Assessment of the Dose Reduction and Discontinuation Associated With Anti-Fibrotic Medications in Patients With Idiopathic Pulmonary Fibrosis
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-23 (1.0) / Saved on: 25 Nov 2019
TITLE PAGE
Non-Interventional Study (NIS) Protocol
TITLE PAGE
Document Number:
c41847952-01
BI Study Number:
1199-0526
BI Investigational
Product(s):
Nintedanib
Title:
Assessment of the Dose Reduction and Discontinuation associated 
with Anti-Fibrotic Medications in Patients with Idiopathic Pulmonary 
Fibrosis
Brief lay title:
Dose Reduction and Discontinuation with Anti-Fibrotic Medications
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
Not applicable
PASS:
Pending
EU PAS register 
number:
Pending
Active substance:
NA
Medicinal product:
Nintedanib (Ofev) and Pirfenidone (Esbriet)
Product reference:
NA
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
NA
Joint PASS:
Not applicable
Research question and 
objectives:
1.
Primary aim - To assess average daily dose, and dose 
reduction/interruption patterns in nintedanib and pirfenidone
initiators separately at 6- and 12- months post-initiation. 
2.
Secondary aim - To assess drug discontinuation patterns in 
nintedanib and pirfenidone initiators separately at 6- and 12-
months post-initiation.

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Country(-ies) of study:
United States
Authors:
Marketing authorisation 
holder(s):
Not applicable
Date:
24 MAR 2023
Page 1 of 36
Proprietary confidential information
© 2023 Boehringer Ingelheim Group of companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES..................................................................... 10
6.
MILESTONES..................................................................................................... 11
7.
RATIONALE AND BACKGROUND................................................................ 12
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 14
9.
RESEARCH METHODS .................................................................................... 15
9.1
STUDY DESIGN............................................................................................ 15
9.2
SETTING........................................................................................................ 16
9.2.1
Study sites ............................................................................................... 16
9.2.2
Study population ..................................................................................... 17
9.2.3
Study visits .............................................................................................. 17
9.2.4
Study discontinuation.............................................................................. 17
9.3
VARIABLES .................................................................................................. 17
9.3.1
Exposures ................................................................................................ 17
9.3.2
Outcomes................................................................................................. 18
9.3.2.1
Primary outcome .............................................................................. 18
9.3.2.2
Secondary outcomes......................................................................... 19
9.3.3
Covariates................................................................................................ 19
9.4
DATA SOURCES........................................................................................... 23
9.5
STUDY SIZE.................................................................................................. 23
9.6
DATA MANAGEMENT................................................................................ 24
9.7
DATA ANALYSIS......................................................................................... 24
9.7.1
Main analysis........................................................................................... 24
9.7.2
Post-hoc analysis..................................................................................... 24
9.8
QUALITY CONTROL................................................................................... 25
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 25
9.10
OTHER ASPECTS ......................................................................................... 26

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9.10.1
Data quality assurance............................................................................. 26
9.10.2
Study records........................................................................................... 26
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 27
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 27
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 27
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 28
11.1
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 28
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 29
13.
REFERENCES .................................................................................................... 30
13.1
PUBLISHED REFERENCES......................................................................... 30
ANNEXES.................................................................................................................... 32
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS............................................ 32
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ............................ 33
ANNEX 3. ADDITIONAL INFORMATION............................................................ 34
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES................................. 35

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special interest
CA
Competent Authority
CCDS
Company Core Data Sheet
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
eCRF
Electronic Case Report Form
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GVP
Good Pharmacovigilance Practices
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
MAH
Marketing Authorization Holder
MedDRA
Medical Dictionary for Regulatory Activities
NIS
Non-Interventional Study
PASS
Post-Authorization Safety Study
SAE
Serious Adverse Event
USD
United States Dollar

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3.
RESPONSIBLE PARTIES
BI NIS 
 
