Conditions: Idiopathic Pulmonary Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 505
Healthy volunteers: no

Brief summary:
This randomized, multicenter, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of lebrikizumab as monotherapy in the absence of background IPF therapy and as combination therapy with pirfenidone background therapy in participants with IPF. Participants will be randomized to receive either lebrikizumab or placebo subcutaneously every 4 weeks.

Detailed description:

Arms:
arm 1: Participants will receive monotherapy with placebo matched to lebrikizumab administered via subcutaneous (SC) injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants will be allowed to receive treatment with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period. arm 2: Participants will receive monotherapy with lebrikizumab at a dose of 250 milligrams (mg) administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants will be allowed to receive treatment with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period. arm 3: Participants will receive pirfenidone at a stable dose of 2403 mg per day (three 267 mg capsules three times a day \[9 capsules daily\] for a total of 2403 mg/day) or at maximum tolerated dose (MTD) administered orally along with placebo matched to lebrikizumab administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. arm 4: Participants will receive pirfenidone at a stable dose of 2403 mg per day (three 267 mg capsules three times a day \[9 capsules daily\] for a total of 2403 mg/day) or at MTD administered orally along with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period.

Interventions: intervention 1: Lebrikizumab intervention 2: Pirfenidone intervention 3: Placebo
Intervention descriptions: intervention 1: Lebrikizumab will be administered at a dose of 250 mg via SC injection once every 4 weeks. intervention 2: Pirfenidone will be administered orally at a stable dose of 2403 mg per day or at MTD. intervention 3: Placebo matched to lebrikizumab will be administered via SC injection once every 4 weeks.

Protocol document:
Prot_SAP_000.pdf: 
 
Title
23-Oct-2016 19:34:27
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, 
especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) 
and therefore is provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional 
Review Board.  It is understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent from persons 
to whom the drug may be administered. 
 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
Protocol GB28547, Version 7 
PROTOCOL 
TITLE: 
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, STUDY TO ASSESS 
THE EFFICACY AND SAFETY OF 
LEBRIKIZUMAB IN PATIENTS WITH IDIOPATHIC 
PULMONARY FIBROSIS 
PROTOCOL NUMBER: GB28547 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2013-001163-24 
IND NUMBER: 
117,062 
TEST PRODUCT: 
Lebrikizumab (RO5490255) 
MEDICAL MONITORS: 
, M.D. 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  17 April 2013 
DATES AMENDED: 
Version 2:  06 June 2013 
Version 3:  02 May 2014 
Version 4:  11 February 2015 
Version 5:  27 March 2015 
Version 6:  02 December 2015 
Version 7:  See electronic date stamp below. 


Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
2/Protocol GB28547, Version 7 
PROTOCOL AMENDMENT, VERSION 7: 
RATIONALE 
Protocol GB28547, Version 7, was amended as follows: 
• 
The Statistical Analysis Plan was amended on 16MAY2016 prior to unblinding to the 
study treatment in Cohort A to change the objectives, endpoints, and statistical 
methods to incorporate the 
 
after the approval of Esbriet and Ofev for idiopathic pulmonary fibrosis.  These 
changes were added to the protocol in this amendment (Section 2.1, Section 3.3.1.1, 
Section 3.3.1.2, Section 3.3.4, Section 6.1, Section 6.4.1, Section 6.4.2, and 
Section 6.5.1). 
• 
The randomization for Cohort B is modified to be stratified by region, baseline lung 
function, and baseline serum periostin concentration.  Stratification by prior 
pirfenidone exposure was introduced in Protocol Amendment 6 which was at 
6 months after the start of enrollment into Cohort B.  This factor is removed because 
this additional factor could not be implemented in the interactive voice/Web 
response system prior to completion of enrollment (Section 3.1.1). 
• 
An Internal Monitoring Committee was added for an unplanned interim analysis of 
the efficacy and safety data of Cohort B (Section 3.1.3) and subsequent results 
were shared with the independent Data Monitoring Committee. 
• 
The safety information for lebrikizumab was updated with the summary results from 
three completed Phase III asthma studies and two Phase II studies in 
atopic dermatitis (Section 1.2). 
• 
The benefit-risk profile for lebrikizumab was updated on the basis of the totality of 
data from completed studies (Section 1.4). 
• 
Optional biosensor assessment sections were removed because the manufacturer 
of the sensor has decommissioned this platform and it is no longer available. 
 
Additional minor changes have been made to improve clarity and consistency and to 
align the protocol with the Sponsor’s current internal guidelines and standard operating 
procedures.  Substantive new information appears in italics. 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
3/Protocol GB28547, Version 7 
PROTOCOL AMENDMENT, VERSION 7: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.1:  BACKGROUND ON IDIOPATHIC PULMUNARY FIBROSIS 
…Other commonly prescribed therapies for IPF including corticosteroid monotherapy, 
N-acetylcysteine, and combined corticosteroid (e.g., azathioprine or cyclophosphamide) 
therapy remain contraindicated (Raghu et al. 2011). 
SECTION 1.2:  BACKGROUND ON LEBRIKIZUMAB 
In Phase I clinical studies, no consistent laboratory abnormalities, clinically significant 
ECG changes, or consistent changes in vital signs were observed.  Safety and efficacy 
information from three Phase II asthma studies supported the continued development of 
this molecule for the treatment of asthma.  Phase II studies in asthma, a disease… 
The clinical data obtained to date from the Phase I and Phase II clinical studies 
supported an acceptable benefit-risk for continuing with the evaluation of lebrikizumab 
for the treatment of asthma.  
 
 
 
 
 
  Overall, no clinically important safety signals were consistently 
identified in the completed Phase II asthma studies.  Injection-site reactions were 
reported in a greater proportion of lebrikizumab-treated patients, but these were all non-
serious and in most cases did not require treatment.  The injection-site reactions 
observed to date in ongoing and completed clinical trials have been consistent with the 
rate and severity of those reported with other biological SC injectable therapies. 
Unblinded study results recently became available from three Phase III studies of 
patients with asthma, two Phase II studies of patients with atopic dermatitis and the 
current study of patients with IPF, which includes a placebo-controlled period for 
Cohort A.  A total of 1798 patients were administered at least one dose of lebrikizumab 
in all these studies combined (1536 patients with asthma, 184 patients with atopic 
dermatitis, and 78 patients with IPF).  
 
 
 
