCLUSION, EXCLUSION AND COVARIATE CODES .............51 
APPENDIX B. TABLE SHELLS ...............................................................................................70 
LIST OF TABLES 
Table 1: 
Composite Endpoints for OCA PBC Studies .............................................................28 
Table 2: 
Comparison of Imaging-based (Global PBC) and Claims-based (HealthCore, 
Optum) Prevalence of Cirrhosis in PBC Patients. ......................................................45 
LIST OF FIGURES 
Figure 1: 
Design Schematic Studies 747-404/405 .....................................................................23 
Figure 2: 
Power estimates by Hazard Ratio by Level of Confounding for Komodo 
Health (A) and Global PBC Registry (B). ..................................................................34 
Figure 3: 
Incidence Rates for Major Hepatic Events Stratified by Cirrhosis, Portal 
Hypertension and Hepatic Decompensation in the Optum (A) and 
HealthCore (B) Databases ..........................................................................................45 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this protocol. 
Abbreviation or Specialist Term 
Explanation 
AASLD 
American Association for the Study of Liver Diseases 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
antimitochondrial antibody 
AST 
aspartate aminotransferase 
CDCA 
chenodeoxycholic acid  
CRC 
Clean Room Committee 
CRO 
Clinical Research Organization 
CVD 
cardiovascular disease 
DB 
double-blind 
DMC 
data monitoring committee 
EASL 
European Association for the Study of the Liver 
eCRF 
electronic case report form 
EU 
European Union 
FDA 
Food and Drug Administration 
FXR 
farnesoid X receptor 
ICD 
International Classification of Diseases 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
HIPAA 
Health Insurance Portability and Accountability Act  
INR 
international normalized ratio 
ITT 
intent-to-treat 
LLN 
lower limit of normal 
LTSE 
long-term safety extension 
MELD 
Model for End-Stage Liver Disease 
NASH 
nonalcoholic steatohepatitis 
NDI 
National Death Index 
OCA 
obeticholic acid 
OPTN  
Organ Transplant Network 

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Abbreviation or Specialist Term 
Explanation 
PBC 
primary biliary cholangitis 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PPV 
positive predictive value 
QD 
once per day 
RWE 
real-world evidence 
SDTM 
Study Data Tabulation Model 
SMD 
standardized mean differences 
SOP 
standard operating procedure 
TB 
total bilirubin 
TEAE 
treatment-emergent adverse event 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 
US 
United States 
 

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4. 
INTRODUCTION 
4.1. 
Overview of Disease State and OCA 
Primary biliary cholangitis, (PBC) is a serious, life-threatening, cholestatic liver disease of 
unknown etiology that, without treatment, frequently progresses to hepatic fibrosis and eventual 
cirrhosis or hepatic decompensation and necessitates liver transplantation or results in death.  
PBC is a rare disease with a reported prevalence in the United States (US) of 40/100,000 
(Kim 2000).  PBC disproportionately affects women (with a female to male ratio of 
approximately 10:1) and is typically diagnosed in patients aged 40 to 60 years. 
The only approved drug therapy for PBC has been the bile acid ursodeoxycholic acid (UDCA), a 
physiological constituent of human bile (Lindor 2009).  While UDCA therapy had a marked 
effect on the treatment of PBC, up to 40% of patients showed a suboptimal response or no 
response to UDCA (Corpechot 2008, Kumagi 2010).  Such patients were at significantly 
increased risk of a poor clinical outcome due to PBC disease progression.  Obeticholic acid 
(OCA) is a farnesoid X receptor (FXR) agonist and a modified bile acid that is derived from the 
primary bile acid chenodeoxycholic acid (CDCA), the natural human FXR ligand.  OCA 
(Ocaliva) has received marketing authorization in the US, the European Union (EU), and 
several other countries for the treatment of PBC in combination with UDCA in adults with an 
inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA.  In the US, 
Ocaliva is contraindicated in patients with decompensated cirrhosis (eg, Child-Pugh Class B or 
C), a prior decompensation event, complete biliary obstruction, or compensated cirrhosis with 
evidence of portal hypertension.  Approval in the US and the EU was based on a surrogate 
endpoint (reduction in ALP), and as part of regulatory commitments in these regions, the 
following postmarketing studies were initiated: Study 747-302, a Phase 3b/4 study designed to 
prospectively obtain evidence to confirm clinical benefit in PBC subjects, and Study 747-401, a 
Phase 4 study designed to evaluate the pharmacokinetics (PK) and safety of OCA in PBC 
subjects with hepatic impairment.  Both 747-302 and 747-401 terminated early, due to the 
challenges of recruitment and long-term retention of patients with a rare disease subsequent to 
Ocaliva regulatory approval.  Changes to endpoints and statistical analysis plans to accommodate 
low recruitment, low events rates, and early termination may necessitate the need for clinical trial 
data to be supplemented with real-world evidence, with the goal of providing regulators with a 
more complete evidence package characterizing the efficacy and safety of OCA in patients with 
PBC.  
4.2. 
Mechanism of Action of OCA 
OCA is a 6α-ethyl derivative of the naturally occurring primary human bile acid CDCA, which is 
the endogenous ligand for FXR.  FXR is a ligand-dependent transcription factor that is part of 
the nuclear receptor superfamily.  FXR regulates a wide variety of target genes involved in the 
control of bile acid, lipid, and glucose homeostasis and in the regulation of immune responses.  
OCA’s potent FXR agonist effects are believed to account for the predominant efficacy of the 
investigational product.  Some of the pharmacological properties of OCA and other FXR 
agonists that have been elucidated in animal models of chronic liver disease relevant to the 
treatment of PBC include the following: 

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• Improvement in hepatic choleresis with reduced inflammation and necrosis 
• Prevention and reversal of hepatic fibrosis 
The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and 
anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury 
and improved liver function in a cholestatic liver disease, such as PBC. 
4.3. 
Nonclinical Experience with OCA 
Intercept Pharmaceuticals, Inc. (the Sponsor) has completed a standard battery of nonclinical 
safety pharmacology and toxicology studies.  No major nonclinical safety effects have been seen 
other than pharmacologic hepatic effects observed at high doses.  These pharmacologic hepatic 
effects are consistent with the detergent effects of a bile acid at exceedingly high hepatocellular 
exposure.  
4.4. 
Clinical Experience with Obeticholic Acid 
As of 03 May 2021, approximately 4438 subjects have received ≥1 dose of OCA.  This 
estimation includes subjects from blinded ongoing studies.  Of these subjects, 978 were healthy 
volunteers, 610 subjects had PBC, 72 subjects had primary sclerosing cholangitis, 7 subjects had 
biliary atresia, 41 subjects had diabetes mellitus with non-alcoholic fatty liver disease, 
2697 subjects had nonalcoholic steatohepatitis (NASH), and 33 subjects had portal hypertension 
due to alcoholic cirrhosis.  
As of 03 May 2021, the clinical pharmacology of OCA had been evaluated in 19 completed 
Phase 1 studies.  Overall, the PK of OCA shows the profile expected of a natural bile acid.  
There is rapid absorption of unconjugated OCA (parent), followed by extensive conjugation to 
glycine and taurine to form glyco-OCA and tauro-OCA, respectively.  Glyco-OCA and 
tauro-OCA occur at significantly higher concentrations than the parent drug does.  There are 
numerous peak and trough plasma concentrations observed, consistent with the expected 
extensive enterohepatic circulation of a bile acid.  Plasma concentrations dramatically increase 
shortly after food intake, consistent with the gall bladder emptying into the duodenum.  The 
glyco-OCA and tauro-OCA conjugates of OCA are known to be pharmacologically active, and 
due to enterohepatic recycling of OCA and its conjugates, their plasma PK profiles are most 
relevant.  
Data that supported approval of Ocaliva included 3 randomized, double-blind, 
placebo-controlled, multi-center, international studies in subjects with PBC:   
• Study 747-201 was a Phase 2, 3-month, international, double-blind, placebo-controlled, 
parallel-group study in subjects with a proven or likely diagnosis of PBC whose disease was 
sub-optimally controlled.  In this study, OCA doses of 10 mg and 50 mg were evaluated as 
monotherapies.   
• Study 747-202 was a Phase 2, 3-month, international, double-blind, placebo-controlled, 
parallel-group study in subjects with a proven or likely diagnosis of PBC who were 
sub-optimally controlled.  OCA doses of 10 mg, 25 mg, and 50 mg were evaluated as add-on 
therapy to UDCA, the current standard of care for PBC.   

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• Study 747-301(POISE) was the pivotal Phase 3, 12-month, international, double-blind, 
placebo-controlled study in subjects with a proven or likely diagnosis of PBC whose disease 
was sub-optimally controlled.  In this study, OCA doses evaluated were 10 mg or a titration 
approach (ie, 5 mg for the initial 6 months, with up-titration to 10 mg for the last 6 months if 
the subject did not meet the primary composite endpoint and had no tolerability issues).   
In the double-blind, Phase 2 Studies 747-201 and 747-202, treatment with OCA for 3 months in 
subjects with PBC resulted in statistically and clinically significant reductions in ALP, a known 
surrogate for risk of long-term clinical outcomes in PBC, as well as markers of hepatic damage 
and inflammation.  Consistent efficacy results were observed irrespective of whether OCA was 
administered as monotherapy or as an add-on to UDCA.  Within each study, OCA doses above 
10 mg did not show substantially better efficacy compared with OCA 10 mg, but the incidence 
and severity of pruritus were increased, suggesting that 10 mg was the maximally efficacious 
dose and that evaluation of lower doses in the Phase 3 program was warranted.   
The Phase 3 study met its primary endpoint.  Both OCA treatment groups (OCA titration and 
OCA 10 mg) were superior to placebo in achieving the primary endpoint at all timepoints across 
the 12-month treatment period (p<0.0001 versus placebo). 
Each of these 3 studies included open-label, uncontrolled, long-term safety extension (LTSE) 
phases to evaluate the long-term effects of OCA treatment.  As of 03 May 2021, the LTSEs of 
Studies 747-201, 747-202, and 747-301 are completed.  
Study 747-301 LTSE:  A total of 217 subjects were enrolled into the double-blind phase of the 
study; of the 198 subjects who completed the double-blind phase, 193 subjects (98%) enrolled 
into the LTSE phase.  Overall, there was good retention in the study:  146 (76%) subjects 
completed the protocol as specified after administrative termination/closure of the study, and 
47 (24%) subjects discontinued the LTSE prematurely.  The majority of subjects discontinued 
because of study closure by the Sponsor.  The efficacy associated with continued treatment with 
OCA up to 6 years was durable and consistent with the effects observed in the double-blind 
phase.   
An additional 8-week, open-label study was also supportive of Ocaliva approval; however, 
efficacy data from this study were not integrated with Studies 747-201, 747-202, and 747-301 
because of differences in study design and endpoints: 
• Study 747-205 assessed the safety, tolerability, and pharmacodynamic (PD) effects of 
OCA on high-density lipoprotein cholesterol metabolism in subjects with PBC on a 
stable dose of UDCA.  The LTSE phase is considered complete the clinical study 
report approved 07 Jan 2021. 
Postmarketing studies in subjects with PBC include the following:   
• Study 747-302 (COBALT; postmarketing requirement) is a double-blind, 
randomized, placebo-controlled, multicenter study designed to prospectively obtain 
evidence to confirm clinical benefit and further evaluate the benefit-risk profile of 
OCA treatment in subjects with PBC.  Last Patient Last Visit occurred on 
23 Dec 2021. 

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4.5.1. 
• 
Study 747-401 (postmarketing requirement) is a double-blind, randomized, 
placebo-contrnlled study evaluating the PK and safety of OCA in subjects with PBC 
and moderate to severe hepatic impanment. This study was closed as of 09 Jul 2021. 
Rationale for Study Design and Dose for OCA 
Rationale for Study Design 
Studies 747-404 and 747-405 are replicate, observational, retrnspective coho1i studies. In rare 
diseases, real-world retrospective observational studies utilizing claims and registry data have 
been recognized by the US Food and Drng Adminisu-ation (FDA) as viable for various 
regulato1y use-cases, including constructing of external contr·ol anns for clinical tr·ials (US Food 
and Drng Administration 2018, US Food and Drng Adminisu-ation 2021). 
The analytic approach, a nested randoinized tr·ial emulation using a tr·eatment decision design to 
identify index events (Heman 2008, Danaei 2013, Brookha1i 2015), was selected to best inimic a 
clinical u-ial and has been shown to replicate tr·ial results in epideiniologic data when other 
real-world approaches have not (Heman 2008). This design emulates a sequence of hypothetical 
randoinized tr·ials, and, though non-randomized and non-blinded, miinics trial eligibility criteria, 
definition of staii of follow-up, and tr·eatment aims (initiators vs. non-initiators). Standardized 
morbidity ratio-weighting is used to adjust for imbalances in patient characteristics at index. The 
approach will produce an average hazard (rate) ratio (HR) and 95% confidence interval, 
comparing OCA initiators to non-initiators, thus yielding the standai·d output of a clinical study 
that is amenable to statistical hypothesis testing (ie, null hypothesis: HR=l). An as-tr·eated 
approach was deemed superior to an intent-to-tr·eat (ITT) approach, as the ITT approach in 
epideiniological data often causes severe tr·eatment inisclassification, paii icularly in chronic 
disease (Heman 2008). 
4.5.2. 
Rationale for Dose 
The Ocaliva prescribing info1mation states that the approved dosing is 5 mg once daily (QD) 
with allowable up-titr·ation to a maximal dose of 10 mg QD. Patients prescribed OCA will be 
censored if they exceed the maximal allowable daily dose. Down-titration (less than daily 
dosing) can be utilized in response to adverse events such as prnritus, and as such, patients dosed 
<5 mg QD will continue to be counted in the OCA-u-eated aim. 
4.5.3. 
Rationale for Control Group 
Using standai·dized eligibility criteria across tr·eated and untr·eated patients and utilizing a 
standai·dized morbidity ratio- weighted-OCA eligible but non-OCA-tr·eated compai·ator group 
will provide the best scientific compai·ative evidence of efficacy. 
4.6. 
4.6.1. 
Summary of Safety with OCA 
Clinical Trial Exposure and Safety Experience 
As of 03 May 2021, approximately 6183 subjects have been emolled in the development 
program for OCA. Approximately 4438subjects received ::::1 dose of OCA in clinical studies 
sponsored by Intercept and Sumitomo Dainippon Phanna Co., Ltd. (Intercept's fo1mer 
Confidential and Proprieta1y 

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development partner in China, Korea, and Japan).  Of these, a total of 610 PBC subjects had 
received ≥1 dose of OCA in completed (Studies 747-201 Double-Blind [DB], 747-201 LTSE, 
747-202 DB, 747-202 LTSE, 747-205 Primary Treatment Phase, 747-301 DB, and 747-301
LTSE), ongoing unblinded (Study 747-205 LTSE), or blinded (Studies 747-302 and 747-401)
studies.
In the completed studies, the majority of subjects had at least 5 years of exposure to OCA, and a 
small subset were exposed for more than 7 years.  A total of 421 (97%) of these subjects who 
received OCA experienced treatment-emergent adverse events (TEAEs) during the study, and 
379 (88%) subjects experienced investigational product–related TEAEs.  Although the rate of 
TEAEs was higher in OCA-treated subjects compared with placebo-treated subjects, the 
differences noted in these incidence rates may be at least partially due to cumulative exposure 
differences between OCA and placebo.  The most frequently reported TEAEs by System Organ 
Class in subjects receiving OCA were those classified as skin and subcutaneous tissue disorders 
(84%), gastrointestinal disorders (62%), and infections and infestations (56%).  The most 
frequently reported (≥20% of subjects) individual TEAEs were pruritus (80%) and fatigue 
(26%).  
While studies were ongoing, the data monitoring committee (DMC) convened at least every 
6 months to review safety data for ongoing, double-blind, placebo-controlled postmarketing 
requirement studies 747-302 and 747-401.  On 25 Mar 2020, the DMC recommended that both 
studies continue without modifications, consistent with prior periodic reviews.  On 28 Sep 2020, 
the DMC reviewed a planned interim efficacy analysis for Study 747-302.  The DMC noted that 
based on their review, they did not have additional analyses to suggest to better understand the 
observed hazard rate.  They also noted that it did not seem feasible to continue the study as 
designed.  On 18 Dec 2020, the DMC reviewed a planned in-depth analysis of unblinded safety 
data from Studies 747-302 and 747-401.  Enrollment and retention were particularly poor in 
Study 747-302 in subjects with decompensated cirrhosis at baseline.  Poor retention was also 
observed in Study 747-401, which is exclusively focused on subjects with CP-B and CP-C 
cirrhosis at baseline.  The DMC noted a high likelihood of futility and difficulty in differentiating 
the etiology of hepatic safety events (OCA-related or progression of underlying disease).  No 
safety concerns were raised by the DMC for either study.  The DMC recommended stopping 
further enrollment in Studies 747-302 and 747-401 and discussing the unblinding of both studies 
with regulators.  On 17 Feb 2021, the DMC recommended that both studies continue with 
modification.  Due to the high likelihood of futility, the DMC recommended no further 
enrollment in the studies.  On 09 Jun 2021, no additional modifications to the study were 
recommended.  The DMC’s previous recommendations remained unchanged (ie, continue 
discussion with regulatory authorities regarding unblinding).  Following the United States 
Prescribing Information update on 26 May 2021, Study 747-401 was closed as of 09 Jul 2021.  
On 03 Nov 2021, after careful consideration of feedback from the DMC and the FDA, Intercept 
terminated Study 747-302 with Last Patient Last Visit completed on 23 Dec 2021. 
4.6.2. 
Known and Potential Risks of OCA 
The risk profile of OCA use in PBC has been evaluated in clinical trials and observational 
studies, as well as from postmarketing experience (estimated cumulative patient exposure from 
marketing experience is 20,554 patient-years).  The key risk for OCA is pruritus.  Potential risks 

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include liver injury and atherosclerotic cardiovascular events secondary to changes in lipids.  The 
following focuses on these risks in the context of PBC, the subject of these current studies.  
Additional information is available in the Investigator’s Brochure. 
Pruritus:  In subjects with PBC, the most commonly reported TEAE across all treatment groups 
was pruritus, which is a frequent symptom experienced by subjects with cholestatic liver disease. 
The incidence of pruritus was higher in the OCA-treated subjects as compared with 
placebo-treated subjects.  In a small proportion of patients, pruritus can be severe and 
significantly interfere with sleep and patient functioning.  Patients with a history of pruritus as 
part of the underlying disease have a higher probability of pruritus with OCA treatment.  
Otherwise, the occurrence and severity of pruritus in an individual patient treated with OCA 
cannot be reliably predicted or prevented, in part because pruritus is a frequent clinical feature of 
the underlying disease.  Pruritus has also been seen in patients participating in clinical trials of 
investigational use of OCA, including NASH, where pruritus is not a common symptom of the 
disease state.  Pruritus is generally clinically manageable.  Reducing OCA dose or transient dose 
or transient treatment interruption helps alleviate, and in some cases, even resolves it.   
Liver Injury:  Liver injury is an important potential risk for OCA.  Risk factors for drug-induced 
adverse hepatic effects are in general poorly understood in patients with chronic liver disease.  
Pre-existing liver disease may not increase the risk of developing drug-induced liver injury 
(Chalasani 2014).  In the US, OCA is contraindicated in adult patients with PBC with 
decompensated cirrhosis or a prior decompensation event and with compensated cirrhosis with 
clinical evidence of portal hypertension.  OCA is also contraindicated in adult patients with PBC 
with complete biliary obstruction. 
In two 3-month, placebo-controlled studies in subjects with PBC, a dose-response was observed 
for the occurrence of liver-related adverse reactions including jaundice, worsening ascites, and 
PBC flare with dosages of OCA 10 mg to 50 mg once daily (up to 5-times the highest 
recommended dosage in PBC).  In a pooled analysis of 3 placebo-controlled studies in subjects 
with PBC, the exposure-adjusted incidence rates for all serious and otherwise clinically 
significant liver-related adverse reactions and isolated elevations in liver biochemical tests, per 
100 patient years of exposure were:  5.2 in the OCA 10 mg group, 19.8 in the OCA 25 mg group, 
and 54.5 in the OCA 50 mg group compared to 2.4 in the placebo group. 
Atherosclerotic Cardiovascular Events Secondary to Changes in Lipids:  This risk has been 
recognized as an important potential risk since OCA is associated with lipid profile changes, 
regardless of background disease state.  Patients with PBC generally exhibit hyperlipidemia 
characterized by a significant elevation in total cholesterol.  A reduction in mean high-density 
lipoprotein and an increase in low-density lipoprotein with OCA treatment have been observed 
in patients with PBC.  It is unknown whether these changes in lipids are associated with or are 
causally related to an increased risk of atherosclerotic cardiovascular disease (CVD) and 
associated morbidity and mortality in PBC patients, when compared with the general population. 
The lipid abnormalities may be managed in PBC patients receiving OCA, by monitoring and 
managing lipid levels and other CVD risk factors. 