BI NIS co-

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Nintedanib (Ofev) and 
Pirfenidone (Esbriet)
Name of active ingredient:
Nintedanib (Ofev) and 
Pirfenidone (Esbriet)
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
24 MAR 2023
1199-0526
Title of study:
Assessment of the Dose Reduction/Interruption and Discontinuation 
with Nintedanib and Pirfenidone Initiators in Patients with Idiopathic 
Pulmonary Fibrosis
Rationale and 
background:
Antifibrotics have demonstrated an ability to slow IPF progression, if 
taken according to the recommended dosing and taken continuously, 
in both clinical trials and real-world evidence. Previous real-world 
studies have compared persistence/discontinuation patterns for
nintedanib and pirfenidone and found similar persistence patterns for 
both drugs. However, these studies have failed to consider the 
differential dosing regimens between these two drugs and 
corresponding incidence of dose reduction/interruption. This study 
will assess both dose reduction/interruption and discontinuation 
patterns for nintedanib and pirfenidone among patients with IPF.
Research 
question and 
objectives:
1. Primary aim - To assess average daily dose, and corresponding 
dose reduction/interruption patterns in nintedanib and 
pirfenidone initiators separately at 6- and 12-months post-
initiation. 
2. Secondary aim - To assess drug discontinuation patterns in 
nintedanib and pirfenidone initiators separately at 6- and 12-
months post-initiation.
Study design:
This is a non-interventional, retrospective cohort study with existing 
data.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Nintedanib (Ofev) and 
Pirfenidone (Esbriet)
Name of active ingredient:
Nintedanib (Ofev) and 
Pirfenidone (Esbriet)
Protocol date:
Study 
number:
Version/Revision:
Version/Revision date:
24 MAR 2023
1199-0526
Population:
The study sample will consist of patients with IPF who initiated either 
nintedanib or pirfenidone between October 2014 to September 2021. 
The study will use data from the Optum Research Database (ORD), a 
claims database containing approximately 14 million commercial 
enrollees and 4 million Medicare-advantage enrollees
Variables:
The main outcome of our study will be incidence of dose 
reduction/interruption, calculated separately for nintedanib and 
pirfenidone. For each patient, average daily dose will be calculated in 
pre-specified time-periods (for example – the first 6 months, the first 
12 months, and the average daily dose calculated separately in each 
month since drug initiation). Incidence of dose reduction/interruption 
will be defined as average daily dose not following the prescribing 
information. 
As a secondary outcome, we will also assess drug discontinuation 
during first 6 and 12 months separately for pirfenidone and 
nintedanib and will be defined as a gap of at least 60 days in filling of 
prescription (a gap of 60 days after the prescription date + days of 
supply for the current prescription).
Data sources:
We will use administrative health insurance claims data from the 
Optum Research Database (ORD) for the period of October 1, 2013 
through end of data availability (currently September 30, 2022). This 
database was chosen as it includes claims of Medicare Advantage and 
commercially enrolled beneficiaries.
Study size:
As this is a descriptive study, no formal calculation of sample size 
was performed. In a preliminary feasibility analysis using Optum data 
to examine sample size, we have found that 1,979 patients newly 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Nintedanib (Ofev) and 
Pirfenidone (Esbriet)
Name of active ingredient:
Nintedanib (Ofev) and 
Pirfenidone (Esbriet)
Protocol date:
Study 
number:
Version/Revision:
Version/Revision date:
24 MAR 2023
1199-0526
initiated pirfenidone, and 2,559 patients who initiated nintedanib 
between 10/2014 to 12/2020. As such, this study is expected to have a 
sufficient sample.
Data analysis:
Average daily dose during first 6 months and 12 months after drug 
initiation will be reported as means with standard deviations (SD), 
and median with interquartile range. Six months and 12-months daily 
dose categories will be presented as frequencies with percentages. 
Incidence of dose reduction/interruption will be reported by month of 
occurrence (using month 2 and onwards) and reported as frequencies 
with percentages. Drug discontinuation will be reported as 
frequencies with percentages, and time to drug discontinuation will 
be reported in months (mean (SD)). As this is a descriptive study, 
there will be no multivariable adjustment and/or direct comparison of 
outcomes between the pirfenidone and nintedanib cohort.
Milestones:
The analytic database is expected to be constructed by April 20, 2023, 
and data analyses are expected to be completed by May 15, 2023.  A 
draft report of the findings from this study is expected to be available 
for review by June 15, 2023 and completed by August 30, 2023.

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5.
AMENDMENTS AND UPDATES
None.

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6.
MILESTONES
Milestone
Planned Date
First draft of summary
09/26/2022
AET summary review
10/17/2022
NPCC summary review
12/02/2022
Study protocol first draft
01/31/2023
NIS disclosure review
02/28/2023
Analytical database creation
04/20/2023
Descriptive results
05/15/2023
Final report first draft
06/15/2023

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7.
RATIONALE AND BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a life-threatening rare disease characterized by decline 
in lung function due to progression of fibrosis in the interstitium of the lung [1]. In patients 
with IPF, a decline in forced vital capacity (FVC) is an important indicator of mortality [6]. 
The median survival of non-treated IPF patients is approximately 3 years from diagnosis [2].
Before anti-fibrotic medications became available in the US, IPF treatment mainly consisted 
of therapeutics that were found not to be of benefit (or even harmful), and a mainstay of care 
focused on symptom relief and included palliative care [3]. In October 2014, two anti-fibrotic 
medications, nintedanib and pirfenidone, were approved by the U.S. Food and Drug 
Administration (FDA) for the treatment of IPF [4, 5], which transformed the treatment of this 
disease. Both medications were found to reduce the rate of decline in FVC compared to 
placebo in phase III clinical trials [7, 8].
From the perspective of treatment, the approvals of antifibrotics for IPF were significant 
breakthroughs. Antifibrotics have demonstrated an ability to slow IPF progression, if taken 
according to the recommended dosing in the prescriber information and taken continuously, 
in both clinical trials [7, 8] and real-world evidence [9]. Previous real-world studies have 
compared persistence/ discontinuation patterns for pirfenidone and nintedanib and found 
similar persistence patterns for both drugs [10, 11]. However, these studies have failed to 
consider the differential dosing regimens between these two drugs and corresponding 
incidence of dose reduction and/or temporary dose interruption. Hence, this study will assess 
both dose reduction and/or temporary dose interruption and discontinuation patterns for 
pirfenidone and nintedanib among patients with IPF. 
In this study, we will investigate the incidence of dose reduction/interruption beyond the label 
recommendations (defined as a dose not following the prescriber information (PI), which 
corresponds to a daily dose of 2165 mg (90% of full dose, which is 2403 mg) for pirfenidone 
[12, 13] or less than a daily dose of 200 mg for nintedanib (66.67% of full dose, which is 300 
mg) [14]) from 10/01/2014 to 09/30/2022 using real-world data. The definition of incidence 
of dose reduction, which is differential for nintedanib and pirfenidone is because of –
1)
In the US, the prescriber information (PI) and/or label for pirfenidone does not 
indicate any particular dose reduction recommended as per Food & Drug Administration 
(FDA). For nintedanib, reducing dose from 150 mg to 100 mg BID is part of the PI.
2)
The post-hoc analysis of clinical trials showed similar slope of FVC decline for 
patients who reduced the dose to 100 mg BID for nintedanib, but for pirfenidone, the slope of 
FVC decline was steeper for patients who reduced the dose, potentially indicating that 
reduced dose might lead to lower benefit on FVC decline (see figures below) [12, 15]