 
 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
4/Protocol GB28547, Version 7 
SECTION 1.4:  BENEFIT-RISK ASSESSMENT 
Given the evidence supporting a key role for IL-13 in disease pathogenesis, there is a 
compelling rationale to consider targeted anti−IL-13 therapy in patients with IPF.  As 
suggested by the experience with uncontrolled asthma, in which IL 13 is hypothesized 
to be a major contributing factor, modulation of IL 13 can translate to clinical 
benefits 
 specifically, improvements in lung function and a potential for reduction in 
exacerbations (as described above). 
The Sponsor unblinded the treatment assignment in Cohort A of the study in May 2016, 
and conducted the planned analysis of this placebo-controlled cohort to assess the 
benefit of lebrikizumab monotherapy in accordance with this protocol.  No 
clinically-meaningful treatment difference was observed between the lung function 
endpoints; however, the trends that were observed for the 6-minute walk test (6MWT) 
distance and A Tool to Assess Quality of Life in Idiopathic Pulmonary Fibrosis 
(ATAQ-IPF) were in favor of treatment with lebrikizumab.  There was no evidence of 
safety concerns in Cohort A and the cohort safety profile was generally consistent with 
the safety profile observed in previous asthma studies with lebrikizumab. 
The Sponsor performed an interim futility analysis for Cohort B in August.  Taken 
together, the Sponsor decided to continue the study for the Cohort A extension and 
Cohort B per the protocol. 
At this time, the benefit-risk ratio that justifiessupports the continuation of this Phase II 
study of lebrikizumab in patients with IPF. 
SECTION 2.1:  EFFICACY OBJECTIVES 
The primary efficacy objective for this study is to evaluate lebrikizumab compared with 
placebo as monotherapy or as combination therapy with pirfenidone background 
compared with placebo in patients with IPF, as measured by the absolute change from 
baseline to Week 52annualized rate of decline in percentage of predicted FVC over 
52 weeks. 
The secondary efficacy objectives are to evaluate lebrikizumab compared with placebo 
as monotherapy or as combination therapy with pirfenidone background therapy 
compared with placebo in patients with IPF as measured by:  
• 
The efficacy on the basis of PFS, pulmonary function, diffusion capacity, 
non-elective hospitalization for any cause, and acute IPF exacerbation, proportion 
of patients with at least 10% decline in percentage of predicted FVC or death, and 
all cause death 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
5/Protocol GB28547, Version 7 
SECTION 2.4:  EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To evaluate the efficacy of lebrikizumab compared with placebo as monotherapy or 
as combination therapy with pirfenidone compared with placebo in patients with IPF 
on the basis of time to death, time to non elective hospitalization from respiratory 
cause, time to addition of supplemental oxygen therapy; changes in DLco, and 
quantitative lung fibrosis (QLF) score on HRCT, ATAQ, and the BORG Category 
Ratio 10 Scale® (BORG CR10), and the proportion of patients with at least 10% 
decline in percentage of predicted FVC or deathtime to first occurrence of the 
St. George’s Respiratory Questionnaire (SGRQ) individual domain worsening as 
defined by reaching minimal important difference (MID; Swigris et al. 2010). 
SECTION 3.1.1:  Overview of Study Design 
At the end of the screening period, and applicable qualifying pirfenidone titration run-in 
period for patients requiring pirfenidone titration, eligible patients will be randomized in a 
1:1 ratio within each cohort to double-blind treatment with SC lebrikizumab 250 mg 
or placebo.  Dynamic hierarchical randomization will be performed centrally and stratified 
by region (United States, Europe/Canada, and other)[limited to Cohort A] or by prior 
pirfenidone exposure (none, < 1 year, > 1 year) [limited to Cohort B], lung function 
(FVC < 50%, 50% to 75%, > 75% predicted), and serum periostin concentration 
(< 50 ng/mL, ≥ 50 ng/mL) in each cohort. 
SECTION 3.1.3:  Internal Monitoring Committee 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Details with regard to the IMC were documented in an IMC agreement. 
SECTION 3.2.3:  Rationale for Patient Population 
…During the open-label lebrikizumab period, at the investigator’s discretion, a patient 
can start background therapy, including use of pirfenidone or other treatment, provided 
that it is an approved therapy for IPF approved in the applicable region (e.g., European 
Union, Canada, Mexico, Peru, or Japan) (see Section 4.4.1.2)… 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
6/Protocol GB28547, Version 7 
The Principal Investigator should notify the Medical Monitor of proposed changes in 
concomitant IPF therapy prior to starting rescue therapy throughout the study for 
patients in either Cohort A or Cohort B. 
SECTION 3.2.5:  Rationale for Control Group 
During the placebo-controlled periods, N-acetylcysteine or IPF therapy approved by 
local regulatory authorities can be initiated only after a confirmed progression event 
(≥ 10% decrease in FVC or non-elective hospitalization).  No other therapies for IPF can 
be started at any time during the study. 
For patients assigned to Cohort B, other approved therapies may be initiated in the 
absence of disease progression if pirfenidone is stopped because of safety considerations 
(see Section 4.4.1.2). 
SECTION 3.3.1.1:  Primary Efficacy Outcomes Measure 
The primary efficacy outcome measure for this study is the absolute change from 
baseline to Week 52 in percent predicted FVCannualized rate of decrease in percentage 
of predicted FVC over 52 weeks (% FVC/year). 
SECTION 3.3.1.2:  Secondary Efficacy Outcomes Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Change from baseline to Week 52Annualized rate of decline in 6MWT distance over 
52 weeks 
• 
Time from randomization to first decrease from baselineoccurrence of a ≥ 10% 
absolute decline in percentage of predicted FVC (L) or death from any cause 
• 
Time from randomization to firstAnnualized rate of decrease from baseline of ≥ 15% 
in percentage of predicted DLCO (mL CO/min 1/mmHg 1)over 52 weeks 
• 
PFS, defined as the time from study treatment randomization to the first occurrence 
of any of the following disease progression or death events: 
Death from any cause 
Non elective All-cause hospitalization for any cause 
A decrease from baseline (relative change) of ≥ 10% in FVC (mL/year) (relative 
change) 
• 
Annualized rate of changedecrease in FVC (L) over a 52-week period (mL/year) 
• 
Change from baseline to Week 52Annualized rate of decrease in ATAQ-IPF 
questionnairetotal score over a 52-week period (see Appendix 5 for a description of 
the instrument) 
• 
Change from baseline to Week 52 inTime from randomization to first occurrence of 
the SGRQ (see Appendix 5 for a description of the questionnaire) worsening (total 
score) as defined by reaching MID (Swigris et al. 2010):  Total Score = 7 or death 
from any cause 
• 
Time from randomization to non-elective hospitalization or death from any cause 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
7/Protocol GB28547, Version 7 
• 
Time from randomization to first event of acute IPF exacerbation as defined below: 
IPF exacerbation is defined as an event that meets all of the following criteria as 
determined by the investigator: 
Unexplained worsening or development of dyspnea within the previous 30 days 
And radiologic evidence of new bilateral ground-glass abnormality or 
consolidation superimposed on a reticular or honeycomb background pattern 
that is consistent with UIP 
And absence of alternative causes, such as left heart failure, pulmonary 
embolism, pulmonary infection (on the basis of endotracheal aspirate or 
bronchoalveolar lavage, if available, or investigator judgment), or other events 
leading to acute lung injury (e.g., sepsis, aspiration, trauma, reperfusion 
pulmonary edema) 
SECTION 3.3.4:  Exploratory Outcome Measures 
The exploratory outcome measures for this study include the following: 
• 
Change from baseline to Week 52 in DLCO % predicted 
• 
Time from randomization to non elective hospitalization for respiratory cause as 
determined by the investigator 
• 
Time from randomization to death 
• 
Time from randomization to addition of supplemental oxygen therapy for patients not 
receiving supplemental oxygen at baseline 
• 
Change from screening (corresponding to timing for randomization strata) in 
serum and plasma biomarkers (e.g., periostin and CCL18) and change from 
baseline in serum and plasma biomarkers (e.g., periostin, CCL18, YKL40, COMP, 
OPN, CCL13) 
• 
Exposure-response relationships (to be evaluated as warranted) 
• 
Change from baseline to Week 52 in physical activity as determined by biosensor 
technology 
• 
Change from baseline to Week 52 in the ATAQ-IPF 
• 
Time from randomization to first occurrence of SGRQ individual domain 
worsening as defined by reaching MID (Swigris et al. 2010):  Symptom = 8, 
Activity = 5, Impact = 7, or death from any cause 
• 
The proportion of patients with at least 10% decline in % predicted FVC or death by 
Week 52 
• 
Change from baseline to Week 52 in the SGRQ 
 
The analysis plan for the exploratory HRCT and biomarkers will be specified in a 
separate document. 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
8/Protocol GB28547, Version 7 
SECTION 4.1:  PATIENTS 
Approximately 480 patients ≥ 40 years of age who have a diagnosis of IPF will beare 
enrolled in this study. 
SECTION 4.1.2:  Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Chronic oral corticosteroid therapy is not permitted within 4 weeks prior to screening 
(Visit 1) or, during screening and run-in, or throughout the study period 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Dynamic hierarchical randomization will be performed centrally and stratified by region 
(United States, Europe/Canada, other), [limited to Cohort A] or by prior pirfenidone 
exposure (none, < 1 year, > 1 year) [limited to Cohort B], lung function (FVC < 50%, 50% 
to 75%, > 75% predicted),… 
As described in Section 6, treatment assignment will be unblinded to the personnel 
performing the analysis when all data for the primary endpoint period are in the database 
and the data have been cleaned and verified.  
 