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5.
STUDY OBJECTIVES AND PURPOSE
The overall objective of these studies is to evaluate the effectiveness of OCA on hepatic 
outcomes in patients with PBC who failed UDCA treatment in 2 real-world data sources:  Global 
PBC registry and Komodo Health claims database. 
5.1. 
Primary Objective 
To evaluate the effect of OCA treatment on time to the first occurrence of the composite 
endpoint of all-cause death, liver transplant, or hospitalization for hepatic decompensation in 
PBC patients in 2 data sources: Global PBC registry and Komodo Health US claims database. 
5.2. 
Exploratory Objectives 
To evaluate the effect of OCA treatment on time to the first occurrence of individual components 
of the composite endpoint (outlined below): 
•
All-cause death
•
Liver transplant
•
Hospitalization for hepatic decompensation based on first occurrence of:
−
Variceal bleed
−
Ascites (including hepatic hydrothorax and spontaneous bacterial peritonitis)
−
Hepatic encephalopathy
6.
INVESTIGATIONAL PLAN
6.1. 
Overall Design
These are replicate, observational, retrospective cohort studies of patients with PBC who failed 
UDCA treatment using 2 real-world data sources:  the Global PBC registry (Study 747-404) and 
the Komodo Health US claims database (Study 747-405).  All analyses will be conducted 
separately by data source (ie, not pooled).  The Komodo Health database will be linked for 
outcome verification and additional data collection through Datavant tokenization to Quest 
Diagnostics, LabCorp, the NDI, and the Organ Transplant Network (OPTN) registry. 
All patients who meet diagnostic criteria for PBC in each database between 01 Jun 2015 and 
31 Dec 2021 and who meet the eligibility criteria (Section 7.2 and Section 7.3) will be 
considered for these studies.  See Figure 1 for the design schematic.  The OCA treatment 
evaluation period will be from 01 Jun 2016 (based on first country approval by FDA on 
27 May 2016).  The Komodo Health database is US-specific, while the Global PBC registry 
includes multiple countries with a range of approval dates.  The Sponsor has applied the date of 
first approval of a participating country, and thus 01 Jun 2016 will be used for both studies.  The 
first date of prescription of OCA after failing UDCA treatment will be defined as the index date 
for OCA-treated PBC patients.  The date of evidence of inadequate UDCA response or UDCA 
intolerance, as defined in Section 7.1, will be used as an index date for the non–OCA-treated 
comparator group.  Each time a patient meets the UDCA inadequate response/intolerance 

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definition or the definition of OCA initiation, as well as all other inclusion criteria, they will 
contribute an index to the study. Therefore, patients may contribute multiple control indices, and 
may contribute control indices before OCA initiation, but can contribute only one OCA initiation 
index.  The non–OCA-treated patient indices will be weighted to have the same baseline 
covariate distribution as the OCA-treated patients at the time of OCA initiation, thus allowing for 
the estimation of the effect of treatment in the treated. Patients must have 12 months of data 
preceding the index date (ie, the pre-index period) to establish the medical history and OCA 
eligibility and for the standardized morbidity ratio-weighting. Follow-up of patients will be until 
the first occurrence of the composite endpoint. Patients will be censored at drop 
out/disenrollment from the database, discontinuation of OCA (+90 days), initiation of fenofibrate 
or bezafibrate, initiation of OCA (for the non–OCA-treated patient indices), unapproved OCA 
dose (>10 mg QD) for those treated with OCA, or the end of the study period (31 Dec 2021); 
whichever comes first.
6.1.1.
Design Diagram
Figure 1:
Design Schematic Studies 747-404/405
6.2.
Number of Patients
The Komodo Health database contains administrative claims from >350 US payers, tokenized to 
allow for patient tracking across payers.  Komodo Health claims will be linked through Datavant 
tokenization to Quest Diagnostics and LabCorp laboratory data, the US National Death Index 
(NDI), and the Organ Transplant Network (OPTN) transplant registry for additional information 
and outcome verification.  The database contains >100,000 patients with a PBC diagnostic code.  
The Global PBC registry includes >5,000 patients with PBC recruited from 17 liver centers 
across 8 countries in Europe and North America.  It utilizes the CASTOR trial platform for 

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electronic case report form (eCRF) collection of medical history, clinical events, and laboratory 
and treatment data. 
Komodo Health:  In the current Komodo Health database, there are 395 patients who meet 
criteria for the OCA treatment group: 
•
Meet PBC claims diagnostic criteria (1 inpatient or 2 outpatient claims)
•
Initiate OCA treatment
•
Have evidence of UDCA failure
There are 5916 who meet criteria for the control group (OCA-eligible but not currently 
OCA-treated) 
•
Meet PBC claims diagnostic criteria (1 inpatient or 2 outpatient claims)
•
Have at least 270 days of UDCA use before elevated ALP and/or TB inclusive of up
to 4 instances of elevation (inadequate response) or <90 days UDCA use before
elevated ALP and/or TB (intolerant)
•
Have evidence of ALP >ULN and/or TB >ULN
The Komodo Health data have not yet been linked to LabCorp laboratory data.  It is anticipated 
that these numbers will approximately double with the availability of LabCorp data. 
Global PBC Registry:  The Global PBC registry data are currently being refreshed.  A previous 
analysis identified that 344 patients who had initiated OCA.  Among the >5000 patients not 
treated with OCA, it is anticipated that >2200 will meet criteria for UDCA failure and for 
inclusion in the control group (Corpechot 2008, Kumagi 2010). 
7.
SELECTION OF PATIENTS
7.1. 
Study Population
All patients who meet diagnostic criteria in each database between 01 Jun 2015 and 31 Dec 2021 
and who meet the eligibility criteria will be considered for these studies.  
All diagnosis, treatment, laboratory, and procedure codes used to identify patients and define 
study variables are listed in Appendix A.  
The treatment group will be patients with PBC with a history of inadequate response or 
intolerance to UDCA who initiated OCA in the study window.  The control group will be PBC 
patients with a history of inadequate response or intolerance to UDCA who were eligible but 
were not treated with OCA (or off-label fibrates) in the study window.  The decision to treat a 
patient with OCA or UDCA is at the discretion of the treating physician and has been made 
independent from inclusion in each of the databases. 
7.1.1. 
Definition of UDCA Failure 
UDCA failure includes both inadequate response to UDCA, and intolerance to UDCA. 
Inadequate UDCA response is defined as: 

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•
At least 1 measure of ALP and/or TB >ULN; and
•
>270 days of UDCA treatment prior to ALP and/or TB elevation
UDCA intolerance is defined as: 
•
A maximum of 90 days of UDCA use with ALP>ULN and/or TB >ULN.
The first date of prescription of OCA after inadequate UDCA response (ALP>upper limit of 
normal [ULN] and/or total bilirubin [TB]>ULN after >270 days of treatment) or UDCA 
intolerance (discontinued UDCA after <90 days despite ALP>ULN and/or TB>ULN) will be 
defined as the index date for OCA-treated PBC patients.  The dates of evidence of inadequate 
UDCA response or UDCA intolerance during which OCA is not utilized will be used as index 
dates for the non–OCA-treated comparator group.   
7.2. 
Inclusion Criteria 
A patient who meets all of the following criteria for a given index date is eligible for inclusion: 
•
Definite or probable PBC diagnosis
−
Global PBC Registry (consistent with American Association for the Study of
Liver Diseases [AASLD] and the European Association for the Study of the Liver
[EASL] practice guidelines; Lindor 2009, EASL 2009): presence of ≥2 of the
following 3 diagnostic factors:
▪
History of elevated ALP levels for at least 6 months
▪
Positive antimitochondrial antibody (AMA) titer
▪
Liver biopsy finding consistent with PBC
−
Komodo Health claims data: one of the following (Meyers 2010):
▪
≥1 inpatient claim with a PBC admission diagnosis at any position
(ie, primary, secondary diagnosis, etc.)
▪
≥2 outpatient claims with a PBC diagnosis on separate days
•
Inadequate response or intolerance to UDCA (see definitions in Section 7.1)
•
Age ≥18 years at the index date
•
Continuous enrollment and evaluable data for at least 12 months before the index date
(inclusive)
7.3. 
Exclusion Criteria
A patient who meets any of the following criteria for a given index date is not eligible for 
inclusion: 
•
History or presence of other concomitant liver diseases before the index date
(inclusive), including:
−
Acute or chronic hepatitis C virus infection
−
Acute or chronic hepatitis B infection

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−
Primary sclerosing cholangitis
−
Active alcoholic liver disease
−
Hepatocellular carcinoma
−
Hepatorenal syndrome
−
Hepatopulmonary syndrome
−
Portopulmonary syndrome
−
NASH
•
History of non-skin malignancy or melanoma before the index date (inclusive)
•
History of HIV before the index date (inclusive)
•
Medical conditions that may cause non-hepatic increases in ALP:
−
Paget's disease during the 12-month period before the index date (inclusive)
−
Fractures within 3 months before the index date (inclusive)
•
Patients with laboratory values indicative of hepatic decompensation or significant
hepatobiliary injury before the index date (inclusive):
−
TB >3 mg/dL
−
ALP >10x ULN
−
ALT and/or AST >10x ULN
•
History of liver transplant before the index date (inclusive)
•
Evidence of OCA, fenofibrate, or bezafibrate use before the index date (inclusive)
•
History or presence of any of the following hepatic decompensating events before the
index date (inclusive):
−
Variceal bleeding
−
Ascites
−
Hepatic hydrothorax
−
Spontaneous bacterial peritonitis
−
Hepatic encephalopathy
7.4. 
Group Assignments 
Treatment group (OCA-treated): ≥1 prescription or medical claim for OCA at or after UDCA 
failure date.  The first date will be the one index date. 
Control Group (Non-OCA-treated but eligible for OCA): Each date corresponding to 
evidence of a patient meeting the definition of UDCA inadequate response or intolerance in 
which the patient meets the inclusion and exclusion criteria and does not initiate OCA will be an 

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index date for the non–OCA-treated patient group.  Patients may contribute indices to this group 
before they initiate OCA, but not after OCA index. 
A thorough description of methodology underlying group assignment can be found in 
Section 10.1.1. 
7.5. 
Study Product, Dosage and Mode of Administration 
The product being studied is obeticholic acid, in tablet form, dosed at 5 mg to 10 mg once daily 
oral administration. The study drug is not provided nor administered by the Sponsor but is 
recorded by either administrative claim or registry eCRF. The total duration of exposure will 
range from 1 to 67 months. 
7.6. 
Study Period 
The total study period is estimated to be a maximum of 6.6 years based on a pre-index period of 
12 months prior to the index date and a maximum follow-up period of 5.6 years after the index 
date.  The OCA treatment evaluation period will be from 01 Jun 2016 (based on FDA approval 
on 27 May 2016) to 31 Dec 2021.  The first date of prescription of OCA after failing UDCA 
treatment will be defined as the index date for OCA-treated PBC patients.  The date of evidence 
of inadequate UDCA response or UDCA intolerance, as defined below, will be used as the index 
date for the non–OCA-treated comparator group.  Each time a patient meets the UDCA 
inadequate response/intolerance definition or the definition of OCA initiation, as well as all other 
inclusion/exclusion criteria, they will contribute an index to the study.  Therefore, patients may 
contribute multiple indices and may appear in both groups, though they may contribute at most 
one index to the OCA-treated group. 
8.
ASSESSMENT OF EFFICACY
8.1. 
Primary Outcomes/Endpoints 
The selection of a composite primary endpoint was informed by previous regulatory interactions 
regarding the 747-301 (POISE) and 747-302 (COBALT) studies (see Table 1).  For COBALT, 
the primary composite endpoint included all-cause death, liver transplant, hospitalization for 
hepatic decompensation (bleeding varices and hepatic encephalopathy), uncontrolled ascites, and 
Model for End-Stage Liver Disease (MELD) Score >15.  Of these endpoints, only MELD cannot 
be adequately assessed in the current databases.  The MELD algorithm includes a measure of the 
international normalized ratio (INR).  A review of the Komodo Health and the Global PBC 
registry databases revealed that, unlike hepatic laboratory measures such as ALP and TB, INR is 
not routinely collected in PBC patients.  Therefore, the Sponsor did not include MELD >15 as 
part of the composite endpoint for these studies. 
COBALT included the endpoint of uncontrolled ascites, defined as diuretic-resistant ascites 
requiring therapeutic paracentesis at a frequency of at least twice in a month.  In a study of the 
POISE LTSE with external controls (Perez 2021), the Sponsor modified this endpoint to be 
consistent with other decompensating events, ie, hospitalization for ascites.  As the FDA 
Guidance on Real-world Data (US Food and Drug Administration 2021) states, “…outpatient 
data sources that do not include hospitalization data would generally not be appropriate for 
studying outcomes likely to result in hospitalization.”  To increase consistency in the measures of 

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hepatic decompensating events, the Sponsor has included ascites (including hepatic hydrothorax 
and spontaneous bacterial peritonitis), along with variceal bleeding and hepatic encephalopathy, 
as part of the “hospitalization for hepatic decompensation” endpoint. 
Table 1: 
Composite Endpoints for OCA PBC Studies 
COBALT 
(747-302) 
POISE (747-301) 
LTSE with External Controls 
HEROES PBC 
(747-404/405) 
All-cause death 
X 
X 
X 
Liver transplant 
X 
X 
X 
Hospitalization for hepatic 
decompensation 
•
Variceal bleed
•
Hepatic encephalopathy
X 
X 
X 
Uncontrolled ascites 
X 
Xa 
Xa 
MELD Score >15 
X 
a Specifies hospitalization for ascites 
The following primary efficacy assessment will be measured as an as-treated time to first 
occurrence of one of the following events: 
•
All-cause death
−
Komodo Health:  The Komodo Health data has been linked to the US National
Death Index (NDI), and mortality will be recorded as date of death as recorded in
the Index
−
Global PBC registry:  Death and date of death are reported by the physician via
electronic Case Report Form (eCRF) and recorded through the CASTOR trial
platform
•
Liver transplantation
−
Komodo Health:  The Komodo Health data will be linked to the OPTN database
to ascertain whether a patient has received a liver transplant and the date of
transplant.
−
Global PBC registry:  Liver transplant and date of transplant are reported by the
physician via eCRF and recorded through the CASTOR trial platform.
•
Hospitalization for hepatic decompensation
−
Komodo Health:  Hospitalization for hepatic decompensation will be assessed by
any hospital admission claim with the following International Classification of
Diseases (ICD)-10 codes (in any position) for decompensating events
▪
Variceal bleed:  ICD-10: I85.01, I85.11, I86.4 and ICD-9: 456.1, 456.21,
456.8
▪
Ascites:  ICD-10: K70.11, K70.31, K71.51, R18.0, R18.8, J94.8, K65.2 and
ICD-9: 567.23, 571.2, 789.51,789.59, 511.8, 567.23

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▪
Hepatic encephalopathy:  ICD-10: B15.0, B16.0, B16.2, B17.11, B19.0,
B19.11, B19.21, K70.41, K72.11, K72.90, K72.91 and ICD-9: 572.2, 070.0,
070.20, 070.41, 070.6, 070.71; or utilization of lactulose and/or rifaximin.
−
Global PBC registry:  Hospitalization for hepatic decompensation and date of
hospitalization are reported by the physician via eCRF and recorded through the
CASTOR trial platform
8.2. 
Exploratory Outcomes 
There will be 3 exploratory evaluations of efficacy, measured as the as-treated: 
−
Time to first occurrence of all-cause death
−
Time to first occurrence of liver transplant
−
Time to first occurrence of hospitalization for hepatic decompensation
8.3. 
Exposure Variable 
The exposure variable initiates at the OCA index date. In the Komodo database, OCA exposure 
will be assessed as date of first filled prescription and quantified as days supply. Discontinuation 
will be assessed by a gap of >90 days after previous days supply.  Treatment exposure will be 
continued for 90 days after last days supply, after which the OCA-treated patient will be 
censored. In the Global PBC database, OCA exposure will be from the first physician reported 
utilization date to discontinuation date, plus 90 days. In this study, exposure can range from 1 to 
67 months. 
9.
ASSESSMENT OF SAFETY
The objective of these replicate observational Real-world Data studies is to evaluate the effective 
of OCA on hepatic outcomes in patients with PBC.  All patients are de-identified in the data 
sources.  These studies are not designed to assess safety, and there are no pre-specified safety 
analyses.  Study outcome variables collected for the 2 cohorts will be presented for analyses as 
aggregate data groups.  The data sources will not be searched for individual patient adverse 
events; however, if an Investigator or Sponsor identifies adverse events that meet postmarketing 
reporting requirements during the course of conducting these studies, such events will be 
reported in accordance with applicable postmarketing reporting requirements. 
10.
STATISTICAL METHODS
10.1. 
Analysis Populations and Blinding
10.1.1. 
Analysis Populations
The statistical analysis of the HEROES PBC studies will follow a nested randomized trial 
emulation approach (Hernán 2008, Danaei 2013) using a treatment decision design to identify 
index events (Brookhart 2015).  The goal of the study design is to emulate a sequence of 
hypothetical randomized trials.  In each hypothetical trial, patients meeting the inclusion and 
exclusion criteria who are making the decision whether to initiate OCA-based treatment are 