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The current study may be able to demonstrate to decision makers the differential complexities 
in dosing regimen for pirfenidone vs. nintedanib and may reveal that IPF patients may not be 
receiving the full benefit of pirfenidone due to possible sub-optimal dosing, even when the 
patient has not discontinued the drug.  

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8.
RESEARCH QUESTION AND OBJECTIVES
The overarching aim of our study is to assess the incidence of dose reduction and 
discontinuations separately for pirfenidone and nintedanib. Specific objectives are:
Primary aim - To assess average daily dose, and corresponding dose 
reduction/interruption patterns in pirfenidone initiators and nintedanib initiators separately at 
6- and 12- months post-initiation. 
Secondary aim - To assess drug discontinuation patterns in pirfenidone initiators 
and nintedanib initiators separately at 6- and 12-months post-initiation.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This study will be a retrospective cohort, descriptive study of patients with idiopathic 
pulmonary fibrosis (IPF). Patients with IPF who initiated either pirfenidone or nintedanib 
between October 2014 to September 2021 will be identified. The study will use data from the 
Optum Research Database (ORD), a claims database containing approximately 14 million 
commercial enrollees and 4 million Medicare-advantage enrollees. The date of the first 
prescription of either pirfenidone or nintedanib will be assigned as index date. Two separate 
cohorts will be created - 1) pirfenidone initiators, and 2) nintedanib initiators, and all 
outcomes will be assessed in the 12 months post-index period. A 12-month time-period prior 
to the index date will be used as the baseline period for determining the characteristics of 
patients in both cohorts. To allow for a 12-months baseline and follow-up periods for all 
patients, the span of data will be from 10/01/2013 to 09/30/2022.  (Figure 1)
Figure 1
Study Design Schematic
The main outcome of our study will be incidence of dose reduction/interruption, calculated 
separately for pirfenidone and nintedanib. For each patient, average daily dose will be 
calculated in pre-specified time-periods (for example – the first 6 months, the first 12 months, 
and the average daily dose calculated separately in each month since drug initiation) (more 
details in section 2.6). Incidence of dose reduction/interruption will be defined as average 
daily dose not following the prescribing information (PI). According to the PI, the daily dose 
of pirfenidone is 2403 mg [13], hence the study will consider average daily dose less than 
2165 mg (90% of PI dose) as dose reduction for pirfenidone [12]. For nintedanib, the daily 
dose allowed under prescriber information is 200 mg [14], hence less than 200 mg will be 
considered a dose reduction for nintedanib patients. As a secondary outcome, we will also 
assess drug discontinuation during first 6 and 12 months separately for pirfenidone and 
nintedanib and will be defined as a gap of at least 60 days in filling of prescription (a gap of 
60 days after the prescription date + days of supply for the current prescription). In a 
sensitivity analysis, we will explore 30- and 90- days gap as a definition for drug 
discontinuation. As this is a descriptive study, assessment of the dose reduction and 
discontinuation for both drugs will be considered separately, and only descriptively, without 
any direct comparison between the two cohorts.