 
  However, patients and all study 
site personnel will remain blinded… 
SECTION 4.4.1.1:  Corticosteroids 
Chronic maintenance oral corticosteroid therapy, defined as daily or alternate day oral 
corticosteroid maintenance therapy is not permitted within the 4 weeks prior to screening 
Visit 1, during screening and run-in, or throughout the study period…. 
SECTION 4.4.1.2:  Rescue Therapy 
Patients in Cohort A who experience confirmed disease progression (≥ 10% decline in 
FVC [mL/year; relative change] or non-elective hospitalization) during the 
placebo-controlled study period will be allowed, at the investigator’s discretion, to start 
rescue therapy, including use of pirfenidone or other IPF treatment provided that it is an 
approved therapy for IPF approved in the applicable region (e.g., European Union, 
Canada, Mexico, Peru, or Japan).  Patients who start rescue therapy will be allowed and 
encouraged to remain in the study and continue study treatment. 
During the open-label lebrikizumab study period, at the investigator’s discretion, a 
patient can initiate additional therapy for IPF that is approved in the applicable region 
(e.g., European Union, Canada, Mexico, Peru, or Japan) without evidence of disease 
progression.  
Patients in Cohort B who experience a confirmed disease progression (≥ 10% decline in 
FVC [mL/Year; relative change] or non-elective hospitalization) during the placebo 
controlled study period should continue the study drug medication, including background 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
9/Protocol GB28547, Version 7 
pirfenidone.  However, at the investigator’s discretion, the initiation of rescue therapy 
that is approved by local regulatory authorities is allowed.  Combination treatment with 
pirfenidone and nintedanib is not permitted throughout the study, given lack of adequate 
safety information on this drug combination.  Patients in Cohort B may initiate other 
approved therapies in the absence of disease progression if pirfenidone is stopped 
because of safety considerations.  The Principal Investigator should notify the Medical 
Monitor of proposed changes in concomitant IPF therapy prior to starting rescue therapy 
for patients in either Cohort A or Cohort B throughout the study. 
No other therapies for IPF may be started at any time during the study prior to 
experiencing a confirmed progression event.Patients who start rescue therapy must 
begin appropriate monitoring per the prescribing information for that therapy.  All safety 
laboratory assessments, including those required for the prescribed rescue medication, 
should be analyzed by the central laboratory utilized for the GB28547 clinical study. 
SECTION 4.4.2:  Prohibited Therapy 
• 
Chronic oral corticosteroid therapy is not permitted within 4 weeks prior to screening 
(Visit 1), or during screening and run-in, or throughout the study period. 
• 
N-acetylcysteine or IPF therapy approved by local regulatory authorities can be 
initiated in the event of disease progression as per Section 4.4.1.2.  Patients in 
Cohort B may initiate other approved IPF therapies in the absence of disease 
progression if pirfenidone is stopped because of safety considerations. 
SECTION 4.4.2.1:  Prohibited Therapy Limited to Cohort B (Background 
Pirfenidone) 
• 
Ongoing use of the following therapies or agents within 4 weeks of randomization 
(Day 1, Visit 2) or during the studyat the initiation of pirfenidone (whichever is 
longer) to the end of the safety follow-up period 
Strong inhibitors of CYP1A2 (e.g., fluvoxamine or enoxacin) 
Moderate inducers of CYP1A2 limited to tobacco smoking and 
tobacco-related products  
 
SECTION 4.5.12:  Protocol-Defined Idiopathic Pulmonary Fibrosis 
Exacerbation 
At each study visit, the investigator will ask directed questions and review the file 
to assess the possibility that the patient experienced an acute IPF exacerbation per 
protocol over the preceding 4 weeks.  A dedicated eCRF will be used to record 
information regarding a protocol defined acute IPF exacerbation.  An acute IPF 
exacerbation should also be reported as an adverse event (or serious adverse event as 
applicable) as per Section 5.2 and Section 5.3.5.9.  An protocol-defined acute IPF 
exacerbation is defined as an event that meets all of the following criteria as determined 
by the investigator: 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
10/Protocol GB28547, Version 7 
SECTION 4.5.14:  Laboratory Assessments 
Samples for the following non-standard laboratory tests will be sent to the Sponsor or a 
designee for analysis: 
• 
Serum samples for antibodies and anti-PLB2 antibody testing 
SECTION 4.5.16:  Optional Biosensor Assessment 
Biosensors provide data on patients’ physiologic status.  Although a patient can 
accurately report on his or her well being and can rate some physiologic symptoms, 
patients may not be able to quantify other physiologic data.  Biosensors have the 
potential to provide more accurate physiologic measurements. 
BodyMedia Wireless Armband Biosensor 
The bodymedia armband biosensor measures patient activity over time.  The data 
collected will be compared with data from the 6MWT, ATAQ IPF and SGRQ 
to understand the correlation between the different data streams.  Patient data will be 
downloaded at the sites during the patients’ monthly visits.  The biosensor assessment 
is limited to patients who provided consent for this substudy prior to publication of 
GB28547 protocol Version 5. 
SECTION 5.1.1:  Adverse Events of Special Interest for Lebrikizumab 
Based on data to date, the theoretical risks associated with IL-13 inhibition, and the risks 
associated with and for biologic agents in general, the following four categories of 
potential adverse events have been identified as adverse events of special interest for 
lebrikizumab (refer to the Lebrikizumab IB for more details):The four categories are the 
following:… 
The documentation and expedited reporting requirements for these adverse events 
of special interest are described in Section 5.2.2 (reporting of serious events) and 
Section 5.2.3 (reporting of non serious events of special interest). 
SECTION 5.1.1.1:  Local Injection-Site Reactions 
In recently-completed Phase IIIII clinical trials with lebrikizumab administered to 
patients with asthma, the reported rate of injection-site reactions were reported in a 
greater proportion of lebrikizumab treated patients than in placebo treated patientswas 
comparable between the group of patients who were treated with lebrikizumab and the 
group of patients who were treated with placebo (117 of 1432 patients [8.2%] vs. 55 of 
716 patients [7.7%], respectively).  In Cohort A of Study GB28547 (RIFF), injection 
site reactions were reported in 13 of 78 patients (16.7%) who were treated with 
lebrikizumab compared with 6 of 76 patients (7.9%) who were treated with placebo.  
These events were all non-serious and in most cases did not require treatment. 
SECTION 5.1.1.2:  Anaphylactic, Anaphylactoid, and Hypersensitivity 
Reactions 
In completed Phase I/II clinical trials of lebrikizumab, no aAnaphylactic, anaphylactoid, 
or serious and hypersensitivity reactions were observed; however, anaphylaxis and 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
11/Protocol GB28547, Version 7 
hypersensitivity reactionsto treatment are considered a potential risk with all biologic 
medications, including lebrikizumab.  On the basis of newly-available safety data from 
six studies that were recently unblinded to the study treatment, there were no reports 
of anaphylaxis per the Sampson's criteria assessed as related to lebrikizumab treatment 
by an independent external adjudication committee that was blinded to the study 
treatment.  Furthermore, in the study of patients with IPF (Study GB28547, Cohort A) 
and both atopic dermatitis studies (Study GS29250 and Study GS29735), there were no 
reported events of anaphylaxis, anaphylactoid, or serious hypersensitivity reactions 
meeting search criteria. 
Patient injections will be administered by a qualified health care professional, andor a 
trained non-health care professional who can legally administer injections.  Patients will 
be monitored by a qualified health care professional for a minimum of 1 hour after dosing 
for the first three treatment visits and for 30 minutes after dosing for all othersubsequent 
treatment visits. 
SECTION 5.1.1.3:  Infections 
The role of IL-13 in other infections is less clear.  In the completed Phase III asthma 
studies of lebrikizumab, infections have not been associated with lebrikizumab.  A single 
case of tuberculosis occurred in a patient living in an endemic area.Safety analysis data 
from five studies (with the exclusion of Study GB28547) that were recently unblinded 
to the study treatment show that lebrikizumab treatment is not associated with 
infections and overall, there were no imbalances in infections (both broad and narrow 
[MedDRA High-Level Group Term of helminthic disorders, mycobacterial infectious 
disorders, and protozoal infectious disorders, or MedDRA High-Level Term of listeria 
infections]).  Analysis results from Cohort A of Study GB28547 showed higher rates of 
infection (broad) in the group of patients who were treated with lebrikizumab versus 
those who were treated with placebo (51 of 78 patients [65.4%] vs. 41 of 76 
patients [53.9%], respectively), which was driven mainly by an imbalance in urinary 
tract infections (UTIs) between the groups of patients.  All patients who were treated 
with lebrikizumab and showed a UTI had predisposing risk factors, including a single 
serious adverse event of UTI that occurred in a patient with prostatic hyperplasia. 
In Phase III studies of patients with moderate-to-severe asthma, herpes infections 
including herpes zoster (shingles) were reported in 2.0% of patients who were treated 
with lebrikizumab compared with 0.7% of patients who were treated with placebo.  In a 
Phase II study of patients with moderate-to-severe atopic dermatitis, herpes infections 
including herpes zoster (shingles) were reported in 3.8% of the patients who were 
treated with lebrikizumab.  None of the herpes infections that were reported, including 
herpes zoster, required a hospital admission.  In Cohort A of Study GB28547, herpes 
viral infections in patients were reported but there were no imbalances noted between 
patients who were treated with lebrikizumab and patients who were treated with 
placebo.  Refer to the Lebrikizumab IB for more detail. 