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randomized to either continue their existing PBC treatment or switch to an OCA-based 
treatment.  Each randomized patient is then followed until the earliest of the end of follow-up or 
the time of the study endpoint (death, liver transplant, or hospitalization for hepatic 
decompensation).  Standard survival analysis methods (eg, a Kaplan-Meier estimator of the 
cumulative incidence function or a Cox proportional hazards model to estimate the hazard ratio) 
will then be used to estimate the effect of OCA on the study endpoint. 
Due to the lack of randomization, non-randomized observational studies will instead be 
conducted, with the goal of mimicking the hypothetical randomized trial as closely as possible.  
All patients will be evaluated over time from the start of the study period to identify evidence of 
inadequate treatment response to UDCA.  Each date of inadequate response identified in the data 
will be considered a treatment decision point, and that date will be considered an index date, with 
a corresponding record being created in the analytic data for that patient index.  Each patient can 
contribute multiple index dates, and thus patient indices, corresponding to each date they have a 
treatment decision point, and therefore each patient may contribute person-time to multiple 
patient index records. 
At each treatment decision point, the inclusion and exclusion criteria will be assessed (see 
Sections 7.2 and 7.3).  For patient indices meeting the study criteria, all baseline covariates and 
treatment variables will be determined.  Person-time corresponding to each patient index will be 
computed relative to the date of the index event.  Notably, because prior treatment with OCA is 
an exclusion criterion, a patient may contribute at most one OCA-treated patient index event, 
though they can contribute multiple non–OCA-treated patient index events. 
After the index date, follow-up will continue until the first of the composite outcome event 
(all-cause death, liver transplant, or hepatic decompensation), censoring, treatment 
discontinuation (for patient indices initiating OCA on the index date), OCA initiation (for patient 
indices not initiating OCA on the index date), or the end of the study period. 
Because treatment will not be randomized, it is likely that OCA-treated and non–OCA-treated 
patient indices will differ on confounding variables, ie, variables that influence both treatment 
and outcome.  Therefore, a simple comparison of outcomes among the OCA-treated versus non–
OCA-treated patient indices is likely to yield a biased estimate of the effect of OCA on the study 
endpoint.  To address differences in the covariate distribution between groups, the Sponsor will 
first conduct descriptive analyses on all baseline variables (demographics, clinical 
characteristics, and treatment history) for the OCA-treated and non–OCA-treated groups at 
index.  Means, standard deviations, medians, inter-quartile ranges, and minimums and 
maximums will be provided for continuous variables.  Counts and percentages will be provided 
for categorical variables.  Appropriate tests comparing cohorts of interest in the primary and 
exploratory analyses (eg, t--test, chi-squared test) will be used based on the distribution of the 
measure.  
Next, standardized mortality/morbidity ratio weights will be used to create a 
“pseudo-population” of non–OCA-treated indices with the same covariate distribution as the 
OCA-treated patients at the time of OCA initiation (Sato 2003), and unweighted and weighted 
standardized mean differences (SMDs) will be computed.  SMR weights result in an average 
effect of treatment among the treated.  They often make more efficient use of data in a situation 
with a small treatment group compared with inverse-probability of treatment weights.  The SMR 
weights will be estimated as: 

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𝑤𝑖
𝑡=
𝜋̂𝑖(1)
𝜋̂𝑖(𝐴𝑖), where  𝑤𝑖
𝑡 is the weight for patient index 𝑖, 𝐴𝑖 is the observed level of treatment for
patient index 𝑖 (𝐴= 1 if the patient index is OCA-treated, 0 otherwise), 𝑋𝑖 is the vector of
confounders measured at the index time for patient index 𝑖, and 𝜋𝑖(𝑎) = Pr (𝐴= 𝑎|𝑋𝑖) is the
probability that patient index 𝑖 receives treatment level 𝑎 conditional on their covariates.  
As the probabilities used to construct the weights are not known, they will be estimated using a 
logistic regression model.  The model will be fit using observed treatment as the outcome and 
main effect terms for each of the covariates.  Covariates (assessed in the pre-index period) will 
include: 
•
Age at index date
•
Sex
•
Most recent liver biochemistry levels (TB, ALP, ALT, AST)
•
Most recent platelet counts
•
Time (in months) since UDCA failure
•
Clinical evidence of portal hypertension (platelets <150,000 and/or non-bleeding
varices)
•
Cirrhosis
−
Komodo Health:  cirrhosis diagnosis with liver imaging and/or biopsy within
6 months before diagnosis
−
Global PBC registry:  biopsy stage 4, transient elastography ≥16.9 kPa,
radiological evidence (nodular liver or enlargement of portal vein with
splenomegaly), clinical features of portal hypertension defined as platelet count
<140 000/mm³ with persistent decrease in serum albumin; or, TB >2x ULN, or
prothrombin time/INR > ULN (not due to antithrombotic use)
•
Most recent Charlson Comorbidity Index Score (Glasheen 2019)
•
Insurance type at the index date (Komodo Health only: commercial, Medicare,
Medicaid, dual eligible, other)
All diagnosis, procedure and laboratory codes used to define the control variables are listed in 
Appendix A.  
Once the weights are constructed, a table of weighted SMDs between the groups will be 
constructed to assess balance.  An absolute SMD of greater than 0.1 will indicate potentially 
problematic residual imbalance for the particular covariate.  In the case that either the model-
fitting algorithm fails to converge, or residual imbalance exists after weighting, the study team 
will attempt to reduce model complexity or reduce imbalances by implementing one or more of 
the following actions: 
•
Adding/removing interaction terms (1st order or higher)
•
Using a spline for continuous variables
•
Shrinking all coefficients in the model using a penalty

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To protect the integrity of the research results, all decisions about updating the analysis will be 
made by the Investigators without knowledge of how those decisions might affect the outcome 
(Clean Room Committee [CRC], see Section 10.11).  Each decision for a set of actions will be 
tracked in a study log along with the results presented to the analysis team to inform the action. 
The final weights will be used for the main analysis.  Results for each stage of the developed 
weights will be documented and presented as supplementary material (and decisions will be 
recorded in the study log). 
Under the identification conditions of causal consistency (Cole 2009, VanderWeele 2009, 
Pearl 2010), (partial) conditional exchangeability (Greenland 1986, Sarvet 2020), and positivity 
(Westreich 2010, Petersen 2012), the pseudo-population resulting from weighting the 
person-indices will emulate the data (at baseline) of the aforementioned hypothetical randomized 
trial.   
10.1.2. 
Blinding 
To ensure that knowledge of outcomes does not influence group creation, all persons involved in 
the studies will be kept blind to outcomes (death, liver transplant, hospitalization for 
decompensation) until after the analytic groups are created and the SMR weights are finalized.  
The event file will be kept separate from the primary data containing patient demographic, 
medical history, treatment, and laboratory data and will not be accessible to study personnel.  
Once the OCA-treated and non–OCA-treated datasets are created and approved by the CRC, the 
CRC will notify non–study-affiliated designees at each site that the event data can now be 
accessed in order to perform the effect size analysis and statistical testing. 
10.2. 
Estimation of Effect Size 
The causal effect of OCA-containing treatments versus non–OCA-containing treatments on the 
study endpoints will be quantified using a hazard ratio.  The hazard ratio will be estimated using 
a weighted version of the sequential Cox proportional hazards model (Gran 2010).  This 
approach entails fitting a weighted Cox proportional hazards regression to the person-index 
dataset, with weights created as previously described, treatment included as a non–time-varying 
indicator of baseline treatment, and the timescale being specified as time since the index event.  
In addition to adjusting for confounding via SMR weighting, baseline covariates for each 
person-index will also be included in the regression model to address possible informative 
censoring by baseline variables.  To test for heterogeneity of effects across each of the nested 
‘trials’, an interaction term between treatment and an indicator representing each trial will be 
included in the model.  A non-significant coefficient for the interaction variables will indicate 
heterogeneity. 
In randomized trials, a common approach to address imperfect treatment adherence is to censor 
patients when they deviate from their assigned treatment, a so-called per-protocol analysis 
(Hernán 2017).  An analogous approach can be used for non-randomized observational studies.  
Here, a person-index is censored when they deviate from their initial treatment.  For instance, if a 
person-index received non-OCA treatment at baseline but OCA was initiated 6 months after the 
index date, that person-index would be censored at 6 months.  Similarly, if a person-index 
received OCA at baseline but discontinued OCA, that person-index would be censored once the 
definition of OCA discontinuation is met, with an extension of 3 months after that time to allow 

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for duration of effect after discontinuation.  As a result of this artificial censoring, all person-time 
included in the analysis reflects adherence to initial treatment.  Similarly, by excluding 
person-time occurring after loss to follow-up, all included person-time additionally reflects 
remaining time under study. 
Because treatment non-adherence and loss to follow-up may not occur completely at random, 
those who remain uncensored may differ from the overall study population on key prognostic 
factors.  To address these differences, the Sponsor will include baseline covariates in the Cox 
model that are potential predictors of both the study outcomes and censoring. 
10.3. 
Hypotheses 
10.3.1. 
Primary Hypothesis 
These studies are intended to assess whether there is a difference between patients treated with 
OCA and comparable OCA-eligible patients who are not treated with OCA in the time from 
index to the first occurrence of all-cause death, liver transplant, or hospitalization for hepatic 
decompensation.  
Two-sided hypotheses are expressed in terms of: 
•
The null hypotheses (H0) that the 2 hazard functions are the same, as determined by a
hazard ratio (HR) equal to 1; that is, at every timepoint, the instantaneous event rates
are the same for the OCA and control populations.
•
The alternative hypothesis (H1) that the 2 hazard rates are not the same (𝐻𝑅≠1).
10.4. 
Determination of Sample Size 
Using the sample size in the 2 populations (Section 6.2), the Sponsor computed power to detect 
treatment effects (relative hazards) of varying sizes, estimated using Cox proportional hazards 
regression.  Computations are based on the formulae of Schoenfeld 1983.  To account for 
confounding control due to the application of IP weights, the Sponsor inflated the variance from 
the Schoenfeld formula using factors derived by Shook-Sa 2020.  It was conservatively assumed 
just one control observation per patient.  In the Komodo Health data, a preliminary investigation 
found that approximately 395 patients who meet entry criteria will initiate OCA and that 
5916 patients will contribute at least one record to the control group (UDCA nonresponders).  In 
the Global PBC registry, the Sponsor expects to have 344 patients meeting entry criteria who 
initiate OCA, and 2200 who contribute at least one observation to the control group.  Power in 
both cohorts was computed for relative hazards ranging from 0.5 to 0.9 with an alpha level of 
0.05.  The Sponsor considered baseline event rates during follow-up from 5% to 15% and 
variance inflation corresponding to mild confounding (VIF=1.05), moderate confounding 
(VIF=1.5), and strong confounding (VIF=2.0).  In each study, power was plotted under these 
assumptions against a reference line of 80% power under moderate confounding (VIF=1.5) 
(Figure 2). 
Under mild confounding, both studies will be well-powered to detect an HR of 0.5.  For 
moderate confounding, the Komodo Health study will be adequately powered to detect HR of 0.5 
for event rates >6%.  The Global PBC registry will be adequately powered to detect event rates 
>8%.  Under strong confounding, the Komodo Health study will be adequately powered to detect

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HR of 0.5 for event rates >9%.  The Global PBC registry will be adequately powered to detect 
event rates >11%.  Power decreases for more moderate HRs.  None of the studies under even the 
most favorable assumptions will be able to detect HRs of 0.9.  The Sponsor notes that the 
assumptions made here are conservative; in particular, it is expected that many more than one 
control observation and that the addition of lab data from LabCorp (as noted in Section 6.2) will 
substantially increase the size of both groups in the Komodo Health study. 
Figure 2: 
Power estimates by Hazard Ratio by Level of Confounding for Komodo 
Health (A) and Global PBC Registry (B). 
A 
    B 
10.5. 
Primary Efficacy Analysis 
Standard error estimation will proceed using the nonparametric cluster bootstrap (Davison 2013) 
as has been suggested for nested trial designs using Cox proportional hazards regression 
(Gran 2010).  The standard error will be used to calculate the 95% CI of the hazard ratio and to 
conduct statistical hypothesis testing.  A total of 1000 bootstrap replicates will be used.  
Bootstrap sampling will occur at the patient level, rather than the patient index level, thus 
preserving the covariance structure between patient indices and properly accounting for variance 
inflation due to the covariance between analytic units.  Within each bootstrap replicate, all 
aspects of estimation will be repeated, including the fitting of the treatment model, the 
construction of the weights, and the fitting of the weighted Cox proportional hazards model used 
to estimate the treatment effect.  The standard deviation of the bootstrap estimates of the 
treatment effect will be used as an estimate of the standard error.  A Wald test will then be 
conducted using the bootstrap standard error (Cameron 2008).  The test statistic is defined as  

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𝑤=
𝛽̂
𝑠𝛽̂, where 𝛽̂ is the estimated coefficient of OCA treatment from the fitted Cox model and 𝑠𝛽̂
is the bootstrap standard error of the estimated coefficient.  With a sufficient sample size, 𝑤 will 
follow a standard normal distribution and the p-value will be computed as the probability of a 
normal random variable being greater than |𝑤| or less than −|𝑤|.  A p-value less than 0.05 will 
be considered statistically significant. 
10.6. 
Exploratory Analyses 
Each component of the study endpoint (all-cause death, liver transplant, and hospitalization for 
hepatic decompensation) will be assessed separately.  For the outcome of death, the analysis will 
proceed using the same approach as for the primary effect size estimation.  For the outcome of 
liver transplant, death will be treated as a competing event.  Here, follow-up will end at the 
earliest of the end of follow-up, liver transplant, death, or censoring.  The analysis will proceed 
as previously described, but instead of a Cox proportional hazards model, a Fine-Gray 
proportional subdistribution hazards model will be used (Fine 1999).  Similarly, for the outcome 
of hospitalization for hepatic decompensation, death and liver transplant will be treated as 
competing events. 
10.7. 
Handling of Dropouts or Missing Data 
Patients who disenroll from the covered health plans in Komodo Health or from the Global PBC 
registry are right-censored at time of disenrollment.  
Dropout / disenrollment will be assumed to be uninformative conditional on the included 
baseline covariates in the Cox model (see Section 10.2).  Missing baseline data will be assumed 
missing completely at random, and a complete case analysis (listwise deletion) will be 
conducted.  During the conduct of the studies, the CRC may recommend refining the missing 
data strategy to better address any observed pattern of missing data. 
10.8. 
Subgroup Analyses 
The entire analysis will be repeated separately by patient race (Komodo Health only), age 
(categorical), sex, region, absence/presence of cirrhosis, and pre-/post-COVID.  Because race is 
not completely captured in Komodo Health, these analyses will only include those with non-
missing values for race. 
10.9. 
Sensitivity Analyses 
A quantitative bias analysis will be used to assess the sensitivity of the estimates to violations of 
the assumption of no unmeasured confounding.  To conduct this analysis, it will be assumed that 
the hazard ratio is a reasonable approximation of the odds ratio, and then previously published 
formulas for the relation of unadjusted or partially adjusted to adjusted odds ratios will be used to 
estimate the effect, given inputs for the strength of the confounder treatment and confounder 
outcome relationships (Lash 2021).  The analysis will be conducted across a range of values for 
the input parameters to assess how much the effect changes given different confounder 
relationships.  Specifically, given the (adjusted for known confounders) odds ratio for the 
association between the unmeasured confounder and the outcome (𝑂𝑅𝐷𝑍) and the prevalence of
the confounder among the OCA-treated (𝑃𝑍1) and non-OCA-treated (𝑃𝑍0) (each assumed

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homogeneous across levels of known confounders), the relationship between the partially 
adjusted and fully adjusted odds ratios is 
𝑂𝑅𝑝𝑎𝑟𝑡𝑖𝑎𝑙
𝑂𝑅𝑓𝑢𝑙𝑙
=
𝑂𝑅𝐷𝑍𝑃𝑍1+1−𝑃𝑍1
𝑂𝑅𝐷𝑍𝑃𝑍0+1−𝑃𝑍0. 
10.10. 
Assessment of Claims-based PBC Definition 
The Komodo Health data are claims-based.  Per AASLD guidelines, PBC diagnosis is based on 
the presence of ≥2 of 3 diagnostic factors: 
•
History of elevated ALP levels for at least 6 months
•
Positive AMA titer
•
Liver biopsy finding consistent with PBC
AMA is normally assessed once to diagnose PBC, and the test may have occurred years prior to 
entry into the Komodo Health claims database.  Indeed, a preliminary analysis shows that ~10% 
of patients with a PBC diagnostic code have an AMA test result in the database.  As AMA 
cannot be used in the definition of PBC, a claims-based analysis will be used to identify PBC 
patients in claims data requiring 2 outpatient claims or 1 inpatient claim based upon the work of 
Meyers (Meyers 2010). 
Using Canadian ambulatory care and inpatient records, Meyers found that a 2-outpatient claim 
algorithm had 89% positive predictive value (PPV) when compared to AMA-verified definite, 
probable, or suspected PBC.  A single inpatient claim had 81% PPV, with limited incremental 
benefit of 2 claims (86% PPV). 
In these studies, in addition to the claims criteria, evidence of UDCA use is required, which the 
Sponsor believes will further improve the PPV of the claims-based algorithm.  To validate this 
approach, the Sponsor will conduct sensitivity and specificity analyses using AMA as the gold 
standard of PBC diagnosis within the Komodo Health database.  The subpopulation of patients 
with AMA test results (positive vs negative) will be compared to those with a positive and 
negative diagnosis by the claims + UDCA definition.  The sensitivity of the non–AMA-based 
definition will be defined as the proportion of patients classified as having PBC with the gold 
standard definition who are also classified as having PBC with the non–AMA-based definition.  
The negative predictive value of the non–AMA-based definition will be defined as the 
proportion of patients not classified as having PBC with the non–AMA-based definition who are 
also not classified as having PBC with the gold standard definition.  The specificity and PPV will 
be assumed to be equal to 1, as the non–AMA-based definition will capture a subset of those 
individuals classified as having PBC by the gold standard definition.   
10.11. 
Clean Room Committee 
In studies of existing data, decisions about study design or analysis should not be informed by 
knowledge of how such decisions might affect study results.  The study team has attempted to 
pre-specify all statistical analysis plans to a sufficient degree of detail that ambiguity about how 
the results will be obtained is minimized.  However, often data will need to be examined to 
inform key aspects of the study design or analysis, and in other cases, issues discovered during 
analysis might require certain deviations from the planned design and/or analysis.   