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9.2
SETTING
9.2.1
Study sites
We will use administrative health insurance claims data from the Optum Research Database 
(ORD) for the period of October 1, 2013 through end of data availability (currently 
September 30, 2021). The ORD contains enrollment information, as well as fully-adjudicated 
medical claims and pharmacy claims for commercial enrollees and MAPD beneficiaries.  In 
2018, the ORD included 14.3 million commercial enrollees with medical and pharmacy 
benefits and 4.3 million beneficiaries with Medicare Part C (commonly referred to as the 
Medicare Advantage program). Medicare Advantage beneficiaries choose to receive all of 
their health care services through a provider organization in lieu of Medicare Part A/B 
coverage (commonly referred to as Medicare Fee for Service). These plans are referred to as 
MAPD when combined with Medicare Part D coverage. The average enrollment duration 
was 31.4 and 37.3 months for commercial enrollees and MAPD enrollees, respectively. 
Underlying information is geographically diverse across the United States and enrollees are 
fairly representative of the U.S. population. Medicare beneficiaries retain a single identifier 
within the system and can be tracked as they change plans, or as they disenroll and reenroll 
over time.
Claims for pharmacy services are typically submitted electronically by the pharmacy at the 
time prescriptions are filled. The claims history is a profile of all outpatient prescription 
pharmacy services provided and covered by the health plan. Pharmacy claims data include 
drug name, dosage form, drug strength, fill date, days of supply, financial information, and 
de-identified patient and prescriber codes, allowing for longitudinal tracking of medication 
refill patterns and changes in medications. Pharmacy claims are typically added to the 
research database within six weeks of dispensing.
Medical claims or encounter data are collected from all available health care sites (inpatient 
hospital, outpatient hospital, emergency department, physician's office, surgery center, etc.) 
for virtually all types of provided services, including specialty, preventive and office-based 
treatments. Medical claims and coding conform to insurance industry standards. Claims for 
ambulatory services submitted by individual providers, such as physicians, use the Health 
Care Financing Administration (HCFA)-1500 or Centers for Medicare and Medicaid Services 
(CMS)-1500 formats. Claims for facility services submitted by institutions, e.g., hospitals, 
use the Uniform Billing (UB)-82, UB-92, UB-04, or CMS-1450 formats. Medical claims 
include: multiple diagnosis codes recorded with the International Classification of Diseases, 
Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of 
Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes; procedures 
recorded with ICD-9-CM and ICD-10-CM procedure codes, Current Procedural Terminology 
(CPT), or Health care Common Procedure Coding System (HCPCS) codes; site of service 
codes; provider specialty codes; revenue codes (for facilities); paid amounts; and other 
information. Typically, facility claims do not include medications dispensed in hospital. 
Approximately six months following the delivery of services is required for complete 
adjudication of medical data.

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9.2.2
Study population
For the primary study objective, patients included in the cohort need to meet the following 
criteria:

Presence of at least one pirfenidone or nintedanib prescription during the 
identification period (the date of first prescription for pirfenidone/nintedanib is the 
index date)

Evidence of IPF: patient with at least one inpatient or two outpatient claims (>14 days 
apart) with a diagnosis code for IPF (ICD-10-CM: J84.112; ICD-9-CM: 516.31) 
during the study period (10/01/2013 to 09/30/2022)

At least 18 years old at the index date

Have at least 12 months of continuous enrollment in the health plan during pre-index 
period, and at least 6 months of continuous enrollment in post-index period (for 12-
months analysis, patients would be required to have 12 months post-index continuous 
enrollment)
Exclusion criteria include the following:

Any history of lung transplant during the 12-months pre-index/baseline period

Any claims for a skilled nursing facility, a long-term care facility or hospice care 
during the 12-month pre-index period

Evidence (≥2 ICD-9-CM or ICD-10-CM diagnostic codes on different dates) of non-
IPF chronic fibrosis ILD or connective tissue diseases during the 12-months pre-index 
period. The following conditions will be excluded: autoimmune, or connective tissue 
diseases (i.e., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), 
dermatopolymyositis, systemic sclerosis, Sjogren’s syndrome, and mixed connective 
tissue disease (CTD)), sarcoidosis, and hypersensitivity pneumonitis).

Missing demographic information (i.e., age or sex)
9.2.3
Study visits
Not applicable
9.2.4
Study discontinuation
Not applicable.
9.3
VARIABLES
9.3.1
Exposures
There is no primary exposure in this study, as this is a descriptive study evaluating dose 
reduction/interruption, and drug discontinuation in pirfenidone and nintedanib initiators, 
separately. There is no direct comparison between the two cohorts (more details in Section 
9.7)

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9.3.2
Outcomes
9.3.2.1
Primary outcome
The main outcome measure of our study is the incidence of dose reduction/interruption, 
calculated separately for each drug. For calculating the primary outcome, we will first need to 
calculate the average daily dose of pirfenidone and nintedanib after drug initiation (post-
index period). Specific details of calculations are –

Average daily dose
Average daily dose for each patient will be calculated by taking the average of total 
drug intake (tablet strength * number of doses) during the time between index date to 
the date of drug discontinuation 
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  " −$ {(
  &') −(& 
}
Where n = number of fills a patient has received for pirfenidone/nintedanib

We will calculate average daily dose of pirfenidone and nintedanib separately for each
month in post-index period (month 1 to 12) and will also calculate for cumulative 
periods of 6 months and 12 months. For all calculations, censoring events will be 
taken into account, with patient censored at the date of drug discontinuation, or end of 
12 months.