 
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13/Protocol GB28547, Version 7 
pirfenidone treatment.  Safety findings should be collected on the dates when 
pirfenidone is taken (see Section 4.5.10). 
SECTION 5.4:  IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Non serious aAdverse events of special interest (see Section 5.4.2 for further 
details) 
SECTION 5.4.2:  Reporting Requirements for Serious Adverse Events and 
Non Serious Adverse Events of Special Interest 
SECTION 5.4.2.1:  Events Occurring prior to Initiation of Study Drug 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
A paper Serious Adverse Event/Non Serious Adverse Event of Special Interest CRF and 
Fax Coversheet should be completed and faxed to Roche Safety Risk Management or 
its designee immediately (i.e., no more than 24 hours after learning of the event), with 
use of the fax numbers provided to investigators.  Patients who undergo screening 
procedures but do not enroll in the study will have serious adverse events recorded only 
in the Roche Drug Safety database and not in the study’s clinical database. 
SECTION 5.4.2.2:  Events Occurring after Initiation of Study Drug 
After initiation of study drug, serious adverse events and non serious adverse events 
of special interest will be reported until study completion.  Investigators should record all 
case details that can be gathered immediately (i.e., within 24 hours after learning of the 
event) on the Adverse Event eCRF and submit the report via the electronic data capture 
(EDC) system.  A report will be generated and sent to Roche Safety Risk Management 
by the EDC system. 
For Cohort B only:  Safety findings should be reported for patients who are 
administered background pirfenidone by their health care provider.  Safety findings 
should be collected as of date of consent for the study for patients who are naive to 
pirfenidone treatment.  Safety findings should be collected on the dates when 
pirfenidone is taken (see Section 4.5.10). 
In the event that the EDC system is unavailable, a paper clinical trial Serious Adverse 
Event/Non Serious Adverse Event of Special Interest reporting form and Fax Coversheet 
should be completed and faxed to Roche Safety Risk Management or its designee 


 
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immediately (i.e., no more than 24 hours after learning of the event), with use of the fax 
numbers or email address provided to investigators.  Once the EDC system is available, 
all information will need to be entered and submitted via the EDC system. 
SECTION 5.5.2:  Sponsor Follow-Up 
For serious adverse events, non serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, or autopsy reports) in order 
to perform an independent medical assessment of the reported case. 
SECTION 5.7:  EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, IECs, 
and applicable health authorities based on applicable legislation. 
SECTION 6:  STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The analysis of data from the placebo-controlled period for each cohort will be performed 
when all patients have either completed the end of the placebo-controlled treatment 
(Week 52/EOT) visit or discontinued early from the study.  Treatment assignment will be 
unblinded to the personnel performing the analysis when all data through the EOT visit 
are in the database and the data have been cleaned and verified for each cohort. 
The analysis of complete data for the study, including data from the placebo-controlled 
period, open-label extension period for Cohort A, and the 14-week safety follow-up 
period, will be performed when all patients have either completed the placebo-controlled 
period, open-label extension period for Cohort A, and 14-week safety follow-up period or 
discontinued early from the study, all data from the study are in the database, and the 
database is locked.  An interim futility analysis of Cohort B was conducted 
(see Section 6.8). 
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE 
In Cohort A, a sample size of 75 patients in each treatment group will provide more 
thanapproximately 80% power to detect a change in the annualized rate of decline in 
percentage of predicted FVC over 52 weeks of a 7.93.7% difference in the means of the 
absolute change from baseline in percentage of predicted FVC at 52 weeks, assuming 
that the common standard deviation is 8% (as reported in the placebo group in the 
ASCEND trial of pirfenidone) using a two group t-test with a 0.05 two-sided significance 
level. 
In Cohort B, a sample size of 165 patients in each treatment group will provide more 
thanapproximately 80% power to detect a 2.5% difference in the means of the absolute 


 
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change from baselineannualized rate of decline in percentage of predicted FVC over 
52 weeks, assuming that the common standard deviation is 8% (as reported in the 
ASCEND trial of pirfenidone) using a two group t-test with a 0.05 two-sided significance 
level. 
SECTION 6.4:  EFFICACY ANALYSES 
However, the Sponsor study team directly involved in the study conduct 
(medical monitoring, clinical operations, drug safety, etc.) will not have access 
to individual treatment assignments until study completion (see Section 3.1.3), when all 
patients have completed the safety follow-up or discontinued the study.  All non-Sponsor 
personnel who are involved in the conduct of the study (e.g., patients, site monitors, and 
investigators) will remain blinded to patient-specific treatment assignments until all 
patients complete the safety follow-up period or discontinue from the study. 
SECTION 6.4.1:  Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is the change from baseline to Week 52 in % 
predicted FVCannualized rate of decrease in percentage of predicted FVC (% FVC/year) 
through Week 52. 
The annualized rate of decrease in percentage of predicted FVC will be compared across 
the treatment arms with the use of a random slope model on observed cases at a 
0.05 two-sided significance level. 
The statistical analysis will be based on a linear mixed effects model with absolute 
change as the dependent variable. Independent variables will be baseline % predicted 
FVC, treatment arm, post baseline visit, treatment arm by visit interaction, and the 
stratification variables with the same categories used for the stratified randomization.   
The statistical model is as follows: 
FVCijk = (β0 + β0k) + (αi * β1 + β1k ) * tk + ηk + εijk 
where FVCijk is the predicted FVC for kth patient at visit j in treatment group 
i; β0 is the intercept; αi and β1 is the interaction term of the treatment effect 
(i = lebrikuzimab or placebo) and the slope; tk is the assessment time 
(continuous in year) for patient k; ηk is the effect of baseline lung function 
(defined as FVC < 50% vs. 50% to 75% vs. > 75% predicted) for the kth patient; 
β0k and β1k are the random components for intercept and slope; εijk is the 
random error for kth patient at time j; β0k, β1k and εijk are assumed to be 
independent and normally distributed with mean 0 and variance of σ02, σ12 and 
σε2 respectively. 
Note that because of a relatively large number of strata defined by the randomization 
stratification factors, the analysis will be adjusted only for baseline lung function 
because baseline FVC may impact the clinical disease course. 


 
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From the model, least squares means for the absolute change from baseline as well as 
placebo corrected absolute changes with 95% confidence intervals for each treatment 
arm at each post baseline visitannualized rate of decline in each treatment arm and the 
difference between the two treatment arms will be estimatedprovided with 95% CIs.  
Missing data will be handled by the model under the missing at random assumption 
without need for imputation for early discontinuation.The model implicitly imputes 
missing data on the basis of a patient’s estimated rate of worsening of lung function 
prior to the study visit discontinuation (i.e., under the assumption that it is missing at 
random). 
SECTION 6.4.2:  Secondary Efficacy Endpoints 
The secondary efficacy end points of this study are as follows: 
• 
PFS, defined as the time from study treatment randomization to the first occurrence 
of any of the following disease progression or death events: 
Death from any cause 
Non elective All-cause hospitalization for any cause 
A decrease from baseline (relative change) of ≥ 10% in FVC (L) 
• 
Annualized rate of changedecrease in FVC (mL/year) over 52 weeks 
• 
Time from randomization to first decrease from baselineoccurrence of a ≥ 10% in 
absolute decrease in percentage in predicted FVC (L) or death from any cause 
• 
Time from randomization to firstAnnualized rate of decrease from baseline of ≥ 15% 
in percentage of predicted DLCO (mL CO/min 1/mmHg 1) at Week 52over 52 weeks 
• 
Change from baseline to Week 52Annualized rate of decrease in the ATAQ-IPF 
total score over 52 weeks (see Appendix 5 for a description of the instrument) 
• 
Time from randomization to non-elective hospitalization or death from any cause 
• 
Change from baseline to Week 52Annualized rate of decrease in the 6MWT distance 
over 52 weeks 
• 
Time from randomization to first event of acute IPF exacerbation (defined below) 
IPF exacerbation is defined as an event that meets all of the following criteria as 
determined by the investigator: 
Unexplained worsening or development of dyspnea within the previous 
30 days 
And radiologic evidence of new bilateral ground-glass abnormality or 
consolidation, superimposed on a reticular or honeycomb background pattern, 
that is consistent with UIP 
And absence of alternative causes, such as left heart failure, pulmonary 
embolism, pulmonary infection (on the basis of endotracheal aspirate or 
bronchoalveolar lavage if available or investigator judgment), or other events 
that lead to acute lung injury (e.g., sepsis, aspiration, trauma, reperfusion 
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• 
Change from baseline to Week 52 in theTime from randomization to first 
occurrence of SGRQ (see Appendix 5 for a description of the questionnaire) 
worsening (total score) as defined by reaching MID (Swigris et al. 2010):  Total 
Score = 7 or death from any cause 
• 
Time from randomization to death from any cause 
 