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To avoid biasing point estimates and standard errors for the primary comparative analysis, the 
individuals making these decisions will be isolated from knowledge about how these decisions 
might affect outcomes.  To do this, the 3 individuals will be designated to be members of the 
CRC, and this designation will be recorded in the study log.  Analysts will have direct access to 
the data and will build all analytic files and implement all data analysis.  Study team members 
not designated as CRC members will work with the analysts to review and understand output 
tables.  
Members of the CRC will make all decisions about the conduct of these studies, including 
decisions about protocol deviations as well as the reporting and interpretation of results in 
reports.  Additionally, based on data supplied to them by the analysts, the CRC will make 
decisions about changes in analytic approaches, model specification, group inclusion/exclusion 
criteria, and variable definitions.  The data supplied by the analyst should not provide any direct 
information about how such protocol changes might affect results.  To accomplish this, 
preliminary results that contain outcome statistics summarized by group (OCA-treated versus not 
OCA-treated) will not be presented to the Investigators.  If, for some reason, results need to be 
presented by group, the group will be masked by the analysts.  All aspects of this process will be 
tracked, specifically: 
•
All requests for interim data or results will be entered into the study log where they
can be viewed by all study team members.
•
All protocol deviations will be logged along with the rationale for the change.
Protocol changes will not be made unless all Investigators agree to the change.
•
Minutes of meetings in which decisions about protocol changes are made will be
saved.
•
The original protocol as well as all modified versions will be accessible to all
Investigators and analysts.
The original protocol and the study log will be made available as appendix material for all 
reports and publications. 
11.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The data in these studies are de-identified.  The Komodo Health data use agreements and the 
Global PBC registry Institutional Review Board (IRB) approval specify that these data may not 
be re-identified.  In addition, the Global PBC registry site agreements do not allow for the 
transfer of data outside of the Global PBC registry. 
The Clinical Research Organization (CRO) will ensure the Investigator's understanding of all 
applicable regulations and standard operating procedures (SOPs) and will ensure an 
understanding of the protocol and maintenance of all requisite documentation.  The CRO will 
have full access to the Komodo Health data and analyses to be able to ensure these studies are 
conducted per protocol.  The CRO can also review data and programming on site with a member 
of the Global PBC Study Group. 
A Study Data Tabulation Model (SDTM) dataset will be provided to the FDA for the Komodo 
Health dataset.  Should the FDA have questions or queries, a member of the Global PBC Study 

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Group will make themselves available on site at the FDA with a laptop computer containing the 
Global PBC registry analytic dataset and can both review data and run queries as required by the 
FDA. 
12.
QUALITY CONTROL AND QUALITY ASSURANCE
In 2021, the FDA released 4 draft guidance documents defining data quality, management, and 
analyses of real-world data, including guidance specific to claims data and disease registries.  
Given the extensive documentation requirements, separate supplemental protocols will be 
submitted, one for the Global PBC registry and one for the Komodo Health dataset. 
12.1. 
Data Collection and Transfer 
12.1.1. 
Komodo Health 
Komodo Health merges administrative claims across >350 health plans including commercial 
(63%); Medicaid (23%); Medicare (10%); dual eligible (<1%); and other (2%).  The dataset 
represents more than 325 million unique patients in the US between June 2015 and July 2021. 
The datasets include all inpatient, outpatient, and procedure claims, as well as service dates, 
associated ICD-9 and ICD-10 codes, and provider data.  
Data from each payer are tokenized, deidentified, and encrypted by the individual payer (see 
Section 12.2.2).  Some examples of file formats Komodo Health intakes from sources include 
TXT, CSV, and DAT file types.  Komodo Health commonly receives data as (but not limited to) 
comma-delimited, pipe-delimited, and tab-delimited files.  A transit token specific to the payer 
and Komodo Health is used, and once received the data are de-encrypted, including a final 
patient token.  Thirty-six percent of plans transfer their data through a Komodo Health secure 
FTP site; 64% of plans provide a secure FTP site to Komodo Health to retrieve the data.  
Komodo Health receives and stores data in AWS S3 buckets. 
Plans provide uncurated (raw) data.  Data cleaning, such as deduplication, will be specified in the 
supplemental submission.  Cleaned data are merged and linked via token, thus patients are able 
to be followed longitudinally across plans that contribute data.  After Komodo Health finishes 
processing the data, they are made available as a Snowflake database in the Sentinel cloud 
environment.   
12.1.2. 
Global PBC Registry 
Data for the Global PBC registry is collected through the CASTOR trial platform.  The 
CASTOR System, which has been employed for registrational trials, includes eCRFs, cloud-
based data collection, and download of data in SAS format for analysis.  The data are only 
transferred to the University Health Network system, with no additional data transfer, and are 
analyzed in the SAS environment.  The eCRF prevents the input of test values outside of 
medically plausible range and the input of duplicate data.  Source data cannot be modified.  The 
Global PBC registry protocol, eCRFs, and all data cleaning and transformations of variables 
included in this analysis will be specified in the supplemental submission. 

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12.1.3. 
National Death Index 
The NDI is a central computerized index of death record information on file in state vital 
statistics offices.  The Centers for Disease Control and Prevention and the National Center for 
Health Statistics compile deaths annually from computer files submitted by state vital statistics 
offices.  Numerous studies have confirmed the validity of the NDI.  The NDI has previously 
been linked to the Komodo Health database (see Section 12.3) and the datafile will be kept 
firewalled from analysts until the CRC authorizes unblinding.  The NDI will be used to ascertain 
death as part of the composite endpoint. 
The Komodo Health data contains information on hospital discharge status, including death at 
discharge.  Death status, combined with a lack of addition claims >30 days after deaths will be 
compared to the NDI database.  If a death on hospital discharge (plus lack of additional claims) 
is observed in the Komodo database but not in the NDI database, it will be included as a primary 
endpoint. 
12.1.4. 
Quest Diagnostics 
Quest Diagnostics has >2000 testing facilities with specimens processed at 26 central 
laboratories in the US (excluding those devoted exclusively to clinical trials).  Specimen 
collection and testing protocols are standardized nationally.  Date of test, laboratory value 
results, normal range limits, and associated ICD-10 codes are entered at each lab facility.  Data 
are sent electronically to the testing site, and also to a centralized main frame and entered into the 
national database within 7 days.  Specifications on data storage, transfer, and cleaning will be 
included in a supplemental submission. 
These studies will utilize ALP, TB, ALT, AST, and platelets to propensity weight treated and 
untreated patients at index, and to determine UDCA treatment failure.  AMA data will be used to 
validate the ICD-10 PBC claims diagnostic criteria. 
12.1.5. 
LabCorp 
LabCorp has >2100 testing facilities with specimens processed at 15 primary laboratories in the 
US (excluding specialty testing facilities such as oncology and genetic testing).  Specimen 
collection and testing protocols are standardized nationally.  Date of test, lab value results, 
normal range limits, and associated ICD-10 codes are entered at each lab facility.  Data are sent 
electronically to the testing site, and also to a centralized main frame and entered into the 
national database.  Specifications on data storage, transfer, and cleaning will be included in a 
supplemental submission. 
These studies will utilize ALP, TB, ALT, AST, and platelets to propensity weight treated and 
untreated patients at index, and to determine UDCA treatment failure.  AMA data will be used to 
validate the ICD-10 PBC claims diagnostic criteria. 
12.1.6. 
OPTN Transplant Registry 
OPTN collects and reports data on every US organ donor, transplant candidate, recipient, and 
outcome.  Data are collected through a standardized eCRF using the online UNet database 
system.  Specifications on data storage, transfer, and cleaning will be included in a supplemental 
submission. 

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The OPTN registry will be the primary data source to ascertain liver transplant as part of the 
composite endpoint.  The Komodo Health data contains information on hospital admissions, 
including codes for liver transplant (see Appendix A).  Hospitalization for liver transplant in 
Komodo Health claims will be compared to the OPTN database.  If a liver transplant is recorded 
on hospital discharge but not in the OPTN database, it will be included as a primary endpoint. 
12.2. 
Data De-identification 
12.2.1. 
Global PBC Registry 
The data collected at each site are de-identified by removing all identifying data fields (name, 
address, date of birth, etc.) prior to being sent to the Central Coordinating Site.  A unique Global 
PBC Study Group study number is assigned to each site and each participant within the site and 
does not utilize identifying information in creating the patient number.  Identifiers and their 
relation to the Global PBC Study Group number are maintained only at the study site and not by 
the central Data Coordinating Site. 
12.2.2. 
Komodo Health 
Datavant's de-identification engine is designed for use on structured healthcare data.  The 
de-identification program performs 2 functions: de-identification of the data set through removal 
or modification of identifying data, and the insertion of encrypted patient tokens.  
De-identification includes the following: 
•
Zip Code:  Reduced to the initial three characters to define a zip area.  Based on the
Health Insurance Portability and Accountability Act (HIPAA) rules, however, even
three-digit zip areas with a combined population of less than 20,000 are either nulled
out or are combined again with additional zip zones to ensure that populations exceed
this minimum.
•
Date of Service:  Dates of service (eg, admission dates, discharge dates, prescription
fill dates, and procedure dates) are typically preserved when using a statistical
de-identification methodology.
•
Date of Birth:  Converts all birth dates to birth year.  All dates of birth where the
individual aged ≥89 years as of the date of de-identification would be modified to
reflect an age of 89.
•
Medical Records Numbers:  Removed where present
•
Telephone Numbers:  Removed where present
•
Email Address:  Removed where present
•
Social Security Numbers:  Removed where present
•
Beneficiary Numbers:  Removed where present
•
Vehicle Information:  Removed where present
•
Device Identifiers and Serial Numbers:  Removed where present
•
URL Addresses:  Removed where present

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•
IP Addresses:  Removed where present
•
Biometric Values:  Removed where present in claims data; retained in Quest
Diagnostics and LabCorp
•
Image Fields:  Removed as defined by the data source
Datavant does not perform de-identification and tokenization itself and does not have access to 
the user’s system or identifying information.  The de-identification process is executed by the 
institution that owns the data, ie, Datavant’s technology is installed and run locally behind the 
users’ firewalls.  
12.3. 
Data Linkages 
Two sets of linkages are relevant for Komodo Health:  initial link of contributing administrative 
claims databases; and linkage of laboratory data (LabCorp and Quest Diagnostics), death date 
(NDI), and transplant date (OPTN registry).  All data linkages will be done through Datavant 
tokenization. 
Across all datasets, as the Datavant program de-identifies a patient record, it also generates one 
or more tokens for that record.  Tokens are based on the personally identifying data in the record, 
but the token itself does not incorporate this information in the identifier.  The tokens are 
consistently created from any data set where the underlying identifying information is the same.  
Matching tokens are used to link a patient’s record in one data set with a record for the same 
patient in a different set, without exposing the identifying information of that patient.  Matching 
can be deterministic (eg, based on social security number) or probabilistic (eg, based on 
combination or name, sex, birthdate, 3-digit zip code, etc). 
The tokens used to link records in de-identified data sets cannot be reversed to reveal the 
patient’s identifying information.  The first step of the token creation process is the use of an 
irreversible hash function, which ensures that the patient’s personally identifying information 
used to create the token cannot be recovered from the output value.  In the second step of the 
process, the hash value (ie, “Master Token”) is encrypted with a site-specific encryption key to 
generate the final encrypted patient token.  While the same patient information will always create 
the same Master Token, site-specific encryption means that a single patient will have a unique 
token (ie, a “site-specific token”) in each specific user’s data set.  Site-specific encryption 
ensures that a breach at one data site will never compromise the tokens or protected health 
information at any other data site.  Datavant's QA testing protocols and results will be included 
in the supplementary submission. 
Across all datasets, Datavant will create 2 tokens based on: 
•
Last name + first name + gender + date of birth
•
Last name (soundex) + first name (soundex) + gender + date of birth
In the event this produces 2 patients with one token (called a “collision”) or one patient with 
2 tokens, Datavant will then match on social security number and/or address (when available in 
the dataset).  In the overall Komodo Health claims database, in the match with the NDI, and in 
the match with Quest Diagnostics data, this has produced 99% exact match.  In the subset of 

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PBC patients, only 873 of 164,942 patients are flagged as a collision and have been removed 
from analysis.  The same process will be used with the OPTN transplant data. 
12.4. 
Data Harmonization 
The Global PBC registry collects data via a standardized eCRF.  As such, data harmonization 
across data sources is not required. 
The Komodo Health database merges administrative claims data from multiple insurers in the 
US.  Claims are then merged with NDI for date of death; LabCorp and Quest Diagnostics 
databases for laboratory tests and values; and OPTN transplant registry for date of liver 
transplant.  Below are the data sources and variables for which data harmonization is required 
and performed. 
12.4.1. 
Komodo Health and National Death Index 
The primary endpoint is a composite of all-cause death, liver transplant, and hospitalization for 
hepatic decompensation.  The primary source for death will be the NDI.  The Komodo Health 
claims database contains hospital discharge status, including “death.”  Hospital discharge of 
death will be compared to the NDI.  Should a death be recorded on hospital discharge but not in 
the NDI, and if the patient has no healthcare claims 30 days after the “death” discharge, the 
patient will be coded as a death using the hospital discharge date. 
12.4.2. 
Komodo Health and OPTN Liver Transplant 
The primary endpoint is a composite of all-cause death, liver transplant, and hospitalization for 
hepatic decompensation.  The primary source for liver transplant will be the OPTN transplant 
registry.  Hospitalization for liver transplant in Komodo Health claims also will be ascertained 
through inpatient ICD-10 codes (see Section 12.4.3 and Appendix A).  Komodo Health liver 
transplant claims will be compared to the OPTN database.  Should a liver transplant be recorded 
for a hospitalization but not in the OPTN database, it will be included as a primary endpoint. 
12.4.3. 
Komodo Health Hospitalization for Hepatic Decompensation 
The primary endpoint is a composite of all-cause death, liver transplant, and hospitalization for 
hepatic decompensation.  The primary source for hospitalization for hepatic decompensation will 
be Komodo Health claims.  The definition will include inpatient admission ICD-10 codes that 
appear in any position, and includes: 
•
Variceal bleed:  ICD-10: I85.01, I85.11, I86.4 and ICD-9: 456.1, 456.21, 456.8
•
Ascites:  ICD-10: K70.11, K70.31, K71.51, R18.0, R18.8, J94.8, K65.2 and ICD-9:
567.23, 571.2, 789.51,789.59, 511.8, 567.23
•
Hepatic encephalopathy:  ICD-10: B15.0, B16.0, B16.2, B17.11, B19.0, B19.11,
B19.21, K70.41, K72.11, K72.90, K72.91 and ICD-9: 572.2, 070.0, 070.20, 070.41,
070.6, 070.71; or utilization of lactulose and/or rifaximin
As ICD-10 codes are standard across the US healthcare industry, there is no need for further 
harmonization across contributing health plans. 

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12.4.4. 
Quest Diagnostics and LabCorp 
Within each laboratory provider, sample collection, test, and normal ranges are standardized.  
Collection and transport specifications, laboratory method, and normal ranges for each test are 
provided by each lab below. 
•
Total bilirubin (test code:  Quest 285, LabCorp 001099)
−
Quest Diagnostics:  Samples are collected in sodium heparin (green-top) or
lithium heparin (green-top) tubes, spun in a serum separator tube, transported in a
serum separator tube wrapped in foil or transferred to an amber transport vial, and
stored/transported at room temperature with stability up to 24 hours.
Spectrophotometry is performed on 1 mL serum.  ULN is 1.2 mg/dL.
−
LabCorp:  Samples are collected in red top gel-barrier tube or lithium heparin
(green-top) tubes, with serum separation in <45 minutes, and stored/transported at
room temperature with stability up to 3 days.  Spectrophotometry testing is
performed on 1 mL serum.  ULN is 1.2 mg/dL for >18-year-olds.
•
Alkaline phosphatase (test code:  Quest 234, LabCorp 001107)
−
Quest Diagnostics:  Samples are collected in sodium heparin (green-top) or
lithium heparin (green-top) tubes, spun and transported in a serum separator tube,
and stored/transported at room temperature with stability up to 7 days.
Spectrophotometry is performed on 1 mL serum.  ULN in U/L for 18- to
19-year-olds is 169 for men and 128 for women; for 20- to 49-year-olds is 130 for
men and 125 for women; and for >50-year-olds 144 for men and 153 for women.
−
LabCorp:  Samples are collected in red top gel-barrier tube or lithium heparin
(green-top) tubes, with serum separation in <45 minutes, and 1 mL serum
transported in plastic separator tube, and stored/transported at room temperature
with stability up to 14 days.  Kinetic testing is performed on 1 mL serum.  ULN in
IU/L for 18- to 20-year-olds is 125 for men and 106 for women; for >21-year-olds
is 121 for men and women.
•
Alanine aminotransferase (test code:  Quest 823, LabCorp 001545)
−
Quest:  Samples are collected in sodium heparin (green-top) or lithium heparin
(green-top) tubes, spun and transported in a serum separator tube, and
stored/transported at room temperature with stability up to 72 hours.
Spectrophotometry is performed on 1 mL serum.  ULN in U/L for 18- to
19-year-olds is 46 for men and 32 for women; for >20-year-olds is 46 for men and
29 for women.
−
LabCorp:  Samples are collected in red top gel-barrier tube or lithium heparin
(green-top) tubes, with serum separation in <45 minutes, and stored/transported at
room temperature with stability up to 7 days.  Kinetic testing is performed on
1 mL serum.  ULN is 44 IU/L for >18-year-olds.

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•
Aspartate Aminotransferase (test code:  Quest 822, LabCorp 001123)
−
Quest Diagnostics:  Samples are collected in sodium heparin (green-top) or
lithium heparin (green-top) tubes, spun and transported in a serum separator tube,
and stored/transported at room temperature with stability up to 4 days.
Spectrophotometry is performed on 1 mL serum.  ULN in U/L for 18- to
19-year-old men and women is 32; for men, 20- to 49-year-olds is 40 and
>50-year-olds is 35; for women, 20- to 44-year olds is 30 and >45-year-olds is 35.
−
LabCorp:  Samples are collected in red top gel-barrier tube or lithium heparin
(green-top) tubes, with serum separation in <45 minutes, and stored/transported at
room temperature with stability up to 7 days.  Kinetic testing is performed on
1 mL serum.  ULN is 40 IU/L for >18-year-olds.
•
Platelets (test code:  Quest 723, LabCorp 005249)
−
Quest Diagnostics:  Samples are collected in lavender-top (EDTA) tubes and
stored/transported at room temperature with stability up to 48 hours.  Testing is
performed on 0.5 mL whole blood using an automated cell counter.  Lower limit
of normal (LLN) is 150,000 per uL for >18-year-olds.
−
LabCorp:  Samples are collected in lavender-top (EDTA) tubes, immediately
inverted 8 to 10 times, and stored/transported at room temperature with stability
up to 1 day.  Testing is performed on 0.5 mL whole blood using an automated cell
counter.  LLN is 150,000 per uL for >18-year-olds.
12.4.5. 
Cirrhosis 
In the Global PBC registry, cirrhosis is assessed as positive for one or more of the following 
criteria: 
•
Biopsy Stage 4;
•
Transient elastography ≥16.9 kPa;
•
Radiological evidence (nodular liver or enlargement of portal vein + splenomegaly);
•
Clinical features of portal hypertension defined as platelet count <140 000/mm³ with:
persistent decrease in serum albumin; or, TB >2x ULN; or prothrombin time/INR >
ULN (not due to antithrombotic use)
In the Komodo Health database, imaging data are not available and measures such as INR are 
not consistently collected.  The Sponsor created and validated an algorithm for a claims-based 
cirrhosis diagnosis, defined as:  cirrhosis ICD-10 (K74.5; K74.60; K74.69) with liver imaging 
and/or biopsy in 6 months preceding diagnosis (for imaging codes see Appendix A).  Prevalence 
estimates in patients with PBC based on these codes in the HealthCore and Optum databases, 
stratified by decompensation and portal hypertension, were compared to data from the Global 
PBC registry (Table 2).  As shown, the concordance was high.  Additional analyses examining 
the association between these groups and clinical outcomes (death, liver transplant and hepatic 
decompensation) demonstrated that the expected relationships, with cirrhosis in the presence of 
portal hypertension or decompensation significantly increasing risk of death, liver failure and 
liver transplantation (Figure 3). 