Six and twelve months average daily dose categories –
For the average daily dose calculations in cumulative periods, we will be dividing the 
patients in following 4 categories –
1) Dose strength less than 50%
2) Dose strength between 51% to 66%
3)
Dose strength between 67% to 90%
4) Dose strength above 90%
Incidence of Dose Reduction and/or temporary dose interruption
Once average daily dose is calculated for each month post-index (month 1 to 12), incidence 
of dose reduction/interruption will be calculated as presence of average daily dose ≤ 90% 
dose strength (for pirfenidone) or ≤ 66.67% dose strength (for nintedanib), as per the PI [12 –
14]. Patients will be required to have the dose reduction for at least for 60 days, to make sure 
that the dose reduction is not temporary. 
In a sensitivity analysis, we will also evaluate temporary dose reductions, i.e., dose reduced 
to below the above defined dose strength only for 1 month.
In the primary analysis, patients who reduce their dose in the prior months will be allowed to 
discontinue the drug in future months (For example, in primary analysis, a patient can reduce 
their index drug dose in month 2 (i.e. dose below label recommendation for the whole month 
2 and 3), and then can discontinue the drug in month 4 (or beyond). We will also evaluate the 
incidence of dose reduction in patients who never discontinue the index drug.

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9.3.2.2
Secondary outcomes
We will assess drug discontinuation as a secondary outcome. Pirfenidone or nintedanib 
discontinuation will be defined as presence of sixty or more days gap in refilling a 
prescription of the drug (sixty days gap counted from the date of last fill plus the days of 
supply for the fill). The date of last fill plus the days of supply for the fill (typically 30 days) 
will be designated as date of discontinuation, and time to discontinuation will be calculated as 
time between date of discontinuation and index date (only for patients who discontinue the 
drug). We will calculate the percentage of patients who discontinue each drug in first 6- and 
12-months post-index period. As a sensitivity analysis, we will calculate drug discontinuation 
using 30 days and 90 days as allowed gap between the scripts (vs. 60 days)
We will also assess how many patients initiate either of the antifibrotic drugs (including the 
same drug the patient has discontinued) during the follow-up time post discontinuation of 
their index drug. We will separately assess initiation of the index drug vs. initiation of the 
other antifibrotic agent.
9.3.3
Covariates
Variable
Description
Demographic and socioeconomic characteristics
Age
Age as of index date in whole years will be 
calculated based on the difference between the 
patient’s birth date and index date. 
Women
Women will be a binary indicator for whether the 
beneficiary was woman as indicated on the 
enrollment record covering the index date.
Census region
Census region will be a categorical variable 
defined by categorizing the beneficiary’s state of 
residence into Census regions (Northeast, South, 
Midwest, West) from the enrollment record 
covering the index date 
Index year
Index year will be a categorical variable defined 
as the year of the index date and will take the 
values 2014, 2015 2016, 2017, 2018, 2019, 2020
or 2021.
Clinical characteristics
Charlson Comorbidity Index (CCI)
Charlson Comorbidity Index (CCI) during pre-
index period: A CCI score will be calculated for 
each patient using diagnosis codes on medical 
claims during the pre-index period. The CCI was 
developed in 1987 based on 1-year mortality data 

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Variable
Description
from internal medicine patients, and encompasses 
19 medical conditions weighted 1–6 with total 
scores ranging from 0–37 (Charlson ME 1987). 
For this study, CCI adapted for use with both 
ICD-9-CM and ICD-10 codes will be used (Quan 
H 2005). The CCI will be reported as both a 
continuous measure and a categorical measure 
(0=low, 1-2=medium, or ≥3=high).
Pulmonary hypertension
A binary indicator for whether the beneficiary had 
a diagnosis code for pulmonary hypertension on at 
least one inpatient, or outpatient claim that 
occurred during the baseline period 
Gastroesophageal reflux disease 
(GERD)
A binary indicator for whether the beneficiary had 
a diagnosis code for gastroesophageal reflux 
disease on at least one inpatient, or outpatient 
claim that occurred during the baseline period 
Asthma
A binary indicator for whether the beneficiary had 
a diagnosis code for asthma on at least one 
inpatient, or outpatient claim that occurred during 
the baseline period 
Sleep apnea
A binary indicator for whether the beneficiary had 
a diagnosis code for obstructive sleep apnea on at 
least one inpatient, or outpatient claim that 
occurred during the baseline period 
Lung biopsy
A binary indicator for whether the beneficiary had 
a diagnosis or procedure code for a lung biopsy on 
at least one inpatient, or outpatient claim that 
occurred during the baseline period 
HRCT scan
A binary indicator for whether the beneficiary had 
a procedure code for a high-resolution 
computerized tomography scan on at least one 
inpatient, or outpatient claim that occurred during 
the baseline period 
Oxygen
A binary indicator for whether the beneficiary had 
a diagnosis, procedure revenue center code for 
oxygen therapy or supplemental oxygen on at 
least one inpatient, outpatient, skilled nursing 
facility, home health or durable medical 