All continuous endpoints will be analyzed with the use of the same methodology as the 
primary endpoint (see previous section) with specifics for models and summaries 
specified in the SAP. 
For time to event endpoints, a Cox Proportional Hazards (CPH) model will be performed 
to compare the treatment groups, with stratification variables included in the model as 
covariates.  Tthe log rank test stratified by baseline lung function (FVC < 50% vs. 50% 
to 75% vs. > 75% predicted) will be used to compare the time to event endpoints 
between the two treatment arms.  Time will be measured relative to the date of study 
treatment randomization (Day 1).  Patients who do not experience anthe event during 
the treatment period will have their data censored at the time when they were last known 
to be event free (EOT visit) or at the time of early treatment discontinuation, whichever 
occurs earlieron the last date during the placebo-controlled period when, on the basis of 
the assessments in accordance with this protocol, the patient can be considered to have 
been event-free.  Any patients who undergo lung transplantation will be censored at the 
date of the transplant.  Sensitivity analyses will be provided with lung transplant 
counted as an event for PFS and time from randomization to death or non-elective 
hospitalization from any cause. 
The primary efficacy assessments for the randomized placebo-controlled period are made 
on the study day of initiation of the open-label lebrikizumab through Week 52.  
Assessment on this day will be included for analyses of the randomized 
placebo-controlled period, but subsequent assessment during the open-label period or 
after Week 52 will be excluded. 
The hazard ratio and its 95% CI will be estimated with the use of a Cox regression 
model stratified by baseline lung function.  In fitting the CPH model, Efron’s approach 
to the treatment of tied event times will be used (Therneau and Grambsch 2000).  Under 
this model, the exponent of the regression coefficient that corresponds to the treatment 
group covariate represents the estimated hazard ratio (lebrikizumab vs. placebo).  
Inference will focus on estimating this hazard ratio and a corresponding 95% CI based 
on the PH regression model.  Risk rates at Week 52 by treatment group will be 
estimated with the use ofIn fitting the Cox model, ties will be handled with the 
approximate likelihood method of Efron (1977).  Kaplan-Meyer curves for PFS, and p
values comparing the two curves based on the score test statistic will be reportedwill be 
provided. 


 
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Summary statistics of the PROATAQ-IPR and SGRQ endpoints and the changes from 
baseline will be calculated at each assessment time-point for each treatment group.  The 
mean, standard error, and median of the absolute scores and the mean changes from 
baseline (and 95% CIs) between treatment groups will be reported for the endpoint.  For 
scores involving change from baseline, patients without baseline values will be excluded 
from the analyses.  Line charts depicting the means and mean changes of subscales 
over time will be also provided.  Scoring for the questionnaire will be based on relevant 
user manuals. 
Frequencies and percentages of missing data for the PROATAQ-IPR and SGRQ 
endpoints will be compared between the two treatment arms.Differences in the 
proportion of dropouts (defined as patients withdrawing from treatment for reasons other 
than documented disease progression or death) between the two treatment arms will be 
tested using the χ2 test. 
The PRO endpoints assessed at multiple timepoints will be analyzed using mixed model 
repeated measures.  Each model will have an intercept term, a linear time trend term 
(in weeks), a term for treatment group, and a term for treatment by time interaction.  A 
baseline score and appropriate covariates will also be added. 
For all endpoints, treatment effects will be summarized using point estimates and 
corresponding two sided 95% CIs will be provided. 
Additional details for summarization, sensitivity analyses, and type I error control are 
provided in the SAP. 
SECTION 6.5:  SAFETY ANALYSES 
Safety analyses will be based on all patients who received at least one dose of 
randomized study drug, with patients grouped according to the actual treatment received.  
Safety summaries will be presented by treatment arm for all treated patients.  In 
addition, safety listings will be provided for any events reported during pirfenidone 
exposure prior to randomization. 
Safety will be assessed through the summary of adverse events, laboratory test results, 
(including antibodies to lebrikizumab), ECG, and vital signs.  These summaries will be 
produced separately for each cohort for the treatment period (placebo-controlled study 
treatment period, the Cohort A open-label lebrikizumab period)and the 14 week safety 
follow up period. 


 
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SECTION 6.5.1:  Adverse Events 
Specific aAnalyses will be performed forby treatment group for events of special interest 
that include anaphylactic reactions, local injection-site reactions, infections, and 
malignancies: 
• 
aAnaphylactic reactions using both the MedDRA "anaphylactic reaction" 
Standardized MedDRA Query and Sampson's Criteria (see Appendix 7)will be 
reviewed and adjudicated by independent, external experts accordingly to a charter. 
• 
Local injection-site reactions, defined through coding (any verbatim term that 
includes "injection site") and will be identified with the usinge of the MedDRA 
high-level term of "injection site reaction", will also be analyzed by treatment arm 
and severity, as well as by whether study drug was discontinued as a result of the 
reaction. 
• 
The rate of iInfections, as identified with the usinge of the MedDRA system organ 
class of “infections and infestations“, will be summarized for each treatment arm. 
• 
Events that occur in the MedDRA neoplasms, benign, malignant, and unspecified 
(including cysts and polyps) system organ class will also be summarized for each 
treatment arm.Malignancies, as identified on the basis of the MedDRA SMQ of 
“Malignancy” and the subSMQ of “Malignant and unspecified tumours” 
SECTION 6.6:  PHARMACOKINETIC ANALYSES 
Individual and mean serum lebrikizumab concentration−versus-time data will be reported.  
During the treatment period, Mmean concentrations will be reported at Weeks 4, 12, 24, 
36, and 52 (Cmin,Wk4, Cmin,Wk12, Cmin,Wk24, Cmin,Wk36, CWk52, respectively) .  The elimination 
half life will also be reported.  Estimates for these parameters will be tabulated and 
summarized (mean, SD, coefficient of variation, median, minimum, and maximum).  
Additional PK analyses during the treatment period or the 14 week safety follow-up 
period may be conducted as appropriate.  Population PK modeling may be performed to 
characterize inter-individual variability, which may be reported separately from the 
clinical study report. 
SECTION 6.8:  OPTIONAL INTERIM ANALYSES 
After the analysis of Cohort A, the Sponsor formed an IMC to perform an unplanned 
interim futility analysis of Cohort B to determine if it should be terminated for lack of 
sufficient efficacy.  Following this analysis, the decision was made to continue the 
study and not perform additional efficacy and/or futility interim analyses. 
SECTION 9.3:  ADMINISTRATIVE STRUCTURE 
This study is sponsored by F. Hoffmann-La Roche Ltd.  Approximately A total of 
120 international study centers willhave participated in this study to enrolling 
approximately 480and enrolled 507 patients…. 
APPENDIX 1:  Schedule of Assessments:  Screening and Placebo 
Controlled Treatment Period – Cohort A 
Appendix 1 has been revised and the row related to BodyMedia biosensor was removed. 