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Table 2: 
Comparison of Imaging-based (Global PBC) and Claims-based (Health Core, 
Optum) Prevalence of Cirrhosis in PBC Patients. 
GlobalPBC 
Optmn 
Health Core 
PBC 
N=2,982 (100%) 
N=4,328 (100%) 
N=4,348 (100%) 
Compensated non-cin-hosis 
N=2,275 (76.3%) 
N=3,303 (76.3%) 
N=3,317 (76.3%) 
Compensated ci.IThosis, without 
N=314 (10.5%) 
N=271 (6.3%) 
N=225 (5.2%) 
portal hype1tension 
Compensated ciiThosis, with 
N=l05 (3.5%) 
N= 276 (6.4%) 
N=295 (6.8%) 
portal hype1tension 
Decompensa.ted 
N=283 (9.5%) 
N=478 (11.0%) 
N=511 (11.8%) 
Figure 3: 
Incidence Rates for Major Hepatic Events Stratified by Cirrhosis, Portal 
Hypertension and Hepatic Decompensation in the Optum (A) and 
HealthCore (B) Databases 
A. Optum 
B. HealthCore 
0.1 
CNC. Over•II mortality 
CC•PH, Overall mortality 
CC+l'H, Overall mortality 
DC, Dw rall mortality 
a.lC.. Liver bilure 
cc .. PH, Liver failure 
CC +PH. liver failure: 
DC, liver loDure 
CNC, Liver traniplant 
cc-PH. L;yer tr•ruplant 
CC+PH, Uver tran.splant 
OC, Uver trirrsplant 
CNC. Variceal bleedinc 
CC-PH, Variceal bleeding 
CC+PH, Variceal bleeding 
DC, V1rice1I bleeding 
CNC, Ascitu 
CC-f>H, Ase.hes 
CC+PH, Ascites 
DC, A5Cites 
CNC, Hepatic encephalopathy 
CC·PH, Hepatic encephalopathy 
CC+PH, Hepatic MCtphalopathy 
DC, Hepatic encephalopathy 
Confidential and Proprieta1y 
10 
27.3 • 
21 -
64.S --
17.6 • 
19.4 -
2.3 -
4.3 
S4.6 ---
111 
4 .3 
.. 
-+-8.4 
38.1 
-+-83.9 
26.8 .... 
2t.9 -
8.S .... 
8.4 
57.7 
-+-
CNC, Overall mortality 
CC-PH, Overall mortality 
CC•PH, Overall mortality 
OC, overall mortality 
CNC. liver failure 
CC-PH, liver failure 
CC+PH, liver failure 
OC, Liver failure 
OJC, Liver transplan\ 
CC..PH, livertr•nsplant 
CC.PH., livor transplant 
DC, liver tr1nsplant 
CNC, Variceal bleedine 
CC-PH, Variceal bleedin2 
CC+PH, Varlceal bleeding 
oc, varlceal bleeding 
CNC, Asdtes 
CC-PH, Ascites 
CC+PH, Ascites 
DC, Ascites 
CNC, Hepatic encephalopathy 
CC·PH, Hepatic encephalopathy 
CC+l'H, Hepatic er,cephalopathy 
DC, Hepatic encephalopathy 
0 
100 
11.78 
lt.88 
~
.92 
°""19.37 
6.49 
~
.36 
_.,_..._s,.12 
°"'93.01 
1.96 
--5.62 
44.67 
'"tr.1s ... 
33.SO 
3,.56 
10.78 _... 
3.58 
...... 
40.43 
~
9.15 
101.ii2 
..... 
1000 

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12.5. 
Characterization of Missing Data 
Missing data will be assumed to be missing at random.  As per FDA draft real-world evidence 
(RWE) guidelines, missing data are characterized by year (see Appendix B) and will undertake 
an analysis of secular trend to determine if missingness varies by time.  Should secular trends 
exist, the CRC will determine the best approach to addressing bias, and that approach will be 
included in a protocol revision. 
12.6. 
Data Management and Analysis SOPs 
The FDA draft guidance on RWE requires a data management plan as well as copies of all 
relevant data management and analysis SOPs.  These will be included in a supplemental 
submission and defined separately for the Global PBC study group and the CRO analyzing the 
Komodo data.   
12.7. 
Audits and Inspections 
The Investigators should understand that it may be necessary for the Sponsor, the 
IRB/Independent Ethics Committee (IEC), and/or regulatory agencies to conduct one or more 
site audits during or after the study and agree to allow access to all study-related documentation 
and information and be available for discussion about the study. 
12.8. 
Quality Control and Quality Assurance 
Logic and consistency checks will be performed on all data in the database to ensure accuracy 
and completeness.  SOPs from the CRO analyzing the Komodo data and the Global PBC Study 
Group governing data management and analysis will be provided in a supplemental submission. 
Given the short length of the study conduct period (approximately 6 months for analysis and 
clinical study report), the Sponsor will conduct a single monitoring visit at each site.  Study 
records will be reviewed to ensure maintenance and documentation of complete, accurate, 
legible, well-organized, and easily retrievable data.  The Sponsor will ensure the Investigator's 
understanding of the protocol, reporting responsibilities, and the validity of the data.  This will 
include ensuring that full and appropriate essential documentation is available.  To perform 
analytic file and analysis verification, the Sponsor must be given access to the analytic file, SAS 
code and code annotation.  The Sponsor will not alter data or programming, nor will transport 
any data from the site. 
12.9. 
Data Retention and Archiving Study Documents 
The CRO analyzing the Komodo data and the Global PBC Study Group will retain the data and 
all study documents after delivery of the project for a maximum period as required by the 
applicable regulatory requirement(s) or the Sponsor.  In the event that storage of data becomes a 
problem at any time during this period, the Sponsor should be consulted for assistance.  At the 
end of the minimum period, the CRO and the Global PBC Study Group should obtain written 
authorization from the Sponsor before the destruction of any records.  The Sponsor will inform 
the CRO and the Global PBC Study Group should it become aware of any changes in storage 
requirements.  

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13.
PROTECTION OF HUMAN SUBJECTS
These studies will be conducted in accordance with HIPAA regulations and US standards of 
privacy of individually identifiable health information. 
The Global PBC registry was approved by the University Health Network IRB at the University 
of Toronto (CAPCR ID: 19-5678). 
All data used in these studies are anonymized, and analyses will be performed on de-identified 
patient-level datasets.  While patient data will be anonymized and the studies are observational 
and retrospective in nature and thus would qualify for exemption under the Common Rule, these 
studies are being submitted to Western IRB for full review.  
The data system will be maintained and secured as requested by the US patient privacy 
regulations.  Processes assuring data security will be employed during data extraction, storage, 
and backup.  The data and all study documents will be kept until the Sponsor’s written 
notification that records may be destroyed. 
14.
ADVERSE EVENT REPORTING
As stated in Section 9 (Assessment of Safety), these studies are not designed to assess safety.  
Study outcome variables collected for the 2 cohorts will be presented for analyses as aggregate 
data groups.  The data sources will not be searched for individual patient adverse events.  
However, if an Investigator or the Sponsor identifies adverse events that meet postmarketing 
reporting requirements during the course of conducting these studies, such events will be 
reported in accordance with applicable postmarketing reporting requirements. 
15.
PUBLICATION POLICY
The Sponsor intends to publish the results of all of the studies that it sponsors, regardless of 
outcome and consistent with the Declaration of Helsinki.  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 study data have been raised in 
the medical press.  Accordingly, the Sponsor has developed publication guidelines for studies 
that are appropriate for these studies.  Key issues include the following: 
•
Clinical Trial Registries (eg, www.clinicaltrials.gov, www.clinicaltrialsregister.eu):  A
description of these studies and relevant design elements (eg, basic design, objectives and
endpoints, sample size, study population, and key inclusion/exclusion criteria) and results
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.

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•
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.
•
Authorship:  Intercept, 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.
•
Intercept Review of External Manuscripts:  Investigators must submit any drafts of any
publications or presentations that may arise from these studies to the Sponsor for review
and approval and to ensure consistency with the policy in this protocol at least 30 days
prior to 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 and data tabulations.  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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16.
LIST OF REFERENCES
Brookhart MA. Counterpoint: The Treatment Decision Design. American Journal of 
Epidemiology. 2015;182:840–845. 
Cameron, AC, Gelbach JB, Miller DL. Bootstrap-based improvements for inference with 
clustered errors. The Review of Economics and Statistics. 2008;90(3):414-427. 
Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG Clinical Guideline: the diagnosis and 
management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 
Jul;109(7):950-66. 
Cole SR, Frangakis CE. The consistency statement in causal inference: a definition or an 
assumption? Epidemiology. 2009;20:3–5. 
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and 
long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48(3):871-877. 
Danaei G, Rodríguez LA, Cantero OF, et al. Observational data for comparative effectiveness 
research: an emulation of randomised trials of statins and primary prevention of coronary heart 
disease. Stat Methods Med Res. 2013;22:70–96. 
Davison AC, Hinkley DV. Further Ideas in ‘Bootstrap Methods and their Application’. 
Cambridge University Press 2013, pp. 70–135. 
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: 
management of cholestatic liver diseases. J Hepatol. 2009;51:237‐267. 
Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk’. 
Journal of the American Statistical Association. 1999;94:496–509.  
Glasheen WP, Cordier T, Gumpina R, et al. Charlson Comorbidity Index: ICD-9 Update and 
ICD-10 Translation. Am Health Drug Benefits. 2019;12:188-197. 
Gran JM, Røysland K, Wolbers M, et al. A sequential Cox approach for estimating the causal 
effect of treatment in the presence of time-dependent confounding applied to data from the Swiss 
HIV Cohort Study. Stat Med. 2010;29:2757–2768.  
Greenland S, Robins JM. Identifiability, exchangeability, and epidemiological confounding. Int J 
Epidemiol. 1986;15:413–419. 
Hernán MA, Alonso A, Logan R, et al. Observational studies analyzed like randomized 
experiments: an application to postmenopausal hormone therapy and coronary heart disease. 
Epidemiology. 2008;19:766–779. 
Hernán MA, Robins JM. Per-Protocol Analyses of Pragmatic Trials. N Engl J Med. 
2017;377:1391–1398.  
Kim WR, Lindor KD, Locke GR 3rd, et al. Epidemiology and natural history of primary biliary 
cirrhosis in a US community. Gastroenterology. 2000;119:1631-1636. 
Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict long-
term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 
2010;105(10):2186-2194. 

Protocol 747-404/405 
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Page 50
Confidential and Proprietary 
Lash TL. Bias Analysis’, in Lash, T. L. et al. (eds) Modern Epidemiology. 4th edn. Wolters 
Kluwer 2021, pp. 711–754. 
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis:  AASLD practice 
guidelines. Hepatology 2009;50:291‐308. 
Meyers RP, Shaheen AA, Fong A, et al. Validation of coding algorithms for the identification of 
patients with primary biliary cirrhosis using administrative data. Can J Gastroenterol. 
2010;24:175-182. 
Perez FM, Fisher H, Hiu S, et al. Patients with primary biliary cholangitis treated with long-term 
obeticholic acid in a trial-setting demonstrate better event-free survival than external controls 
from the GLOBAL PBC and UK-PBC study groups. Oral presentation at: American Association 
for the Study of Liver Disease; November, 2011; Anaheim, CA. 
Pearl J. On the consistency rule in causal inference: axiom, definition, assumption, or theorem? 
Epidemiology. 2010;21:872–875. 
Petersen ML, Porter KE, Gruber S, et al. Diagnosing and responding to violations in the 
positivity assumption. Stat Methods Med Res. 2012;21:31–54. 
Sarvet AL, Wanis KN, Stensrud MJ, et al. A Graphical Description of Partial Exchangeability. 
Epidemiology. 2020; 31:365–368.  
Sato T, Matsuyama Y. Marginal structural models as a tool for standardization. Epidemiology. 
2003;14:680–686. 
Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 
1983;39(2):499-503. 
Shook-Sa BE, Hudgens MG. Power and sample size for observational studies of point exposure 
effects [published online ahead of print, 2020 Nov 23]. Biometrics. 2020;10.1111/biom.13405. 
doi:10.1111/biom.13405. 
US Food and Drug Administration. Framework for FDA’s Real-World Evidence Program. 
December 2018: US Department of Health & Human Services; 
https://www.fda.gov/media/120060/download. 
US Food and Drug Administration. Real-World Data: Assessing Electronic Health Records and 
Medical Claims Data To Support Regulatory Decision Making for Drug and Biological Products. 
Guidance for Industry. September 2021: US Department of Health & Human Services; 
https://www.fda.gov/media/152503/download 
VanderWeele TJ. Concerning the consistency assumption in causal inference. Epidemiology. 
2009;20:880–883.  
Westreich D, Cole SR. Invited commentary: positivity in practice. Am J Epidemiol. 
2010;171:674–681.  

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APPENDIX A. LIST OF INCLUSION, EXCLUSION AND COVARIATE 
CODES 
INCLUSION/EXCLUSION CRITERIA CODES 
CODE 
TYPE 
DESCRIPTION 
Inclusion criteria 
K74.3 
ICD10 Primary biliary cholangitis 
571.6 
ICD9 Biliary cirrhosis (for rule-out in the baseline period) 
Exclusion criteria 
0FY00Z1 ICD10 pcs 
Transplantation of liver, syngeneic, open approach 
0FY00Z0 ICD10 pcs 
Transplantation of Liver, Allogeneic, Open Approach 
47135 
HCPCS/ 
CPT-4 
Liver allotransplantation; orthotopic; partial or whole, from cadaver or living 
donor, any age 
B17.10 
ICD10 Acute hepatitis C without hepatic coma 
B17.11 
ICD10 Acute hepatitis C with hepatic coma 
070.41 
ICD9 Acute hepatitis C with hepatic coma 
070.51 
ICD9 Acute hepatitis C without mention of hepatic coma 
B18.2 
ICD10 Chronic viral hepatitis C 
070.44 
ICD9 Chronic hepatitis C with hepatic coma 
070.54 
ICD9 Chronic hepatitis C without mention of hepatic coma 
070.70 
ICD9 Unspecified viral hepatitis C without hepatic coma 
070.71 
ICD9 Unspecified viral hepatitis C with hepatic coma 
B16.0 
ICD10 Acute hepatitis B with delta-agent with hepatic coma 
B16.1 
ICD10 Acute hepatitis B with delta-agent without hepatic coma 
B16.2 
ICD10 Acute hepatitis B without delta-agent with hepatic coma 
B16.9 
ICD10 Acute hepatitis B without delta-agent and without hepatic coma 
B17.0 
ICD10 Acute delta-(super) infection of hepatitis B carrier 
070.20 
ICD9 Viral hepatitis B with hepatic coma, acute or unspecified, without mention of 
hepatitis delta  
070.21 
ICD9 Viral hepatitis B with hepatic coma, acute or unspecified, with hepatitis delta 
070.30 
ICD9 Viral hepatitis B without mention of hepatic coma, acute or unspecified, without 
mention of hepatitis delta 
070.31 
ICD9 Viral hepatitis B without mention of hepatic coma, acute or unspecified, with 
hepatitis delta 
B18.0 
ICD10 Chronic viral hepatitis B with delta-agent 
B18.1 
ICD10 Chronic viral hepatitis B without delta-agent 
070.23 
ICD9 Chronic viral hepatitis B with hepatic coma with hepatitis delta 
070.22 
ICD9 Chronic viral hepatitis B with hepatic coma without hepatitis delta 
070.33 
ICD9 Chronic viral hepatitis B without mention of hepatic coma with hepatitis delta 
070.32 
ICD9 Chronic viral hepatitis B without mention of hepatic coma without mention of 
hepatitis delta 
K83.01 
ICD10 Primary sclerosing cholangitis (2019-2021 only) 
K70.0 
ICD10 Alcoholic fatty liver 

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CODE 
TYPE 
DESCRIPTION 
K70.10 
ICD10 Alcoholic hepatitis without ascites 
K70.11 
ICD10 Alcoholic hepatitis with ascites 
K70.2 
ICD10 Alcoholic fibrosis and sclerosis of liver 
K70.30 
ICD10 Alcoholic cirrhosis of liver without ascites 
K70.31 
ICD10 Alcoholic cirrhosis of liver with ascites 
K70.40 
ICD10 Alcoholic hepatic failure without coma 
K70.41 
ICD10 Alcoholic hepatic failure with coma 
K70.9 
ICD10 Alcoholic liver disease, unspecified 
571.0 
ICD9 Alcoholic fatty liver 
571.1 
ICD9 Acute alcoholic hepatitis 
571.2 
ICD9 Alcoholic cirrhosis of liver 
571.3 
ICD9 Alcoholic liver damage, unspecified 
C22.0 
ICD10 Liver cell carcinoma 
C22.8 
ICD10 Malignant neoplasm of liver, primary, unspecified as to type 
C22.9 
ICD10 Malignant neoplasm of liver, not specified as primary or secondary 
155.0 
ICD9 Malignant neoplasm of liver, primary 
155.2 
ICD9 Malignant neoplasm of liver, not specified as primary or secondary 
K76.7 
ICD10 Hepatorenal syndrome 
572.4 
ICD9 Hepatorenal syndrome 
K76.81 
ICD10 Hepatopulmonary syndrome 
573.5 
ICD9 Hepatopulmonary syndrome 
I27.21 
ICD10 Secondary pulmonary arterial hypertension 
K75.81 
ICD10 Nonalcoholic steatohepatitis 
571.8 
ICD9 Other chronic nonalcoholic liver disease 
C00 
ICD10 Malignant neoplasm of lip 
C02 
ICD10 Malignant neoplasm of other and unspecified parts of tongue 
C03 
ICD10 Malignant neoplasm of gum 
C04 
ICD10 Malignant neoplasm of floor of mouth 
C05 
ICD10 Malignant neoplasm of palate 
C06 
ICD10 Malignant neoplasm of other and unspecified parts of mouth 
C08 
ICD10 Malignant neoplasm of other and unspecified major salivary glands 
C09 
ICD10 Malignant neoplasm of tonsil 
C10 
ICD10 Malignant neoplasm of oropharynx 
C11 
ICD10 Malignant neoplasm of nasopharynx 
C13 
ICD10 Malignant neoplasm of hypopharynx 
C14 
ICD10 Malignant neoplasm of other and ill-defined sites in the lip, oral cavity & pharynx 
C15 
ICD10 Malignant neoplasm of esophagus 
C16 
ICD10 Malignant neoplasm of stomach 
C17 
ICD10 Malignant neoplasm of small intestine 
C18 
ICD10 Malignant neoplasm of colon 
C21 
ICD10 Malignant neoplasm of anus and anal canal 