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Variable
Description
equipment claim that occurred during the baseline 
period 
Pulmonary rehabilitation
A binary indicator for whether the beneficiary had 
a procedure or revenue center code for pulmonary 
rehabilitation services on at least one inpatient, 
outpatient, skilled nursing facility, home health or 
durable medical equipment claim that occurred 
during the baseline period 
Ventilator use
A binary indicator for whether the beneficiary had 
a diagnosis or procedure code for ventilator use on 
at least one inpatient, or outpatient claim that 
occurred during the baseline period 
COPD
A binary indicator for whether the beneficiary had 
a diagnosis code for chronic obstructive 
pulmonary disease on at least one inpatient, or 
outpatient claim that occurred during the baseline 
period 
Hypoxia
A binary indicator for whether the beneficiary had 
a diagnosis code for hypoxia on at least one 
inpatient, or outpatient claim that occurred during 
the baseline period 
Pharmacy use and spending
Medication count
The count of the number of unique outpatient 
prescription medications for which beneficiary has 
pharmacy claims during the baseline period  
Total pharmacy spending
A continuous, non-negative variable representing 
the total amount paid by all parties for outpatient 
prescription medications as reported in pharmacy
claims during the baseline period.
OOP pharmacy spending
A continuous, non-negative variable representing 
the total amount paid out-of-pocket by the 
beneficiary for outpatient prescription medications 
as reported in pharmacy claims during the 
baseline period.
Inpatient hospitalization use and spending
Any inpatient stay
A binary indicator for whether a beneficiary had at 
least one inpatient hospitalization for any cause 
during the baseline period.

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Variable
Description
Inpatient stay count
A count of the number of inpatient 
hospitalizations for any cause a beneficiary had 
during the baseline period.
Inpatient length of stay
A count of the number of days (length of stay) a 
beneficiary was hospitalized in an inpatient 
facility during the baseline period.  Length of stay 
for each inpatient hospitalization claim will be 
calculated as the arithmetic difference between 
each claim’s from and through dates.
Total inpatient spending
A continuous, non-negative variable representing 
the total amount paid by all parties for all inpatient 
hospitalizations (for any cause) as reported in 
inpatient facility claims during the baseline 
period. 
Outpatient facility use and spending
Any outpatient visit
A binary indicator for whether a beneficiary had at 
least one claim for services provided by an 
outpatient facility for any cause during the 
baseline period.
Outpatient visit count
A count of the number of unique dates with an 
outpatient facility for any cause claim a 
beneficiary had during the baseline period.
Total outpatient spending
A continuous, non-negative variable representing 
the total amount paid by all parties for outpatient 
facility claims during the baseline period.  
Medical spending
Total Medical spending
A continuous, non-negative variable representing 
the total amount paid by all parties all medical 
claims during the baseline period, calculated as 
the sum of the allowed amounts on each claim.
OOP Part B spending
A continuous, non-negative variable representing 
the total amount paid out-of-pocket by the 
beneficiary for all medical claims during the 
baseline period.
Total spending
Total spending
A continuous non-negative variable representing 
the total amount paid by all parties for all medical 

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Variable
Description
and pharmacy claims during the baseline period 
and will be calculated as the sum of total 
pharmacy and total medical spending.
Other use
Any ED visit
A binary indicator for whether a beneficiary had at 
least one emergency department visit during the 
baseline visit.  
ED visit count
A count of the number of unique dates with an 
emergency department visit that a beneficiary had 
during the baseline period.
Any pulmonology visit
A binary indicator for whether a beneficiary was 
treated by a specialist in pulmonary disease during 
the baseline period.  Treatment by a 
pulmonologist will be identified by the presence 
of a pulmonary specialty code in inpatient, or 
outpatient claims.
Pulmonology visit count
A count of the number of unique dates with 
treatment by a specialist in pulmonary disease that 
a beneficiary had during the baseline period.  
9.4
DATA SOURCES
As described above in Section 9.2.1, We will use administrative health insurance claims data 
from the Optum Research Database (ORD) for the period of October 1, 2013 through end of 
data availability (September 30, 2022). The ORD contains enrollment information, as well as 
fully-adjudicated medical claims and pharmacy claims for commercial enrollees and MAPD 
beneficiaries.  In 2018, the ORD included 14.3 million commercial enrollees with medical 
and pharmacy benefits and 4.3 million beneficiaries with Medicare Part C (commonly 
referred to as the Medicare Advantage program). 
9.5
STUDY SIZE
As this is a descriptive study, no formal calculation of sample size was performed. In a 
preliminary feasibility analysis using Optum data to examine sample size, we have found that 
1,979 patients newly initiated pirfenidone, and 2,559 patients who initiated nintedanib 
between 10/2014 to 12/2020. As such, this study is expected to have a sufficient sample.