 
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APPENDIX 2:  Schedule of Assessments:  Open-Label Lebrikizumab 
Treatment Period – Cohort A 
Appendix 2 has been revised and footnote l was amended as follows: 
l Includes IL-13 or IPF-related biomarkers (e.g., periostin, CCL18, YKL40, COMP, OPN, 
CCL13).  Screening serum periostin sample should be collected and shipped to the central 
laboratory within the first 2 weeks of screening. 
APPENDIX 3:  Schedule of Assessments:  Screening, Pirfenidone Titration 
Run-In, and Placebo Controlled Treatment Period – Cohort B 
Appendix 3 has been revised and footnote q was amended as follows: 
q On lebrikizumab dosing days.  Samples for serum PK, PD, antibody (including anti-therapeutic 
antibody), and optional PAXgene mRNA analysis will be taken prior to lebrikizumab dosing.  
An additional sample for serum antibody and PK analysis must be taken in the event of an 
anaphylactic, anaphylactoid, or serious hypersensitivity reaction.  Anti-PLB2 antibody testing 
may be performed as appropriate using serum samples collected at pre-specified timepoints. 
APPENDIX 4:  Schedule of Assessments:  Safety Follow-Up Period 
Appendix 4 has been revised and footnote k was amended as follows: 
k On lebrikizumab dosing days.  Samples for serum PK, PD, antibody (including anti-therapeutic 
antibody), and optional PAXgene mRNA analysis will be taken prior to lebrikizumab dosing.  
An additional sample for serum antibody and PK analysis must be taken in the event of an 
anaphylactic, anaphylactoid, or serious hypersensitivity reaction.  Anti-PLB2 antibody testing 
may be performed as appropriate using serum samples collected at pre-specified timepoints. 
SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Forms have been revised to reflect the changes to the protocol. 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 28 
PROTOCOL SYNOPSIS .................................................................................... 29 
1. 
BACKGROUND .......................................................................................... 39 
1.1 
Background on Idiopathic Pulmonary Fibrosis....................... 39 
1.2 
Background on Lebrikizumab ................................................ 40 
1.3 
Study Rationale ..................................................................... 41 
1.4 
Benefit-Risk Assessment....................................................... 42 
2. 
OBJECTIVES.............................................................................................. 43 
2.1 
Efficacy Objectives ................................................................ 43 
2.2 
Safety Objectives................................................................... 44 
2.3 
Pharmacokinetic Objective .................................................... 44 
2.4 
Exploratory Objectives........................................................... 44 
3. 
STUDY DESIGN ......................................................................................... 44 
3.1 
Description of Study .............................................................. 44 
3.1.1 
Overview of Study Design ..................................................... 44 
3.1.2 
Data Monitoring Committee................................................... 47 
3.1.3 
Internal Monitoring Committee............................................... 47 
3.2 
End of Study.......................................................................... 48 
3.2.1 
Rationale for Test Product Dosage........................................ 48 
3.2.2 
Rationale for Pirfenidone Dosage.......................................... 49 
3.2.3 
Rationale for Patient Population ............................................ 49 
3.2.4 
Rationale for Primary and Disease 
Response-Based Endpoints .................................................. 50 
3.2.5 
Rationale for Control Group................................................... 52 
3.2.6 
Rationale for Biomarker Assessments................................... 52 
3.3 
Outcome Measures ............................................................... 53 
3.3.1 
Efficacy Outcome Measures.................................................. 53 
3.3.1.1 
Primary Efficacy Outcome Measure ...................................... 53 
3.3.1.2 
Secondary Efficacy Outcome Measures................................ 53 
3.3.2 
Safety Outcome Measures .................................................... 54 


 
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3.3.3 
Pharmacokinetic Outcome Measures.................................... 54 
3.3.4 
Exploratory Outcome Measures ............................................ 54 
4. 
MATERIALS AND METHODS .................................................................... 55 
4.1 
Patients.................................................................................. 55 
4.1.1 
Inclusion Criteria.................................................................... 55 
4.1.2 
Exclusion Criteria................................................................... 56 
4.1.2.1 
Additional Exclusions Limited to Cohort B 
(Pirfenidone Background)...................................................... 58 
4.2 
Method of Treatment Assignment and Blinding..................... 59 
4.3 
Study Treatment.................................................................... 60 
4.3.1 
Formulation, Packaging, and Handling.................................. 60 
4.3.1.1 
Lebrikizumab and Placebo .................................................... 60 
4.3.2 
Pirfenidone/Background Treatment in Cohort B .................... 60 
4.3.3 
Dosage, Administration, and Compliance.............................. 61 
4.3.3.1 
Lebrikizumab and Placebo (Cohort A)................................... 61 
4.3.4 
Pirfenidone Background Treatment....................................... 61 
4.3.5 
Investigational Medicinal Product Accountability ................... 62 
4.3.6 
Post-Study Access to Lebrikizumab and 
Pirfenidone ............................................................................ 62 
4.4 
Concomitant Therapy ............................................................ 63 
4.4.1 
Permitted Therapy ................................................................. 63 
4.4.1.1 
Corticosteroids....................................................................... 63 
4.4.1.2 
Rescue Therapy .................................................................... 63 
4.4.2 
Prohibited Therapy ................................................................ 64 
4.4.2.1 
Prohibited Therapy Limited to Cohort B 
(Background Pirfenidone)...................................................... 65 
4.5 
Study Assessments ............................................................... 65 
4.5.1 
Description of Study Assessments ........................................ 65 
4.5.2 
Medical History and Demographic Data ................................ 65 
4.5.3 
Physical Examinations........................................................... 66 
4.5.4 
Vital Signs, Resting Pulse Oximetry, Weight, and 
Height .................................................................................... 66 
4.5.5 
Spirometry ............................................................................. 66 


 
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4.5.6 
Gas Exchange-Diffusion Capacity of the Lung for 
Carbon Monoxide Assessment.............................................. 67 
4.5.7 
High-Resolution Computed Tomography............................... 67 
4.5.8 
Optional Quantitative High-Resolution Computed 
Tomography Scan ................................................................. 67 
4.5.9 
Surgical Lung Biopsy............................................................. 68 
4.5.10 
Pirfenidone Background Therapy (Cohort B)......................... 68 
4.5.11 
Non-Elective Hospitalizations ................................................ 69 
4.5.12 
Protocol-Defined Idiopathic Pulmonary Fibrosis 
Exacerbation.......................................................................... 69 
4.5.13 
Six-Minute Walk Test............................................................. 69 
4.5.14 
Laboratory Assessments ....................................................... 71 
4.5.14.1 
Electrocardiograms................................................................ 72 
4.5.15 
Patient-Reported Outcomes .................................................. 73 
4.5.15.1 
A Tool to Assess Quality of Life in Idiopathic 
Pulmonary Fibrosis................................................................ 73 
4.5.15.2 
St. George’s Respiratory Questionnaire ................................ 74 
4.5.15.3 
EuroQol 5-Dimension Questionnaire ..................................... 74 
4.5.15.4 
Borg Category Ratio 10 Scale ............................................... 74 
4.5.16 
Optional Samples for Roche Clinical Repository ................... 74 
4.5.16.1 
Overview of the Roche Clinical Repository............................ 74 
4.5.16.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 75 
4.5.16.3 
Sample Collection.................................................................. 75 
4.5.16.4 
Confidentiality........................................................................ 76 
4.5.16.5 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 76 
4.5.16.6 
Withdrawal from the Roche Clinical Repository..................... 77 
4.5.16.7 
Monitoring and Oversight....................................................... 77 
4.5.17 
Timing of Study Assessments ............................................... 77 
4.5.17.1 
Screening and Pretreatment Assessments............................ 77 
4.5.17.2 
Assessments during Treatment............................................. 78 
4.5.17.3 
Assessments at Study Completion/Early 
Termination Visit.................................................................... 78 
4.5.17.4 
Follow-Up Assessments ........................................................ 79 




 
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5.3.5 
Procedures for Recording Adverse Events............................ 91 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 92 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 92 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 92 
5.3.5.4 
Abnormal Laboratory Values ................................................. 93 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 94 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 94 
5.3.5.7 
Deaths ................................................................................... 95 
5.3.5.8 
Preexisting Medical Conditions.............................................. 95 
5.3.5.9 
Lack of Efficacy or Worsening of Idiopathic 
Pulmonary Fibrosis................................................................ 95 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 96 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 96 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 96 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 97 
5.4.1 
Emergency Medical Contacts:  
Operations/Clinical ................................................................ 97 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 98 
5.4.2.1 
Events Occurring prior to Initiation of Study Drug.................. 98 
5.4.2.2 
Events Occurring after Initiation of Study Drug...................... 98 
5.4.3 
Reporting Requirements for Pregnancies.............................. 98 
5.4.3.1 
Pregnancies in Female Patients............................................ 98 
5.4.3.2 
Abortions ............................................................................... 99 
5.4.3.3 
Congenital Anomalies/Birth Defects ...................................... 99 
5.4.4 
Reporting Requirements for Medical Device 
Complaints............................................................................. 99 
5.5 
Follow-Up of Patients after Adverse Events ........................ 100 
5.5.1 
Investigator Follow-Up......................................................... 100 
5.5.2 
Sponsor Follow-Up .............................................................. 100 
5.6 
Post-Study Adverse Events................................................. 100 


 
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5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 100 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 101 
6.1 
Determination of Sample Size ............................................. 101 
6.2 
Summaries of Conduct of Study.......................................... 102 
6.3 
Summaries of Treatment Group Comparability ................... 102 
6.4 
Efficacy Analyses ................................................................ 102 
6.4.1 
Primary Efficacy Endpoint.................................................... 103 
6.4.2 
Secondary Efficacy Endpoints............................................. 103 
6.5 
Safety Analyses................................................................... 105 
6.5.1 
Adverse Events ................................................................... 105 
6.5.2 
Electrocardiogram ............................................................... 106 
6.5.3 
Laboratory Tests.................................................................. 106 
6.5.4 
Vital Signs............................................................................ 106 
6.6 
Pharmacokinetic Analyses................................................... 106 
6.7 
Exploratory Analyses........................................................... 107 
6.7.1 
High-Resolution, Thin-Section Computed 
Tomography Quantitative Scores ........................................ 107 
6.8 
Optional Interim Analyses.................................................... 107 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 107 
7.1 
Data Quality Assurance....................................................... 107 
7.2 
Electronic Case Report Forms............................................. 108 
7.3 
Source Data Documentation................................................ 108 
7.4 
Use of Computerized Systems ............................................ 109 
7.5 
Retention of Records........................................................... 109 
8. 
ETHICAL CONSIDERATIONS.................................................................. 109 
8.1 
Compliance with Laws and Regulations .............................. 109 
8.2 
Informed Consent ................................................................ 110 
8.3 
Institutional Review Board or Ethics Committee.................. 111 
8.4 
Confidentiality...................................................................... 111 
8.5 
Financial Disclosure ............................................................ 112 