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CODE 
TYPE 
DESCRIPTION 
C22 
ICD10 Malignant neoplasm of liver and intrahepatic bile ducts 
C24 
ICD10 Malignant neoplasm of other and unspecified parts of biliary tract 
C25 
ICD10 Malignant neoplasm of pancreas 
C26 
ICD10 Malignant neoplasm of other and ill-defined digestive organs 
C30 
ICD10 Malignant neoplasm of nasal cavity and middle ear 
C31 
ICD10 Malignant neoplasm of accessory sinuses 
C32 
ICD10 Malignant neoplasm of larynx 
C34 
ICD10 Malignant neoplasm of bronchus and lung 
C38 
ICD10 Malignant neoplasm of heart, mediastinum and pleura 
C39 
ICD10 Malignant neoplasm of other and ill-defined sites in the respiratory system and 
intrathoracic organs 
C40 
ICD10 Malignant neoplasm of bone and articular cartilage of limbs 
C41 
ICD10 Malignant neoplasm of bone and articular cartilage of other and unspecified sites 
C47 
ICD10 Malignant neoplasm of peripheral nerves and autonomic nervous system 
C48 
ICD10 Malignant neoplasm of retroperitoneum and peritoneum 
C49 
ICD10 Malignant neoplasm of other connective and soft tissue 
C50 
ICD10 Malignant neoplasm of breast 
C51 
ICD10 Malignant neoplasm of vulva 
C53 
ICD10 Malignant neoplasm of cervix uteri 
C54 
ICD10 Malignant neoplasm of corpus uteri 
C56 
ICD10 Malignant neoplasm of ovary 
C57 
ICD10 Malignant neoplasm of other and unspecified female genital organs 
C60 
ICD10 Malignant neoplasm of penis 
C62 
ICD10 Malignant neoplasm of testis 
C63 
ICD10 Malignant neoplasm of other and unspecified male genital organs 
C64 
ICD10 Malignant neoplasm of kidney, except renal pelvis 
C65 
ICD10 Malignant neoplasm of renal pelvis 
C66 
ICD10 Malignant neoplasm of ureter 
C67 
ICD10 Malignant neoplasm of bladder 
C68 
ICD10 Malignant neoplasm of other and unspecified urinary organs 
C69 
ICD10 Malignant neoplasm of eye and adnexa 
C70 
ICD10 Malignant neoplasm of meninges 
C71 
ICD10 Malignant neoplasm of brain 
C72 
ICD10 Malignant neoplasm of spinal cord, cranial nerves and other parts of central 
nervous system 
C74 
ICD10 Malignant neoplasm of adrenal gland 
C75 
ICD10 Malignant neoplasm of other endocrine glands and related structures 
C76 
ICD10 Malignant neoplasm of other and ill-defined sites 
C77 
ICD10 Secondary and unspecified malignant neoplasm of lymph nodes 
C78 
ICD10 Secondary malignant neoplasm of respiratory and digestive organs 
C79 
ICD10 Secondary malignant neoplasm of other and unspecified sites 

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CODE 
TYPE 
DESCRIPTION 
C80 
ICD10 Malignant neoplasm without specification of site 
140 
ICD9 Malignant neoplasm of lip 
141 
ICD9 Malignant neoplasm of tongue 
142 
ICD9 Malignant neoplasm of major salivary glands 
143 
ICD9 Malignant neoplasm of gum 
144 
ICD9 Malignant neoplasm of floor of mouth 
145 
ICD9 Malignant neoplasm of other and unspecified parts of mouth 
146 
ICD9 Malignant neoplasm of oropharynx 
147 
ICD9 Malignant neoplasm of nasopharynx 
148 
ICD9 Malignant neoplasm of hypopharynx 
149 
ICD9 Malignant neoplasm of other and ill-defined sites within the lip, oral cavity, and 
pharynx 
150 
ICD9 Malignant neoplasm of esophagus 
151 
ICD9 Malignant neoplasm of stomach 
152 
ICD9 Malignant neoplasm of small intestine, including duodenum 
153 
ICD9 Malignant neoplasm of colon 
154 
ICD9 Malignant neoplasm of rectum, rectosigmoid junction, and anus 
155 
ICD9 Malignant neoplasm of liver and intrahepatic bile ducts 
156 
ICD9 Malignant neoplasm of gallbladder and extrahepatic bile ducts 
157 
ICD9 Malignant neoplasm of pancreas 
158 
ICD9 Malignant neoplasm of retroperitoneum and peritoneum 
159 
ICD9 Malignant neoplasm of other and ill-defined sites within the digestive organs and 
peritoneum 
160 
ICD9 Malignant neoplasm of nasal cavities, middle ear, and accessory sinuses 
161 
ICD9 Malignant neoplasm of larynx 
162 
ICD9 Malignant neoplasm of trachea, bronchus, and lung 
163 
ICD9 Malignant neoplasm of pleura 
164 
ICD9 Malignant neoplasm of thymus, heart, and mediastinum 
165 
ICD9 Malignant neoplasm of other and ill-defined sites within the respiratory system and 
intrathoracic organs 
170 
ICD9 Malignant neoplasm of bone and articular cartilage 
171 
ICD9 Malignant neoplasm of connective and other soft tissue 
174 
ICD9 Malignant neoplasm of female breast 
175 
ICD9 Malignant neoplasm of male breast 
180 
ICD9 Malignant neoplasm of cervix uteri 
182 
ICD9 Malignant neoplasm of body of uterus 
183 
ICD9 Malignant neoplasm of ovary and other uterine adnexa 
184 
ICD9 Malignant neoplasm of other and unspecified female genital organs 
186 
ICD9 Malignant neoplasm of testis 
187 
ICD9 Malignant neoplasm of penis and other male genital organs 
188 
ICD9 Malignant neoplasm of bladder 

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CODE 
TYPE 
DESCRIPTION 
189 
ICD9 Malignant neoplasm of kidney and other and unspecified urinary organs 
190 
ICD9 Malignant neoplasm of eye 
191 
ICD9 Malignant neoplasm of brain 
192 
ICD9 Malignant neoplasm of other and unspecified parts of nervous system 
194 
ICD9 Malignant neoplasm of other endocrine glands and related structures 
195 
ICD9 Malignant neoplasm of other and ill-defined sites 
196 
ICD9 Secondary and unspecified malignant neoplasm of lymph nodes 
197 
ICD9 Secondary malignant neoplasm of respiratory and digestive systems 
198 
ICD9 Secondary malignant neoplasm of other specified sites 
199 
ICD9 Malignant neoplasm without specification of site 
B20 
ICD10 Human immunodeficiency virus infection 
B21 
ICD10 Human immunodeficiency virus [HIV] disease resulting in malignant neoplasms 
B22 
ICD10 Human immunodeficiency virus [HIV] disease resulting in other specified diseases 
042 
ICD9 Human immunodeficiency virus [HIV] infection 
M88.0 
ICD10 Osteitis deformans of skull 
M88.1 
ICD10 Osteitis deformans of vertebrae 
M88.811 
ICD10 Osteitis deformans of right shoulder 
M88.812 
ICD10 Osteitis deformans of left shoulder 
M88.819 
ICD10 Osteitis deformans of unspecified shoulder 
M88.821 
ICD10 Osteitis deformans of right upper arm 
M88.822 
ICD10 Osteitis deformans of left upper arm 
M88.829 
ICD10 Osteitis deformans of unspecified upper arm 
M88.831 
ICD10 Osteitis deformans of right forearm 
M88.832 
ICD10 Osteitis deformans of left forearm 
M88.839 
ICD10 Osteitis deformans of unspecified forearm 
M88.841 
ICD10 Osteitis deformans of right hand 
M88.842 
ICD10 Osteitis deformans of left hand 
M88.849 
ICD10 Osteitis deformans of unspecified hand 
M88.851 
ICD10 Osteitis deformans of right thigh 
M88.852 
ICD10 Osteitis deformans of left thigh 
M88.859 
ICD10 Osteitis deformans of unspecified thigh 
M88.861 
ICD10 Osteitis deformans of right lower leg 
M88.862 
ICD10 Osteitis deformans of left lower leg 
M88.869 
ICD10 Osteitis deformans of unspecified lower leg 
M88.871 
ICD10 Osteitis deformans of right ankle and foot 
M88.872 
ICD10 Osteitis deformans of left ankle and foot 
M88.879 
ICD10 Osteitis deformans of unspecified ankle and foot 
M88.88 
ICD10 Osteitis deformans of other bones 
M88.89 
ICD10 Osteitis deformans of multiple sites 
M88.9 
ICD10 Osteitis deformans of unspecified bone 
731.0 
ICD9 Osteitis deformans without mention of bone tumor 

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CODE 
TYPE 
DESCRIPTION 
S02 
ICD10 Fracture of skull and facial bones 
S12 
ICD10 Fracture of cervical vertebra and other parts of neck 
S22 
ICD10 Fracture of rib(s), sternum and thoracic spine 
S32 
ICD10 Fracture of lumbar spine and pelvis 
S42 
ICD10 Fracture of shoulder and upper arm 
S52 
ICD10 Fracture of forearm 
S62 
ICD10 Fracture at wrist and hand level 
S72 
ICD10 Fracture of femur 
S82 
ICD10 Fracture of lower leg, including ankle 
S92 
ICD10 Fracture of foot and toe, except ankle 
800 
ICD9 Fracture of vault of skull 
801 
ICD9 Fracture of base of skull 
802 
ICD9 Fracture of face bones 
803 
ICD9 Other and unqualified skull fractures 
804 
ICD9 Multiple fractures involving skull or face with other bones 
805 
ICD9 Fracture of vertebral column without mention of spinal cord injury 
806 
ICD9 Fracture of vertebral column with spinal cord injury 
807 
ICD9 Fracture of rib(s) sternum larynx and trachea 
808 
ICD9 Fracture of pelvis 
809 
ICD9 Ill-defined fractures of bones of trunk 
810 
ICD9 Fracture of clavicle 
811 
ICD9 Fracture of scapula 
812 
ICD9 Fracture of humerus 
813 
ICD9 Fracture of radius and ulna 
814 
ICD9 Fracture of carpal bone(s) 
815 
ICD9 Fracture of metacarpal bone(s) 
816 
ICD9 Fracture of one or more phalanges of hand 
817 
ICD9 Multiple fractures of hand bones 
818 
ICD9 Ill-defined fractures of upper limb 
819 
ICD9 Multiple fractures involving both upper limbs and upper limb with rib(s) and 
sternum 
820 
ICD9 Fracture of neck of femur 
821 
ICD9 Fracture of other and unspecified parts of femur 
822 
ICD9 Fracture of patella 
823 
ICD9 Fracture of tibia and fibula 
824 
ICD9 Fracture of ankle 
825 
ICD9 Fracture of one or more tarsal and metatarsal bones 
826 
ICD9 Fracture of one or more phalanges of foot 
827 
ICD9 Other multiple and ill-defined fractures of lower limb 
828 
ICD9 Multiple fractures involving both lower limbs lower with upper limb and lower 
limb(s) with rib(s) and sternum 
829 
ICD9 Fracture of unspecified bones 

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CODE 
TYPE 
DESCRIPTION 
I85.01 
ICD10 Esophageal varices with bleeding 
I85.11 
ICD10 Secondary esophageal varices with bleeding 
456.0 
ICD9 Esophageal varices with bleeding 
K70.11 
ICD10 Alcoholic hepatitis with ascites 
K70.31 
ICD10 Alcoholic cirrhosis of liver with ascites 
K71.51 
ICD10 Toxic liver disease with chronic active hepatitis with ascites 
R18.0 
ICD10 Malignant ascites 
R18.8 
ICD10 Other ascites 
571.2 
ICD9 Alcoholic cirrhosis of liver 
789.51 
ICD9 Malignant ascites 
789.59 
ICD9 Other ascites 
J94.8 
ICD10 Other specified pleural conditions 
511.8 
ICD9 Other specified forms of pleural effusion, except tuberculous 
567.23 
ICD9 Spontaneous bacterial peritonitis 
K65.2 
ICD10 Spontaneous bacterial peritonitis 
B15.0 
ICD10 Hepatitis A with hepatic coma 
B16.0 
ICD10 Acute hepatitis B with delta-agent with hepatic coma 
B16.2 
ICD10 Acute hepatitis B without delta-agent with hepatic coma 
B17.11 
ICD10 Acute hepatitis C with hepatic coma 
B19.0 
ICD10 Unspecified viral hepatitis with hepatic coma 
B19.11 
ICD10 Unspecified viral hepatitis B with hepatic coma 
B19.21 
ICD10 Unspecified viral hepatitis C with hepatic coma 
K70.41 
ICD10 Alcoholic hepatic failure with coma 
K72.11 
ICD10 Chronic hepatic failure with coma 
K71.11 
ICD10 Toxic liver disease with hepatic necrosis, with coma 
K72.01 
ICD10 Acute and subacute hepatic failure with coma 
K72.91 
ICD10 Hepatic failure, unspecified with coma 
572.2 
ICD9 Hepatic encephalopathy 
070.0 
ICD9 Viral hepatitis A with hepatic coma 
070.21 
ICD9 Viral hepatitis B with hepatic coma, acute or unspecified, with hepatitis delta 
070.20 
ICD9 Viral hepatitis B with hepatic coma, acute or unspecified, without mention of 
hepatitis delta 
070.2 
ICD9 Viral hepatitis b with hepatic coma 
070.6 
ICD9 Unspecified viral hepatitis with hepatic coma 
070.4 
ICD9 Other specified viral hepatitis with hepatic coma 
070.41 
ICD9 Acute hepatitis C with hepatic coma 
070.6 
ICD9 Unspecified viral hepatitis with hepatic coma 
070.71 
ICD9 Unspecified viral hepatitis C with hepatic coma 
Z48.23 
ICD10 Encounter for aftercare following liver transplant 
V42.7 
ICD9 Liver transplant status 
T86.40 
ICD10 Unspecified complication of liver transplant 
T86.41 
ICD10 Liver transplant rejection 

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CODE 
TYPE 
DESCRIPTION 
T86.42 
ICD10 Liver transplant failure 
T86.43 
ICD10 Liver transplant infection 
T86.49 
ICD10 Other complications of liver transplant 
996.82 
ICD9 Complications of transplanted liver 

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COVARIATE CODES (INLCUDING CHARLESON COMORBIDITY INDEX 
CODE 
TYPE 
DESCRIPTION 
K76.6 
ICD10 Portal hypertension 
572.3 
ICD9 Portal hypertension 
I86.4 
ICD10 Gastric varices 
456.8 
ICD9 Varices of other sites (non-specific) 
I85.00 
ICD10 Esophageal varices without bleeding 
I85.10 
ICD10 Secondary esophageal varices without bleeding 
456.1 
ICD9 Esophageal varices without mention of bleeding 
456.21 
ICD9 Esophageal varices in diseases classified elsewhere, without mention of bleeding 
K74.5 
ICD10 Biliary cirrhosis, unspecified 
K74.60 
ICD10 Unspecified cirrhosis of liver 
K74.69 
ICD10 Other cirrhosis of liver 
571.5 
ICD9 Cirrhosis of liver without mention of alcohol 
I21 
ICD10 Acute myocardial infarction 
I22 
ICD10 Subsequent ST elevation and non-ST elevation myocardial infarction 
I25.2 
ICD10 Old myocardial infarction 
410 
ICD9 Acute myocardial infarction 
412 
ICD9 Old myocardial infarction 
I11.0 
ICD10 Hypertensive heart disease with heart failure 
I13.0 
ICD10 Hypertensive heart and chronic kidney disease with heart failure and stage 1 through 
stage 4 chronic kidney disease, or unspecified chronic kidney disease 
I13.2 
ICD10 Hypertensive heart and chronic kidney disease with heart failure and with stage 5 
chronic kidney disease, or end stage renal disease 
I25.5 
ICD10 Ischemic cardiomyopathy 
I42.0 
ICD10 Cardiomyopathy 
I42.5 
ICD10 Other restrictive cardiomyopathy 
I42.6 
ICD10 Alcoholic cardiomyopathy 
I42.7 
ICD10 Cardiomyopathy due to drug and external agent 
I42.8 
ICD10 Other cardiomyopathies 
I42.9 
ICD10 Cardiomyopathy, unspecified 
I43 
ICD10 Cardiomyopathy in diseases classified elsewhere 
I50 
ICD10 Heart failure 
P29.0 
ICD10 Neonatal cardiac failure 
398.91 
ICD9 Rheumatic heart failure (congestive) 
402.01 
ICD9 Malignant hypertensive heart disease with heart failure 
402.11 
ICD9 Benign hypertensive heart disease with heart failure 
402.91 
ICD9 Unspecified hypertensive disease with heart failure 
404.01 
ICD9 Hypertensive heart and chronic kidney disease with heart failure and stage 1 through 
stage 4 chronic kidney disease, or unspecified chronic kidney disease. 
404.03 
ICD9 Hypertensive heart and chronic kidney disease, malignant, with heart failure and with 
chronic kidney disease stage V or end stage renal disease 

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CODE 
TYPE 
DESCRIPTION 
404.11 
ICD9 Hypertensive heart and chronic kidney disease, benign, with heart failure and with 
chronic kidney disease stage I through stage IV, or unspecified 
404.13 
ICD9 Hypertensive heart and chronic kidney disease, benign, with heart failure and chronic 
kidney disease stage V or end stage renal disease 
404.91 
ICD9 Hypertensive heart and chronic kidney disease, unspecified, with heart failure and 
with chronic kidney disease stage I through stage IV, or unspecified 
404.93 
ICD9 Hypertensive heart and chronic kidney disease, unspecified, with heart failure and 
chronic kidney disease stage V or end stage renal disease 
425.4 
ICD9 Other primary cardiomyopathies 
425.5 
ICD9 Alcoholic cardiomyopathy 
425.6 
ICD9 Cardiomyopathy in Chagas disease 
425.7 
ICD9 Nutritional and metabolic cardiomyopathy 
425.8 
ICD9 Cardiomyopathy in other disease classified elsewhere 
425.9 
ICD9 Secondary cardiomyopathy 
428 
ICD9 unspecified, Heart failure 
I70 
ICD10 Atherosclerosis 
I71 
ICD10 Aortic aneurysm and dissection 
I73.1 
ICD10 Thromboangiitis obliterans [Buerger's disease] 
I73.8 
ICD10 Other specified peripheral vascular diseases 
I73.9 
ICD10 Peripheral vascular disease, unspecified 
I77.1 
ICD10 Stricture of artery 
I79.0 
ICD10 Aneurysm of aorta in diseases classified elsewhere 
I79.1 
ICD10 Aortitis in diseases classified elsewhere 
I79.8 
ICD10 Other disorders of arteries, arterioles, and capillaries in diseases classified elsewhere 
K55.1 
ICD10 Chronic vascular disorders of intestine 
K55.8 
ICD10 Other vascular disorders of intestine 
K55.9 
ICD10 Vascular disorder of intestine, unspecified 
Z95.8 
ICD10 Presence of other cardiac and vascular implants and grafts 
Z95.9 
ICD10 Presence of cardiac and vascular implant and graft, unspecified 
093.0 
ICD9 Aneurysm of aorta, specified as syphilitic 
437.3 
ICD9 Cerebral aneurysm, non-ruptured 
440 
ICD9 Atherosclerosis 
441 
ICD9 Aortic aneurysm and dissection 
443.1 
ICD9 Thromboangiitis obliterans [Buerger's disease] 
443.2 
ICD9 Other arterial dissection 
443.8 
ICD9 Other specified peripheral vascular diseases 
443.9 
ICD9 Peripheral vascular disease, unspecified 
447.1 
ICD9 Stricture of artery 
557.1 
ICD9 Chronic vascular insufficiency of intestine 
557.9 
ICD9 Unspecified vascular insufficiency of intestine 
V43.4* 
ICD9 Blood vessels replaced by other means 