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9.6
DATA MANAGEMENT
Data cleaning and analysis will be executed by US HEOR group. Paper printouts of the data 
are not required and will not be produced. Study documents, including synopsis, protocol, 
final results, and publications, will be archived on the BIRDS (Boehringer Ingelheim 
Regulatory Documents for Submission).
9.7
DATA ANALYSIS
9.7.1
Main analysis
Baseline characteristics for the pirfenidone and nintedanib cohorts will be reported as 
frequencies with percentages for categorical data, and means with standard deviations (SD), 
and median with interquartile range will be reported for continuous variables. We will 
compare the baseline characteristics using Student’s T-test or Wilcoxon rank-sum test for 
continuous variable, and chi-square test for categorical variable
Average daily dose during first 6 months and 12 months after drug initiation will be reported 
as means with standard deviations (SD), and median with interquartile range. Six months and 
12-months daily dose categories will be presented as frequencies with percentages. Incidence 
of dose reduction will be reported by month of occurrence (using month 2 and onwards) and 
reported as frequencies with percentages. Time to drug dose reduction will be reported in 
months (mean (SD)). Drug discontinuation will be reported as frequencies with percentages, 
and time to drug discontinuation will be reported in months (mean (SD)). As this is a 
descriptive study, there will be no multivariable adjustment and/or direct comparison of 
outcomes between the pirfenidone and nintedanib cohort.
9.7.2
Post-hoc analysis
As this study is a descriptive analysis, no adjustments or direct comparison between 
pirfenidone and nintedanib cohort is proposed a-priori. If significant differences in the 
baseline characteristics between the pirfenidone and nintedanib cohorts are observed, we 
propose to conduct propensity score matching (PSM) to balance the baseline characteristics 
between the two cohort. Specifically, pirfenidone initiators will be matched to nintedanib 
initiators using the technique of nearest neighbor match on an estimated propensity score 
(caliper width of ±0.001 unit). The propensity score for this analysis will be obtained from a 
logistic regression model using pre-index measures to predict the probability of being in the 
pirfenidone initiator cohort. Pre-index measures which will be included are demographic 
(age, sex, census region, index year), clinical (CCI, pulmonary hypertension, COPD, asthma, 
GERD, HRCT scan, oxygen use, and ventilator use), and healthcare utilization measures 
(total pharmacy spend, total medical spend, number of pulmonology visits)
We will compare differences in baseline characteristics between the pirfenidone and 
nintedanib cohorts before and after propensity score matching. The success of the propensity 
score-matching to reduce confounding will be assessed by evaluating the standardized 
differences in the covariates between the study groups after matching. For each covariate, the 
standardized difference percent (di) will be calculated as: di = 100 * (xi − xni)/√({s2i + 

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s2ni}/2) where xi and xni are the sample means of the ith covariate in the pirfenidone and 
nintedanib cohorts, respectively, and s2i and s2ni are the corresponding sample variances. A 
standardized difference of <10% is considered an acceptable level of difference (or supports 
the assumption of balance) between the comparison groups.
We will reassess the primary and secondary outcomes in the matched cohorts (see Section 
9.7.1 for more details)
9.8
QUALITY CONTROL
The following quality assurance and quality control measures will be applied to all 
programming that executes data extraction and transformation by US HEOR team:

Check program logs for notes, warning messages, and errors

Check derived data values against source data for a patient sample to ensure correct 
derivation

Verify that variables needed to support tables/listings/figures/ are found in the derived 
data set

Check that data fields are not truncated

Check data points for values outside expected ranges, where appropriate

Check that data are rounded correctly and in accordance to the analysis plan

Check that abbreviations, range categories, and subgroups conform to the analysis 
plan

Ensure the consistency of sample counts across relevant tables/listings/figures

Check formats consistent with the analysis plan

Ensure no typos, misspellings, or false values

Check that summary statistics are correct; check at least one category in each 
summary table against the data listings

Check that data are in accordance with the Data Plan

Check that subgroups conform to the Data Plan

Ensure there are no duplicate observations
9.9
LIMITATIONS OF THE RESEARCH METHODS
Several potential limitations of this study are discussed below:

This study is based on healthcare claims data, daily dose calculations derived from 
monthly pharmacy fills may not represent the actual daily intake of the patient

We could not ascertain reasons for discontinuations and/or dose reduction in this 
study, as adverse events may not be reliably captured in the claims database, and also 
the reasons for drug discontinuation are not captured in the claims database

We will not be able to distinguish between dose reduction vs. temporary dose 
interruption for a patient, as the main outcome is based on calculation of daily dose
based on pharmacy claims

Due to lack of availability of laboratory data and clinical information (for example 
FVC% at baseline), severity of IPF, and results of the laboratory tests will not be 

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observed. The severity of IPF may influence the initiation, discontinuation, and dose-
reduction of an anti-fibrotic agents

This study cannot be generalized to the entire U.S. population. ORD only covers 
patients with commercial insurance or Medicare Advantage plan. The findings of this 
study may not be applicable for patients with public insurance such as Medicare Fee-
For-Service or without insurance.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
See Section 9.8
9.10.2
Study records
Not applicable. 

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10.
PROTECTION OF HUMAN SUBJECTS
Not applicable.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
IRB exemption has been granted to this study.
10.2
STATEMENT OF CONFIDENTIALITY
IRB exemption has been granted to this study.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Given the information available within the Optum claims database for this study, extraction 
on adverse events data will not be conducted and only data related to the study objectives will 
be extracted. Therefore, information about individual adverse events will not be available.
Only data on aggregate-level medication use will be analyzed.
11.1
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
Not applicable based on secondary use of data without any potential that any employee of BI
will access individually identifiable patient data.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The results of this study will be considered for dissemination in the form of scientific 
publications (e.g., an abstract/poster for presentation at a national conference, a manuscript 
for submission to a peer-reviewed journal).