 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 112 
9.1 
Study Documentation .......................................................... 112 
9.2 
Site Inspections ................................................................... 112 
9.3 
Administrative Structure....................................................... 112 
9.4 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 112 
9.5 
Protocol Amendments ......................................................... 113 
REFERENCES................................................................................................. 114 
 
  
LIST OF TABLES 
Table 1 
Combined High-Resolution Computed Tomography and 
Surgical Lung Biopsy Eligibility Assessment............................... 56 
Table 2 
Adverse Event Severity Grading Scale ....................................... 91 
 
 
LIST OF FIGURES 
Figure 1 
Study Schematic......................................................................... 47 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments: Screening and Placebo 
Controlled Treatment Period - Cohort A.................................... 119 
Appendix 2 
Schedule of Assessments: Open-Label Lebrikizumab 
Treatment Period - Cohort A..................................................... 124 
Appendix 3 
Schedule of Assessments: Screening, Pirfenidone Titration 
Run-In, and Placebo-Controlled Treatment Period - Cohort B.. 128 
Appendix 4 
Schedule of Assessments: Safety Follow-Up Period ................ 134 
Appendix 5 
A Tool to Assess Quality of Life in Idiopathic Pulmonary 
Fibrosis (ATAQ-IPF) ................................................................. 137 
Appendix 6 
St. George’s Respiratory Questionnaire (SGRQ)...................... 142 
Appendix 7 
EuroQol 5-Dimension Questionnaire (EQ-5D) .......................... 148 
Appendix 8 
Clinical Criteria for Diagnosing Anaphylaxis.............................. 151 
Appendix 9 
Childbearing Potential, Pregnancy Testing, and 
Contraception............................................................................ 152 
Appendix 10 High-Resolution Computed Tomography Criteria for UIP 
Pattern ...................................................................................... 153 
Appendix 11 Histopathological Criteria for UIP Pattern ................................. 154 
Appendix 12 Borg Category Ratio 10 Scale®................................................ 155 


Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
28/Protocol GB28547, Version 7 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, STUDY TO ASSESS 
THE EFFICACY AND SAFETY OF LEBRIKIZUMAB 
IN PATIENTS WITH IDIOPATHIC PULMONARY 
FIBROSIS 
PROTOCOL NUMBER: GB28547 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2013-001163-24 
IND NUMBER: 
117,062 
TEST PRODUCT: 
Lebrikizumab (RO5490255) 
MEDICAL MONITORS: 
, M.D. 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy 
of the form as instructed by your local study monitor/Roche Affiliate. 
 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
29/Protocol GB28547, Version 7 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, STUDY TO ASSESS THE EFFICACY 
AND SAFETY OF LEBRIKIZUMAB IN PATIENTS 
WITH IDIOPATHIC PULMONARY FIBROSIS 
PROTOCOL NUMBER: 
GB28547 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2013-001163-24 
IND NUMBER: 
117,062 
TEST PRODUCT: 
Lebrikizumab (RO5490255) 
PHASE: 
II 
INDICATION: 
Idiopathic Pulmonary Fibrosis 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is to evaluate lebrikizumab compared with placebo 
as monotherapy or as combination therapy with pirfenidone background compared with placebo 
in patients with idiopathic pulmonary fibrosis (IPF), as measured by the annualized rate of 
decline in percentage of predicted forced vital capacity (FVC) over 52 weeks. 
The secondary efficacy objectives are to evaluate lebrikizumab compared with placebo as 
monotherapy or as combination therapy with pirfenidone background therapy compared with 
placebo in patients with IPF as measured by:  
• 
The efficacy on the basis of Progression Free Survival (PFS), pulmonary function, diffusion 
capacity, non-elective hospitalization for any cause, acute IPF exacerbation, proportion of 
patients with at least 10% decline in percentage of predicted FVC or death, and all cause 
of death 
• 
The distance walked in 6 minutes and health-related quality of life questionnaires 
 
Safety Objectives 
The safety objectives for this study are the following: 
• 
To evaluate the safety of lebrikizumab as monotherapy compared with placebo in patients 
with IPF 
• 
To evaluate the safety of lebrikizumab with pirfenidone as background therapy compared 
with placebo with pirfenidone as background therapy in patients with IPF 
 
Pharmacokinetic Objective 
The pharmacokinetic (PK) objective for this study is as follows: 
• 
To characterize the PK of lebrikizumab in patients with IPF 
 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
30/Protocol GB28547, Version 7 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate the efficacy of lebrikizumab compared with placebo as monotherapy or as 
combination therapy with pirfenidone compared with placebo in patients with IPF on the 
basis of changes in quantitative lung fibrosis (QLF) score on HRCT, A Tool to Assess 
Quality of Life in IPF (ATAQ), and the BORG Category Ratio 10 Scale® (BORG CR10), 
and time to first occurrence of St. George’s Respiratory Questionnaire (SGRQ) individual 
domain worsening as defined by reaching minimal important difference (MID). 
• 
To evaluate potential prognostic and predictive serum and whole blood RNA and DNA 
biomarkers associated with IPF 
 
Study Design 
Description of Study 
This is a randomized, multicenter, double-blind, placebo-controlled, parallel-group study of 
lebrikizumab in patients with IPF.  Approximately 480 patients with a diagnosis of IPF will be 
enrolled in the study across two cohorts (approximately 150 patients in Cohort A having 
approximately 75 patients per treatment arm and approximately 330 patients in Cohort B having 
approximately 165 patients per treatment arm) at approximately 120 sites located globally.  The 
total treatment duration will be based on all patients receiving at least 13 doses (one dose every 
4 weeks [Q4W]) of blinded treatment over 48 weeks.  The study primary endpoint will measure 
the absolute change from baseline to Week 52 in percent predicted FVC. 
Two cohorts of patients will be enrolled in the study; Cohort A patients will be treated in the 
absence of pirfenidone IPF background therapy; Cohort B patients will be treated with 
pirfenidone as background therapy. 
Number of Patients 
Approximately 480 patients with a diagnosis of IPF will be enrolled in the study across two 
cohorts (approximately 150 patients in Cohort A having approximately 75 patients per treatment 
arm and approximately 330 patients in Cohort B having approximately 165 patients per 
treatment arm) at approximately 120 sites located globally. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Able and willing to provide written informed consent and to comply with the study protocol 
• 
Age ≥ 40 years at Visit 1 
• 
Have a diagnosis of IPF based on the ATS/ERS/JRS/ALAT consensus statement on IPF 
within the previous 5 years from time of screening and confirmed at baseline. 
• 
Have a central review assessment of an HRCT performed during the screening period or 
within 12 months prior to the start of screening. 
All patients who have undergone a SLB as part of their initial workup should have 
pathology slides sent in for SLB central review assessment. 
Eligibility will be determined on the basis of assessments in Table 1. 
• 
A Multidisciplinary Discussion of Diagnosis (MDD) based on 2011 ATS/ERS/JRS/ALAT 
guidelines will be utilized to finalize the diagnosis in the event the initial central review 
outcome results for HRCT and SLB are disparate (inconsistent with UIP/definite UIP). 
 