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CODE 
TYPE 
DESCRIPTION 
G45 
ICD10 Transient cerebral ischemic attacks and related syndromes 
G46 
ICD10 Vascular syndromes of brain in cerebrovascular diseases 
H34.0 
ICD10 Transient retinal artery occlusion 
H34.1 
ICD10 Central retinal artery occlusion 
H34.2 
ICD10 Other retinal artery occlusions 
I60 
ICD10 Non-traumatic subarachnoid hemorrhage 
I61 
ICD10 Non-traumatic intracerebral hemorrhage 
I62 
ICD10 Other and unspecified non-traumatic intracranial hemorrhage 
I63 
ICD10 Cerebral infarction 
I64 
ICD10 Stroke, not specified as hemorrhage or infarction 
I65 
ICD10 Occlusion and stenosis of precerebral arteries, not resulting in cerebral infarction 
I66 
ICD10 Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction 
I67 
ICD10 Other cerebrovascular diseases 
I68 
ICD10 Cerebrovascular disorders in diseases classified elsewhere 
362.34 
ICD9 Transient retinal arterial occlusion 
430 
ICD9 Subarachnoid hemorrhage 
431 
ICD9 Intracerebral hemorrhage 
432 
ICD9 Other and unspecified intracranial hemorrhage 
433 
ICD9 Occlusion and stenosis of precerebral arteries 
434 
ICD9 Occlusion of cerebral arteries 
435 
ICD9 Transient cerebral ischemia 
436 
ICD9 Acute, but ill-defined, cerebrovascular disease 
437 
ICD9 Other and ill-defined cerebrovascular disease 
438 
ICD9 Late effects of cerebrovascular disease 
F01 
ICD10 Vascular dementia 
F02 
ICD10 Dementia in other diseases classified elsewhere 
F03 
ICD10 Unspecified dementia 
F04 
ICD10 Amnestic disorder due to known physiological condition 
F05 
ICD10 Delirium due to known physiological condition 
F06.1 
ICD10 Catatonic disorder due to known physiological condition 
F06.8 
ICD10 Other specified mental disorders due to known physiological condition 
G13.2 
ICD10 Systemic atrophy primarily affecting the central nervous system in myxedema 
G13.8 
ICD10 Systemic atrophy primarily affecting central nervous system in other diseases 
classified elsewhere 
G30 
ICD10 Alzheimer's disease 
G31.0 
ICD10 Frontotemporal dementia 
G31.1 
ICD10 Senile degeneration of brain, not elsewhere classified 
G31.2 
ICD10 Degeneration of nervous system due to alcohol 
G91.4 
ICD10 Hydrocephalus in diseases classified elsewhere 
G94 
ICD10 Other disorders of brain in diseases classified elsewhere 
R41.81 
ICD10 Age-related cognitive decline 
R54 
ICD10 Age-related physical debility 

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CODE 
TYPE 
DESCRIPTION 
290.0 
ICD9 Senile dementia, uncomplicated 
290.1 
ICD9 Presenile dementia 
290.2 
ICD9 Senile dementia with delusional or depressive features 
290.3 
ICD9 Senile dementia with delirium 
290.4 
ICD9 Vascular dementia 
294.0 
ICD9 Amnestic disorder in conditions classified elsewhere 
294.1 
ICD9 Dementia in conditions classified elsewhere 
294.2 
ICD9 Dementia, unspecified 
294.8 
ICD9 Other persistent mental disorders due to conditions classified elsewhere 
331.0 
ICD9 Alzheimer's disease 
331.1 
ICD9 Frontotemporal dementia 
331.2 
ICD9 Senile degeneration of brain 
331.7 
ICD9 Cerebral degeneration in diseases classified elsewhere 
797 
ICD9 Senility without mention of psychosis 
J40 
ICD10 Bronchitis, not specified as acute or chronic 
J41 
ICD10 Simple and mucopurulent chronic bronchitis 
J42 
ICD10 Unspecified chronic bronchitis 
J43 
ICD10 Emphysema 
J44 
ICD10 Other chronic obstructive pulmonary disease 
J45 
ICD10 Asthma 
J46 
ICD10 Status asthmaticus 
J47 
ICD10 Bronchiectasis 
J60 
ICD10 Coal worker's pneumoconiosis 
J61 
ICD10 Pneumoconiosis due to asbestos and other mineral fibers 
J62 
ICD10 Pneumoconiosis due to dust containing silica 
J63 
ICD10 Pneumoconiosis due to other inorganic dusts 
J64 
ICD10 Unspecified pneumoconiosis 
J65 
ICD10 Pneumoconiosis associated with tuberculosis 
J66 
ICD10 Airway disease due to specific organic dust 
J67 
ICD10 Hypersensitivity pneumonitis due to organic dust 
J68.4 
ICD10 Chronic respiratory conditions due to chemicals, gases, fumes and vapors 
J70.1 
ICD10 Chronic and other pulmonary manifestations due to radiation 
J70.3 
ICD10 Chronic drug-induced interstitial lung disorders 
490 
ICD9 Bronchitis, not specified as acute or chronic 
491 
ICD9 Chronic bronchitis 
492 
ICD9 Emphysema 
493 
ICD9 Asthma 
494 
ICD9 Bronchiectasis 
495 
ICD9 Extrinsic allergic alveolitis 
496 
ICD9 Chronic airway obstruction, not elsewhere classified 
500 
ICD9 Coal workers' pneumoconiosis 

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CODE 
TYPE 
DESCRIPTION 
501 
ICD9 Asbestosis 
502 
ICD9 Pneumoconiosis due to other silica or silicates 
503 
ICD9 Pneumoconiosis due to other inorganic dust 
504 
ICD9 Pneumonopathy due to inhalation of other dust 
505 
ICD9 Pneumoconiosis, unspecified 
506.4 
ICD9 Chronic respiratory conditions due to fumes and vapors 
508.1 
ICD9 Chronic and other pulmonary manifestations due to radiation 
508.8 
ICD9 Respiratory conditions due to other specified external agents 
M05 
ICD10 Rheumatoid arthritis with rheumatoid factor 
M06 
ICD10 Other rheumatoid arthritis 
M31.5 
ICD10 Giant cell arteritis with polymyalgia rheumatica 
M32 
ICD10 Systemic lupus erythematosus (SLE) 
M33 
ICD10 Dermatopolymyositis 
M34 
ICD10 Systemic sclerosis [scleroderma] 
M35.1 
ICD10 Other overlap syndromes 
M35.3 
ICD10 Polymyalgia rheumatica 
M36.0 
ICD10 Dermato(poly)myositis in neoplastic disease 
446.5 
ICD9 Polyarteritis nodosa and allied conditions 
710.0 
ICD9 Systemic lupus erythematosus 
710.1 
ICD9 Systemic sclerosis 
710.2 
ICD9 Sicca syndrome 
710.3 
ICD9 Dermatomyositis 
710.4 
ICD9 Polymyositis 
714.0 
ICD9 Rheumatoid arthritis 
714.1 
ICD9 Felty's syndrome 
714.2 
ICD9 Other rheumatoid arthritis with visceral or systemic involvement 
714.8 
ICD9 Other specified inflammatory polyarthropathies 
725 
ICD9 Polymyalgia rheumatica 
K25 
ICD10 Gastric ulcer 
K26 
ICD10 Duodenal ulcer 
K27 
ICD10 Peptic ulcer, site unspecified 
K28. 
ICD10 Gastrojejunal ulcer 
531 
ICD9 Gastric ulcer 
532 
ICD9 Duodenal ulcer 
533 
ICD9 Peptic ulcer, site unspecified 
534 
ICD9 Gastrojejunal ulcer 
B18 
ICD10 Chronic viral hepatitis 
K70.0 
ICD10 Alcoholic fatty liver 
K70.1 
ICD10 Alcoholic hepatitis 
K70.2 
ICD10 Alcoholic fibrosis and sclerosis of liver 
K70.3 
ICD10 Alcoholic cirrhosis of liver 

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CODE 
TYPE 
DESCRIPTION 
K70.9 
ICD10 Alcoholic liver disease, unspecified 
K71.3 
ICD10 Toxic liver disease with chronic persistent hepatitis 
K71.4 
ICD10 Toxic liver disease with chronic lobular hepatitis 
K71.5 
ICD10 Toxic liver disease with chronic active hepatitis 
K71.7 
ICD10 Toxic liver disease with fibrosis and cirrhosis of liver 
K73 
ICD10 Chronic hepatitis, not elsewhere classified 
K74 
ICD10 Fibrosis and cirrhosis of liver 
K76.0 
ICD10 Fatty (change of) liver, not elsewhere classified 
K76.2 
ICD10 Central hemorrhagic necrosis of liver 
K76.3 
ICD10 Infarction of liver 
K76.4 
ICD10 Peliosis hepatis 
K76.8 
ICD10 Other specified diseases of liver 
K76.9 
ICD10 Liver disease, unspecified 
Z94.4 
ICD10 Liver transplant status 
070.22 
ICD9 Chronic viral hepatitis B with hepatic coma without hepatitis delta 
070.23 
ICD9 Chronic viral hepatitis B with hepatic coma with hepatitis delta 
070.32 
ICD9 Chronic viral hepatitis B without mention of hepatic coma without mention of 
hepatitis delta 
070.33 
ICD9 Chronic viral hepatitis B without mention of hepatic coma with hepatitis delta 
070.44 
ICD9 Chronic hepatitis C with hepatic coma 
070.54 
ICD9 Chronic hepatitis C without mention of hepatic coma 
070.6 
ICD9 Unspecified viral hepatitis with hepatic coma 
070.9 
ICD9 Unspecified viral hepatitis without mention of hepatic coma 
570 
ICD9 Acute and subacute necrosis of liver 
571 
ICD9 Chronic liver disease and cirrhosis 
573.3 
ICD9 Hepatitis, unspecified 
573.4 
ICD9 Hepatic infarction 
573.8 
ICD9 Other specified disorders of liver 
573.9 
ICD9 Unspecified disorder of liver 
V42.7* 
ICD9 Liver replaced by transplant 
E08 
ICD10 Diabetes mellitus due to underlying condition 
E09 
ICD10 Drug or chemical induced diabetes mellitus 
E10 
ICD10 Type 1 diabetes mellitus 
E11 
ICD10 Type 2 diabetes mellitus 
E13 
ICD10 Other specified diabetes mellitus 
250.8 
ICD9 Diabetes with other specified manifestations 
250.9 
ICD9 Diabetes with unspecified complication 
249.0 
ICD9 Secondary diabetes mellitus without mention of complication 
249.1 
ICD9 Secondary diabetes mellitus with ketoacidosis 
249.2 
ICD9 Secondary diabetes mellitus with hyperosmolarity 
249.3 
ICD9 Secondary diabetes mellitus with other coma 
249.9 
ICD9 Secondary diabetes mellitus with unspecified complication, no stated an uncontrolled, 

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CODE 
TYPE 
DESCRIPTION 
or unspecified 
I12.9 
ICD10 Hypertensive chronic kidney disease with stage 1 through stage 4 chronic kidney 
disease, or unspecified chronic kidney disease  
I13.0 
ICD10 Hypertensive heart and chronic kidney disease with heart failure and stage 1  
through stage 4 chronic kidney disease, or unspecified chronic kidney disease 
I13.10 
ICD10 Hypertensive heart and CKD without heart failure with stage 1 through stage 4 
chronic kidney disease, or unspecified chronic kidney disease  
N03 
ICD10 Chronic nephritic syndrome 
N05 
ICD10 Unspecified nephritic syndrome 
N18.1 
ICD10 Chronic kidney disease, Stage 1 
N18.2 
ICD10 Chronic kidney disease, Stage 2 (mild) 
N18.3 
ICD10 Chronic kidney disease, Stage 3 (moderate) 
N18.4 
ICD10 Chronic kidney disease, Stage 4 (severe) 
N18.9 
ICD10 Chronic kidney disease, unspecified 
Z94.0 
ICD10 Kidney transplant status 
403.00 
ICD9 Hypertensive chronic kidney disease, malignant, with chronic kidney disease  
stage I through stage IV, or unspecified 
403.10 
ICD9 Hypertensive chronic kidney disease, malignant, with chronic kidney disease  
stage I through stage IV, or unspecified 
403.90 
ICD9 Hypertensive chronic kidney disease, unspecified, with chronic kidney disease 
stage I through stage IV, or unspecified 
404.00 
ICD9 Hypertensive heart and chronic kidney disease, malignant, without heart failure and 
with chronic kidney disease stage I through stage IV, or unspecified 
404.01 
ICD9 
Hypertensive heart and chronic kidney disease, malignant, with heart failure and with 
chronic kidney disease stage I 
through stage IV, or unspecified 
404.10 
ICD9 
Hypertensive heart and chronic kidney disease, benign, without heart failure and with 
chronic kidney disease stage I 
through stage IV, or unspecified 
404.11 
ICD9 Hypertensive heart and chronic kidney disease, benign, with heart failure and with 
chronic kidney disease stage I through stage IV, or unspecified 
404.90 
ICD9 Hypertensive heart and chronic kidney disease, unspecified, without heart failure and 
with chronic kidney disease stage I through stage IV, or unspecified 
404.91 
ICD9 Hypertensive heart and chronic kidney disease, unspecified, with heart failure and 
with chronic kidney disease stage I through stage IV, or unspecified 
582 
ICD9 Chronic glomerulonephritis 
583 
ICD9 Nephritis/nephropathy 
585.1 
ICD9 Chronic kidney disease, Stage I 
585.2 
ICD9 Chronic kidney disease, Stage II (mild) 
585.3 
ICD9 Chronic kidney disease, Stage III (moderate) 
585.4 
ICD9 Chronic kidney disease, Stage IV (severe) 
585.9 
ICD9 Chronic kidney disease, unspecified 

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CODE 
TYPE 
DESCRIPTION 
V42.0 
ICD9 Kidney replaced by transplant  
E08 
ICD10 Diabetes mellitus due to underlying condition 
E09 
ICD10 Drug or chemical induced diabetes mellitus 
E10 
ICD10 Type 1 diabetes mellitus 
E11 
ICD10 Type 2 diabetes mellitus 
E13 
ICD10 Other specified diabetes mellitus 
250.4 
ICD9 Diabetes with renal manifestations 
250.5 
ICD9 Diabetes with ophthalmic complications 
250.6 
ICD9 Diabetes with neurological manifestations 
250.7 
ICD9 Diabetes with peripheral circulatory disorders 
G04.1 
ICD10 Tropical spastic paraplegia 
G11.4 
ICD10 Hereditary spastic paraplegia 
G80.0 
ICD10 Spastic quadriplegic cerebral palsy 
G80.1 
ICD10 Spastic diplegia cerebral palsy 
G80.2 
ICD10 Spastic hemiplegic cerebral palsy 
G81 
ICD10 Hemiplegia and hemiparesis 
G82 
ICD10 Paraplegia (paraparesis s) and quadriplegia 
G83 
ICD10 Other paralytic syndromes 
334.1 
ICD9 Hereditary spastic paraplegia 
342 
ICD9 Hemiplegia and hemiparesis 
343 
ICD9 Infantile cerebral palsy 
344 
ICD9 Other paralytic syndromes 
 I85.0 
ICD10  Esophageal varices  
I86.4 
ICD10 Gastric varices 
K70.4 
ICD10 Alcoholic hepatic failure 
K71.1 
ICD10 Toxic liver disease with hepatic necrosis 
K72.1 
ICD10 Chronic hepatic failure 
K72.9 
ICD10 Hepatic failure, unspecified 
K76.5 
ICD10 Hepatic veno-occlusive disease 
K76.6 
ICD10 Portal hypertension 
K76.7 
ICD10 Hepatorenal syndrome 
456.0 
ICD9 Esophageal varices with bleeding 
456.1 
ICD9 Esophageal varices without mention of bleeding 
456.2 
ICD9 Esophageal varices in diseases classified elsewhere 
572.2 
ICD9 Hepatic encephalopathy 
572.3 
ICD9 Portal hypertension 
572.4 
ICD9 Hepatorenal syndrome 
572.8 
ICD9 Other sequelae of chronic liver disease 
I12.0 
ICD10 Hypertensive chronic kidney disease with stage 5 chronic kidney disease or end 
stage renal disease 

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CODE 
TYPE 
DESCRIPTION 
I13.11 
ICD10 Hypertensive heart and CKD without heart failure with stage 5 chronic kidney 
disease, or end stage renal disease 
I13.2 
ICD10 Hypertensive heart and chronic kidney disease with heart failure and with stage 5 
chronic kidney disease, or end stage renal disease 
N18.5 
ICD10 Chronic kidney disease, Stage 5 
N18.6 
ICD10 End stage renal disease 
N19 
ICD10 Unspecified kidney failure 
N25.0 
ICD10 Renal osteodystrophy 
Z49 
ICD10 Encounter for care involving renal dialysis 
Z99.2 
ICD10 Dependence on renal dialysis 
403.01 
ICD9 Hypertensive chronic kidney disease, malignant, with chronic kidney disease 
stage V or end stage renal disease 
403.11 
ICD9 Hypertensive chronic kidney disease, benign, with chronic kidney disease 
stage V or end stage renal disease 
403.91 
ICD9 Hypertensive chronic kidney disease, unspecified, with chronic kidney disease 
stage V or end stage renal disease 
404.02 
ICD9 Hypertensive heart and chronic kidney disease, malignant, without heart failure and 
with chronic kidney disease stage V or end stage renal disease 
404.03 
ICD9 Hypertensive heart and chronic kidney disease, malignant, with heart failure and with 
chronic kidney disease stage V or end stage renal disease 
404.12 
ICD9 Hypertensive heart and chronic kidney disease, benign, without heart failure and with 
chronic kidney disease stage V or end stage renal disease 
404.13 
ICD9 Hypertensive heart and chronic kidney disease, benign, with heart failure and chronic 
kidney disease stage V or end stage renal disease 
404.92 
ICD9 Hypertensive heart and chronic kidney disease, unspecified, without heart failure and 
with chronic kidney disease stage V or end stage renal disease 
404.93 
ICD9 Hypertensive heart and chronic kidney disease, unspecified, with heart failure and 
chronic kidney disease stage V or end stage renal disease 
585.5 
ICD9 Chronic kidney disease, Stage V 
585.6 
ICD9 End stage renal disease 
586 
ICD9 Renal failure NOS 
588.0 
ICD9 Renal osteodystrophy 
V45.11 
ICD9 Renal dialysis status 
V45.12 
ICD9 Noncompliance with renal dialysis 
V56.0 
ICD9 Encounter for extracorporeal dialysis 
V56.1 
ICD9 Fitting and adjustment of extracorporeal dialysis catheter 
V56.2 
ICD9 Fitting and adjustment of peritoneal dialysis catheter 
V56.31 
ICD9 Encounter for adequacy testing for hemodialysis 
V56.32 
ICD9 Encounter for adequacy testing for peritoneal dialysis 
V56.8 
ICD9 Encounter for other dialysis 