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
1.
Meltzer, EB, Noble, PW. Idiopathic pulmonary fibrosis. Orphanet journal of rare 
diseases. 2008; 3(1), 1-15.
2.
Strongman H, Kausar I, Maher TM. Incidence, prevalence, and survival of patients 
with idiopathic pulmonary fibrosis in the UK. Adv Ther. 2018;35(5):724–36.
3.
Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, et al; 
ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official 
ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary 
fibrosis. An update of the 2011 clinical practice guideline, Am J Respir Crit Care 
Med 2015; 192: e3–19.
4.
U.S. Food and Drug Administration. News release. FDA approves Esbriet to treat 
idiopathic pulmonary fibrosis. October 15, 2014. Available at: 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418991.html
. 
5.
U.S. Food and Drug Administration. News release. FDA approves Esbriet to treat 
idiopathic pulmonary fibrosis. October 15, 2014. Available at: 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418991.html
. 
6.
Paterniti MO, Bi Y, Rekić D, Wang Y, Karimi-Shah BA, Chowdhury BA. Acute 
exacerbation and decline in forced vital capacity are associated with increased 
mortality in idiopathic pulmonary fibrosis. Ann Am Thorac Soc. 2017;14(9):1395–
402.
7.
King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg 
MK, et al.; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with 
idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370:2083–2092.
8.
Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al.; 
INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic 
pulmonary fibrosis. N Engl J Med. 2014; 370:2071–82.
9.
Dempsey T, Sangaralingham LR, Yao X, Sanghavi D, Shah ND, Limper AH. 
Clinical Effectiveness of Antifibrotic Medications for Idiopathic Pulmonary 
Fibrosis. Am J Respir Crit Care Med 2019; Iss 2, pp 168–174
10.
Corral M, Reddy S, Chang E, Broder M, Gokhale S, Raimundo K. Rates of 
Adherence and Persistence of Antifibrotic Therapies in the U.S. Medicare 
Population. Poster presented at: American Thoracic Society 2019 International 
Meeting; 2019 May 17–22; Dallas, TX.
11.
Corral M, DeYoung K, Kong AM. Treatment patterns, healthcare resource 
utilization, and costs among patients with idiopathic pulmonary fibrosis treated with 
antifibrotic medications in US-based commercial and Medicare Supplemental 
claims databases: a retrospective cohort study. BMC Pulm Med. 2020 Jul 
11;20(1):188. doi: 10.1186/s12890-020-01224-5.

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12.
Nathan SD, Lancaster LH,2 Albera C, Glassberg MK, Swigris JJ, Gilberg F, et al.; 
Dose modification and dose intensity during treatment with pirfenidone: analysis of 
pooled data from three multinational phase III trials. BMJ Open Resp Res 
2018;5:e000323. doi:10.1136/bmjresp-2018-000323
13.
Genentech. https://www.gene.com/download/pdf/esbriet_prescribing.pdf. Accessed 
09/26/2022, 2022
14.
PI BI. https://docs.boehringer-
ingelheim.com/Prescribing%20Information/PIs/Ofev/ofev.pdf. Accessed 
09/26/2022, 2022
15.
Data on File, Boehringer Ingelheim, Nintedanib (BIBF 1120) Summary of Clinical 
Efficacy, Document Number: c02155681-02

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ANNEXES
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference 
Number
Date
Title
1
<Number>
11/12/2021
1276_Code_List.xlsx

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
1276 
ENCePPChecklistforSt

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ANNEX 3. ADDITIONAL INFORMATION
Not applicable

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ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES
The NIS Protocol must be sent for review to the following individuals prior to approval.
Reviewer
NIS involving BI 
product(s)
NIS not involving BI 
product(s)
Global 
NIS
Local NIS
NIS Lead
X
X
X
Global TM Epi
X
X
X
Global TMM / TMMA / TM 
Market Access
X
X
Global Project Statistician
X
X
Global TM RA
X
Global PVWG Chair
X
GPV SC
X
X
X
Global CTIS representative
X
Local Medical Director 
X (if local study)
X
Local Head MAcc / HEOR 
Director
X (if local study)
X
Global TA Head Epi*
X
X
Global TA Head Clinical 
Development / Medical Affairs
/ Market Access*
X
X
Global TA Head PV RM*
X
RWE CoE
X
X
PSTAT / PSTAT-MA (for 
NISnd only)
X
X
X
NIS DM
X
X
X
Local Head MA/Clinical 
Development
X (does not apply to 
NISed without chart 
abstraction)
* After review by Global TM for function
Include this Annex if signatures of external investigators are required and/or for studies that
will not be stored in the DMS for submission documents. For non-interventional studies 

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approval signatures must be obtained from the individuals as noted in section 5.1.3 “Manage 
NIS Protocol” in the corresponding SOP 001-MCS-90-118. If the study is a PASS, additional 
approvals are necessary; refer to SOP 001-MCS-90-140 “Post Authorization Safety Studies”.
Study Title: 
Study Number: 
Protocol Version:
I herewith certify that I agree to the content of the study protocol and to all documents 
referenced in the study protocol.
Note: Please insert respective signatories with regard to the SOP.
Position: ___
I_
Name/Date: <
 /dd mmm yyyy> Signature: _______________
Position: NIS 
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