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BIOPSY AND IMAGING PROCEDURE CODES FOR CIRRHOSIS 
CODE 
TYPE 
DESCRIPTION 
47000 
HCPCS/CPT-4 
Biopsy of liver, needle 
47001 
HCPCS/CPT-4 
Biopsy of liver, needle 
47100 
HCPCS/CPT-4 
Excision procedures on the liver 
0FB00ZX 
ICD10 pcs 
Excision of Liver, Open Approach, Diagnostic 
0FB03ZX 
ICD10 pcs 
Excision of Liver, Percutaneous Approach, Diagnostic 
0FB04ZX 
ICD10 pcs 
Excision of Liver, Percutaneous Endoscopic Approach, Diagnostic 
0FB10ZX 
ICD10 pcs 
Excision of Right Lobe Liver, Open Approach, Diagnostic 
0FB13ZX 
ICD10 pcs 
Excision of Right Lobe Liver, Percutaneous Approach, Diagnostic 
0FB14ZX 
ICD10 pcs 
Excision of Right Lobe Liver, Percutaneous Endoscopic Approach, 
Diagnostic 
0FB20ZX 
ICD10 pcs 
Excision of Left Lobe Liver, Open Approach, Diagnostic 
0FB23ZX 
ICD10 pcs 
Excision of Left Lobe Liver, Percutaneous Approach, Diagnostic 
0FB24ZX 
ICD10 pcs 
Excision of Left Lobe Liver, Percutaneous Endoscopic Approach, 
Diagnostic 
5012 
ICD9 pcs 
Open liver biopsy 
5011 
ICD9 pcs 
Closed liver biopsy (Closed (percutaneous) [needle] biopsy of liver) 
5014 
ICD9 pcs 
Laparoscopic liver bx (Laparoscopic liver biopsy) 
91200 
HCPCS/CPT-4 
Nonimaging liver elastography 
76700 
HCPCS/CPT-4 
Complete ultrasound examination of the abdomen 
76705 
HCPCS/CPT-4 
Ultrasound, abdominal, real time with image documentation 
BF45ZZZ 
ICD10 pcs 
Ultrasonography of Liver 
BF46ZZZ 
ICD10 pcs 
Ultrasonography of Liver and Spleen 
8874 
ICD9 pcs 
Dx ultrasound-digestive (Diagnostic ultrasound of digestive system) 
74181 
HCPCS/CPT-4 
MRI scan of abdomen 
74182 
HCPCS/CPT-4 
MRI scan of abdomen with contrast 
74183 
HCPCS/CPT-4 
MRI scan of abdomen before and after contrast 
74185 
HCPCS/CPT-4 
MRI scan of blood vessels of abdomen 
BF35Y0Z 
ICD10 pcs 
Magnetic Resonance Imaging (MRI) of Liver using Other Contrast, 
Unenhanced and Enhanced 
BF35YZZ 
ICD10 pcs 
Magnetic Resonance Imaging (MRI) of Liver using Other Contrast 
BF35ZZZ 
ICD10 pcs 
Magnetic Resonance Imaging (MRI) of Liver 
74150 
HCPCS/CPT-4 
CT imaging of the abdomen and pelvis 
74160 
HCPCS/CPT-4 
CT imaging of the abdomen 
74170 
HCPCS/CPT-4 
CT imaging of the abdomen with and without IV contrast 
BF2500Z 
ICD10 pcs 
Computerized Tomography of Liver using High Osmolar Contrast, 
Unenhanced and Enhanced 
BF250ZZ 
ICD10 pcs 
Computerized Tomography of Liver using High Osmolar Contrast 
BF2510Z 
ICD10 pcs 
Computerized Tomography of Liver using Low Osmolar Contrast, 
Unenhanced and Enhanced 
BF251ZZ 
ICD10 pcs 
Computerized Tomography of Liver using Low Osmolar Contrast 
BF25Y0Z 
ICD10 pcs 
Computerized Tomography of Liver using Other Contrast, 
Unenhanced and Enhanced 

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CODE 
TYPE 
DESCRIPTION 
BF25YZZ 
ICD10 pcs 
Computerized Tomography of Liver using Other Contrast 
BF25ZZZ 
ICD10 pcs 
Computerized Tomography of Liver 
BF2600Z 
ICD10 pcs 
Computerized Tomography of Liver and Spleen using High Osmolar 
Contrast, Unenhanced and Enhanced 
BF260ZZ 
ICD10 pcs 
Computerized Tomography of Liver and Spleen using High Osmolar 
Contrast 
BF2610Z 
ICD10 pcs 
Computerized Tomography of Liver and Spleen using Low Osmolar 
Contrast, Unenhanced and Enhanced 
BF261ZZ 
ICD10 pcs 
Computerized Tomography of Liver and Spleen using Low Osmolar 
Contrast 
BF26Y0Z 
ICD10 pcs 
Computerized Tomography of Liver and Spleen using Other 
Contrast, Unenhanced and Enhanced 
BF26YZZ 
ICD10 pcs 
Computerized Tomography of Liver and Spleen using Other 
Contrast 
BF26ZZZ 
ICD10 pcs 
Computerized Tomography of Liver and Spleen 
BF2C00Z 
ICD10 pcs 
Computerized Tomography of Hepatobiliary System, All using High 
Osmolar Contrast, Unenhanced and Enhanced 
BF2C0ZZ 
ICD10 pcs 
Computerized Tomography of Hepatobiliary System, All using High 
Osmolar Contrast 
BF2C10Z 
ICD10 pcs 
Computerized Tomography of Hepatobiliary System, All using Low 
Osmolar Contrast, Unenhanced and Enhanced 
BF2C1ZZ 
ICD10 pcs 
Computerized Tomography of Hepatobiliary System, All using Low 
Osmolar Contrast 
BF2CY0Z 
ICD10 pcs 
Computerized Tomography of Hepatobiliary System, All using 
Other Contrast, Unenhanced and Enhanced 
BF2CYZZ 
ICD10 pcs 
Computerized Tomography of Hepatobiliary System, All using 
Other Contrast 
BF2CZZZ 
ICD10 pcs 
Computerized Tomography of Hepatobiliary System, All 
BW2000Z 
ICD10 pcs 
Computerized Tomography of Abdomen using High Osmolar 
Contrast, Unenhanced and Enhanced 
BW200ZZ 
ICD10 pcs 
Computerized Tomography of Abdomen using High Osmolar 
Contrast 
BW2010Z 
ICD10 pcs 
Computerized Tomography of Abdomen using Low Osmolar 
Contrast, Unenhanced and Enhanced 
BW201ZZ 
ICD10 pcs 
Computerized Tomography of Abdomen using Low Osmolar 
Contrast 
BW20Y0Z 
ICD10 pcs 
Computerized Tomography of Abdomen using Other Contrast, 
Unenhanced and Enhanced 
BW20YZZ 
ICD10 pcs 
Computerized Tomography of Abdomen using Other Contrast 
BW20ZZZ 
ICD10 pcs 
Computerized Tomography of Abdomen 

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APPENDIX B. TABLE SHELLS 
Table 1A: 
Eligibility Criteria June 2015 to December 2021 (Komodo Health Only) 
Eligibility Criteria 
All Patients 
N = XX 
n (%) 
All patients with PBC code 
PBC diagnosis 
1 inpatient claim 
2 outpatient claims 
1 inpatient and/or 2 outpatient claims 
PBC Dx + Laboratory data 
ALP 
Bilirubin 
AST 
ALT 
ALP and Bilirubin and AST and ALT 
PBC Dx + Labs + Prescription record for UDCA 
PBC Dx + Labs + UDCA failure 
UDCA intolerant 
Inadequate UDCA response 
PBC Dx + Labs + UDCA failure + 12 months data before UDCA failure 
PBC Dx + Labs + UDCA failure + 12 months pre-index data + 12 months closed claims 
PBC Dx + Labs + UDCA failure + 12 months pre-index data + 12 months closed claims + OCA 

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Table 1B: 
Eligibility Criteria June 2015 to December 2021 (Global PBC Registry Only) 
Eligibility Criteria 
All Patients 
 N = XX 
n (%) 
All patients with PBC diagnosis 
PBC Dx + Laboratory data 
ALP 
Bilirubin 
AST 
ALT 
ALP and Bilirubin and AST and ALT 
PBC Dx + Labs + Prescription record for UDCA 
PBC Dx + Labs + UDCA failure 
UDCA intolerant 
Inadequate UDCA response 
PBC Dx + Labs + UDCA failure + 12 months data before UDCA failure 
PBC Dx + Labs + UDCA failure + 12 months pre-index data + OCA 
Table 2: 
Sex of All Eligible Patients by Year 
All Eligible Patients 
Sex 
2016 
N=X 
2017 
N=X 
2018 
N=X 
2019 
N=X 
2020 
N=X 
2021 
N=X 
Overall 
N=X 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Female 
Male 
Missing 
Table 3: 
Age of All Eligible Patients by Year 
All Eligible Patients 
Age 
2016 
N=X 
2017 
N=X 
2018 
N=X 
2019 
N=X 
2020 
N=X 
2021 
N=X 
Overall 
N=X 
Valid, n (%) 
Missing, n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 

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Table 4: 
Race of All Eligible Patients by Year* 
All Eligible Patients 
Race 
2016 
N=X 
2017 
N=X 
2018 
N=X 
2019 
N=X 
2020 
N=X 
2021 
N=X 
Overall 
N=X 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
White 
Black or African American 
Asian, Native Hawaiian or 
other Pacific Islander 
American Indian or Alaskan 
Native 
Other 
Missing 
*
Note that race is not systematically reported in either database, and thus is only available on a subset of patients.
Table 5A: 
Region by Year (Komodo Health Only) 
Region 
All Eligible Patients 
2016 
N=X 
2017 
N=X 
2018 
N=X 
2019 
N=X 
2020 
N=X 
2021 
N=X 
Overall 
N=X 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Northeast 
Midwest 
West 
South 
Missing, n (%) 

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Table 5B: 
Patients by Country and by Year (Global PBC Registry Only) 
All Eligible Patients 
Country 
2016 
N=X 
2017 
N=X 
2018 
N=X 
2019 
N=X 
2020 
N=X 
2021 
N=X 
Overall 
N=X 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
The Netherlands 
UK 
Belgium 
Germany 
France 
Italy 
Spain 
Greece 
Canada 
USA 
Argentina 
Israel 
Japan 
China 

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Table 6: 
Index Hepatic Laboratory Values by Year (TB, ALP, ALT, AST) 
Laboratory Value 
Statistic 
All Eligible Patients 
2016 
N pts=X 
2017 
N pts=X 
2018 
N pts=X 
2019 
N pts=X 
2020 
N pts=X 
2021 
N pts=X 
Overall 
N pts=X 
N index =X 
N index =X 
N index =X 
N index =X 
N index =X 
N index =X 
N index =X 
TB 
Valid, n (%) 
Missing, n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
ALP 
Valid, n (%) 
Missing, n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
ALT 
Valid, n (%) 
Missing, n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
AST 
Valid, n (%) 
Missing, n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 

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Table 7: 
Index Platelet Counts by Year 
All Eligible Patients 
Platelet counts 
2016 
N pts=X 
2017 
N pts=X 
2018 
N pts=X 
2019 
N pts=X 
2020 
N pts=X 
2021 
N pts=X 
Overall 
N pts=X 
N index =X 
N index =X 
N index =X 
N index =X 
N index =X 
N index =X 
N index =X 
Valid, n (%) 
Missing, n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
Table 8: 
On UDCA Treatment by Year 
On UDCA treatment 
All Eligible Patients 
N=X 
n (%) 
2016 
2017 
2019 
2020 
2021 
Table 9: 
UDCA Failure by Year 
UDCA failure 
All Eligible Patients 
N=X 
n (%) 
2016 
2017 
2019 
2020 
2021 

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Table 10: 
Time (Months) Since First UDCA Failure Until the Index Date (inclusive) by 
Year 
All Eligible Patients 
Months since UDCA 
failure until index date 
2016 
N=X 
2017 
N=X 
2018 
N=X 
2019 
N=X 
2020 
N=X 
2021 
N=X 
Overall 
N=X 
Valid, n (%) 
Missing, n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
Table 11: Clinical Evidence of Portal Hypertension (Platelets <150k; Non-Bleeding 
Varices; Platelets and/or Non-Bleeding Varices) by Year 
Clinical evidence of portal hypertension by year 
All Eligible Patients 
N=X 
n (%) 
2016 
2017 
2019 
2020 
2021 
Table 12: 
Cirrhosis by Year 
Cirrhosis by year 
All Eligible Patients 
N=X 
n (%) 
2016 
2017 
2019 
2020 
2021 

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Table 13: 
Charlson Comorbidity Index Score by Year 
All Eligible Patients 
Charlson Comorbidity 
Index Score by year 
2016 
N=X 
2017 
N=X 
2018 
N=X 
2019 
N=X 
2020 
N=X 
2021 
N=X 
Overall 
N=X 
Valid, n (%) 
Missing, n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
Table 14: 
Insurance Type at Index Date by Year (Komodo Health Only) 
All Eligible Patients 
Health Insurance Type on 
the index date 
2016 
N=X 
2017 
N=X 
2018 
N=X 
2019 
N=X 
2020 
N=X 
2021 
N=X 
Overall 
N=X 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Commercial 
Self-insured/Exchanges 
Medicare 
Medicaid 
Dual eligible 
Other 
Missing 

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Table 15: 
Number of Index Dates by Year 
Year 
Patients 
Statistic 
2016 
N=X 
2017 
N=X 
2018 
N=X 
2019 
N=X 
2020 
N=X 
2021 
N=X 
Overall 
N=X 
All Eligible Patients 
Patients with index date 
# index dates/patient with 
index date 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
Non-OCA 
Patients with index date 
# index dates/patient with 
index date 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
OCA 
Patients with index date 
# index dates/patient with 
index date 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
Table 16: 
Sex of Patients by Group before and After Weighting 
Sex 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
n (%) 
n (%) 
n (%) 
n (%) 
Female 
Male 

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Table 17: 
Age of Patients by Group Before and After Weighting 
Age 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
Table 18A: 
Region by Group Before and After Weighting (Komodo Health Only) 
Region 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
n (%) 
n (%) 
n (%) 
n (%) 
Northeast 
Midwest 
West 
South 
Missing 
Table 18B: 
Country by Group Before and After Weighting (Global PBC Registry Only) 
Countries in 
Global PBC 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
n (%) 
n (%) 
n (%) 
n (%) 

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Table 19: 
Hepatic Laboratory Values by Group (TB, ALP, ALT, AST) Before and 
After Weighting 
Hepatic 
Laboratory Value 
Statistic 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
TB 
n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
ALP 
n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
ALT 
n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
AST 
n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 

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Table 20: 
Platelet Counts by Group Before and After Weighting 
Platelet counts 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
n (%) 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
Table 21: 
Patients on UDCA Treatment by Group Before and After Weighting 
UDCA Treatment 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
n (%) 
n (%) 
n (%) 
n (%) 
Yes 
No 
Table 22: 
Duration (Months) of Receiving UDCA by Group Before and After 
Weighting 
Duration (in 
months) of UDCA 
treatment 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 

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Table 23: 
Time (Months) from UDCA Failure Until the Index Date by Group Before 
and After Weighting 
Time (in months) 
from UDCA failure 
until the index date 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
Table 24: 
Clinical Evidence of Portal Hypertension (Platelets <150k; Non-Bleeding 
Varices; Platelets and/or Non-Bleeding Varices) by Group Before and After 
Weighting 
Clinical evidence 
of portal 
hypertension 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
n (%) 
n (%) 
n (%) 
n (%) 
Yes 
No 
Table 25: 
Cirrhosis by Group Before and After Weighting 
Cirrhosis 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
n (%) 
n (%) 
n (%) 
n (%) 
Yes 
No 

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Table 26: 
Charlson Comorbidity Index Score by Group Before and After Weighting 
Charlson 
Comorbidity Index 
Score 
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 
Table 27: 
Insurance Type at Index Date by Group Before and After Weighting 
(Komodo Health Only) 
Insurance type at 
index date   
Before Weighting 
After Weighting 
Non-OCA-treated 
OCA-treated 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N patients = 
N patients = 
N index dates = 
N index dates = 
N index dates = 
N index dates = 
n (%) 
n (%) 
n (%) 
n (%) 
Commercial 
Medicare 
Medicaid 
Dual eligible 
Other 
Missing 

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Table 28: 
Logistic regression for Non-OCA vs OCA-treated 
Parameter 
N 
Estimate 
SE 
Non-OCA 
OCA 
Gender 
Age 
Region/Country 
Time (in months) since PBC diagnosis 
Calendar year of PBC diagnosis 
Labs 
ALP 
Total bilirubin 
ALT 
AST 
UDCA duration 
Clinical evidence of portal HTN 
Cirrhosis 
Charlson Comorbidity Index Score 
Insurance type 
Table 29: 
Distribution of Propensity Weights 
Propensity weights 
Non-OCA-treated 
OCA-treated 
N patients = 
N patients = 
N index dates = 
N index dates = 
Mean (SD) 
Skewness 
Median 
(Q1, Q3) 
Range 

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Table 30: 
Standardized Differences of the Mean Before and After Weighting 
Parameter 
Standardized Mean Difference 
Unweighted 
Weighted 
Gender 
Age 
Region/Country 
Time (in months) since PBC diagnosis 
Calendar year of PBC diagnosis 
ALP 
Total bilirubin 
ALT 
AST 
UDCA duration 
Clinical evidence of portal HTN 
Cirrhosis 
Charlson Comorbidity Index Score 
Insurance type 
Table 31: 
Results Unadjusted, Adjusted and Weighted Cox Regression on Time to 
Composite Event 
Parameter 
n 
HR 
95% CI 
p-value
Unique cases 
Unique persons 
Cases 
Person trials 
Unadjusted 
Adjusted for baseline covariates 
Weighted 
Figure 1: 
Adherence to OCA Treatment over Time 

Protocol 747-404/405 
Fi2ure 2A: 
Eli2ible Patients by Number of Trials 
60,000 ----------------
:? 50,000 
C: 
GI ·; 40,000 
Q. 
GI 
::0 30,000 
:~ 
w 
20,000 
10,000 
0 
Figure 2B: 
60,000 
., 
..., 
C: 
50,000 
.!! 
1ii 
Q. 
°E 
40,000 
..., 
C: 
0 u 
30,000 
GI 
:;; :~ 20,000 
;;.;; 
10,000 
0 
Figure 2C: 
.fl 
C: 
2000 
GI 
.:; 
ftl 
1500 
Q. 
-0 
GI ... 
ftl 
1000 
!! 
500 
0 
GI :a 
:iii> 
0 
jjj 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Number ofTrials 
Eligible Control Patients by Number of Trials 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Number ofTrials 
Eligible OCA-treated Patients by Number of Trials 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Number ofTrials 
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Pa0 e 86 

Protocol 747-404/405 
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Figure 3A: 
4 
C 0 
3 
·.:; 
u 
C :, ... 2 
·;;; 
C 
1 
ti 
0 
0 
-0.2 
Figure 3B: 
4 
C 
0 
3 
·.:; 
u 
C :, ... 2 
·;;; 
C 
1 
QI 
0 
0 
-0.2 
Figure 4: 
1.0 
t 0.8 
:i:i 
IV 
.fJ 
0 .... 0.6 
Q. 
ii 0.4 
:> 
:, 0.2 
VI 
0 
1 
Distribution of Propensity Scores: Unweighted 
-
DCA-treated 
-
NonOCA-treated 
0 
0.2 
0.4 
0.6 
0.8 
1.0 
Propensity Score (unweighted) 
Distribution of Propensity Scores: Weighted 
-
OCA-treated 
-
Non OCA-treated 
0 
0.2 
0.4 
0.6 
0.8 
1.0 
Propensity Score (weighted) 
Kaplan-Meier Survival Curve: Composite Event-free Survival by Treatment 
Arm 
-
OCA-treateC 
-
Non OCA-treated 
2 
3 
4 
5 
Time (in Years) 
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