Additionally, patients must meet the following criteria for study entry: 
• 
FVC ≥ 40% and ≤ 100% of predicted at screening 
• 
Stable baseline lung function as evidenced by a difference of < 10% in FVC (L) 
measurements between screening and Day 1, Visit 2 prior to randomization 
• 
Diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 25% and ≤ 90% of predicted at 
screening 


 
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• 
Ability to walk ≥ 100 meters unassisted in 6 minutes 
• 
Cohort A:  No background IPF therapy for ≥ 4 weeks allowed prior to randomization and 
throughout the placebo-controlled study period 
• 
Cohort B:  Tolerated dose of pirfenidone ≤ 2403 mg/QD for ≥ 4 weeks required prior to 
randomization and throughout the placebo-controlled study period 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known 
hypersensitivity to any component of the lebrikizumab injection 
• 
Evidence of other known causes of interstitial lung disease (ILD) (e.g., domestic and 
occupational environmental exposures, connective-tissue disease (CTD), and drug toxicity) 
• 
Lung transplant expected within 12 months of screening 
• 
Evidence of clinically significant lung disease other than IPF (e.g., asthma or chronic 
obstructive pulmonary disease [COPD]) 
• 
Post-bronchodilator forced expiratory volume in 1 second (FEV1)/FVC ratio < 0.7 at 
screening 
• 
Positive bronchodilator response evidenced by an increase of ≥ 12% predicted and 200 mL 
increase in either FEV1 or FVC 
• 
Any clinically significant medical disease (other than IPF) that is associated with an 
expected survival of < 12 months, likely to require a change in therapy during the study, or 
likely to impact the ability of the patient to participate in the study in the opinion of the 
investigator, or impact the study efficacy or safety assessments 
• 
Requirement for continuous medical care and assistance, or limited ability to self-care that 
would impact the ability of patient to participate in the study or to perform the study-related 
assessments 
• 
Class IV New York Heart Association chronic heart failure or historical evidence of left 
ventricular ejection fraction < 35% 
• 
Hospitalization due to an exacerbation of IPF within 4 weeks prior to or during screening 
• 
Known current malignancy or current evaluation for a potential malignancy 
• 
Major episode of infection requiring any of the following: 
Admission to the hospital for ≥ 24 hours within 4 weeks prior to screening or during 
screening and run-in period 
Treatment with antibiotics (IV, IM, oral, or inhaled) within 4 weeks prior to screening or 
during screening and run-in period 
• 
An active upper or lower respiratory tract infection occurring at any time within the 
screening period prior to the randomization visit (Visit 1 to Day 1, Visit 2) 
• 
Listeria monocytogenes infection or active parasitic infection within 6 months prior to Day 1, 
Visit 2 
• 
Active tuberculosis requiring treatment within 12 months prior to screening 
• 
Known immunodeficiency, including but not limited to HIV infection 
• 
Past use of any anti–IL-13 or anti–IL-4/IL-13 therapy, including lebrikizumab 
Patients participating in a clinical trial that has not been unblinded should be assumed 
to have received the active drug 
• 
Evidence of acute or chronic hepatitis or known liver cirrhosis 
• 
AST, ALT, or total bilirubin elevation ≥ 2.0 × the upper limit of normal during screening 
• 
Clinically significant abnormality on ECG at screening or laboratory tests (hematology, 
serum chemistry, and urinalysis) that, in the opinion of the investigator, may pose an 
additional risk in administering study drug to the patient 


 
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32/Protocol GB28547, Version 7 
• 
Receipt of a live/attenuated vaccine within the 4 weeks prior to Visit 1 
• 
Chronic treatment with any of the following within 4 weeks or five half-lives prior to 
screening (whichever is longer) to the end of the placebo-controlled period (Day 365, 
Visit 16): 
Immunosuppressive or immunomodulatory therapies (e.g., azathioprine, cyclosporine 
A, cyclophosphamide, D-penicillamine, interferon-gamma, tumor necrosis 
factor-α antagonists) 
Cytotoxic drugs (e.g., colchicine) if used for IPF indication 
Pirfenidone (Exclusion Limited to Cohort A) 
N-acetylcysteine 
Pulmonary hypertension therapies (e.g., endothelin receptor antagonist, 
phosphodiesterase type-5 inhibitor, riociguat, prostacyclin or prostacyclin analogue) 
Tyrosine kinase inhibitors including exclusion of nintedanib for Cohort A and Cohort B 
Warfarin or other anticoagulant therapy if given for IPF indication 
Any unlicensed therapy given for IPF indication 
Any investigational agent 
• 
Chronic oral corticosteroid therapy is not permitted within 4 weeks prior to screening 
(Visit 1), during screening and run-in, or throughout the study period. 
• 
History of alcohol, drug, or chemical abuse that would impair or risk the patient’s full 
participation in the study, in the opinion of the investigator 
• 
Female patients of reproductive potential who are not willing to use a highly effective 
method of contraception (e.g., contraceptive pill or transdermal patch, spermicide and 
barrier [i.e., condoms], intrauterine device, implants for contraception, injections for 
contraception [with prolonged release], hormonal vaginal device, sterilization, surgical tubal 
ligation) for the duration of the study and for at least 18 weeks after the last dose of 
lebrikizumab or placebo study treatment. 
• 
Pregnant or lactating 
• 
Body weight <40 kg 
 
Additional exclusions that are limited to Cohort B (Pirfenidone Background): 
• 
Known achalasia, esophageal stricture, or esophageal dysfunction sufficient to limit the 
ability to swallow oral medication 
• 
Tobacco smoking or use of tobacco-related products within 3 months of screening or 
unwillingness to avoid smoking throughout the study (e.g., cigarette, pipe, cigar) 
• 
Any condition that, as assessed by the investigator, might be significantly exacerbated by 
the known side effects associated with pirfenidone 
• 
Known or suspected peptic ulcer 
• 
Creatinine clearance < 40 mL/min, calculated using the Cockcroft-Gault formula 
• 
Ongoing use or following therapies within 4 weeks of randomization (Day 1, Visit 2) or 
during the study 
Strong inhibitors of CYP1A2 (e.g., fluvoxamine or enoxacin) 
Moderate inducers of CYP1A2, limited to tobacco smoking and tobacco-related 
products 
 
Length of Study 
The total length of the study will be approximately 4 years from first patient screened to 
completion of the last patient visit.  Individual patients may participate in the study for up to 
2.9 years. 


 
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End of Study 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  The 
LPLV is expected to occur a maximum of 118 weeks after the last patient is enrolled and 
randomized into Cohort A.  This timeframe includes a 52-week placebo-controlled period and a 
maximum of an additional 52 week open-label Lebrikizumab treatment period followed by the 
safety follow-up period.  In the case that enrollment in Cohort B is slower than anticipated, LPLV 
is expected occur a maximum of 66 weeks after the last patient is enrolled and randomized into 
Cohort B.  This timeframe includes a 52-weeks placebo-controlled period followed by the safety 
follow-up period.  All patients will be followed for safety for 18 weeks after the last dose of study 
treatment of lebrikizumab or placebo by subcutaneous injection. 
Outcome Measures 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is the annualized rate of decrease in 
percentage of predicted FVC over 52 weeks (% FVC/year). 
Secondary Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Annualized rate of decline in 6-minute walk test (6MWT) distance over 52 weeks 
• 
Time from randomization to first occurrence of a ≥ 10% absolute decline in percentage of 
predicted FVC or death from any cause 
• 
Annualized rate of decrease in percentage of predicted DLCO over 52 weeks 
• 
PFS, defined as the time from study treatment randomization to the first occurrence of any 
of the following disease progression or death events: 
Death from any cause 
All cause hospitalization 
A decrease from baseline (relative change) of ≥ 10% in FVC (mL/year) 
• 
Annualized rate of decrease in FVC over a 52-week period (mL/year) 
• 
Annualized rate of decrease in ATAQ-IPF total score over a 52-week period 
• 
Time from randomization to first occurrence of the SGRQ worsening (total score) as 
defined by reaching MID:  Total Score = 7 or death from any cause 
• 
Time from randomization to non-elective hospitalization or death from any cause 
• 
Time from randomization to first event of acute IPF exacerbation as defined below 
IPF exacerbation is defined as an event that meets all of the following criteria as 
determined by the investigator: 
Unexplained worsening or development of dyspnea within the previous 30 days 
And radiologic evidence of new bilateral ground-glass abnormality or consolidation 
superimposed on a reticular or honeycomb background pattern that is consistent with 
UIP 
And absence of alternative causes, such as left heart failure, pulmonary embolism, 
pulmonary infection (on the basis of endotracheal aspirate or bronchoalveolar lavage, 
if available, or investigator judgment), or other events leading to acute lung injury 
(e.g., sepsis, aspiration, trauma, reperfusion pulmonary edema) 
 
Safety Outcome Measures 
All safety outcome measures will be assessed by comparing results from the lebrikizumab 
treatment group with the placebo group.  The safety outcome measures for this study are as 
follows: 
• 
Frequency of adverse events during the study 
• 
Severity of adverse events during the study 
• 
Incidence of anti-therapeutic antibodies (ATAs) against lebrikizumab throughout the study 
 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
34/Protocol GB28547, Version 7 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Serum lebrikizumab concentration at Week 52 (CWk52) 
• 
Predose serum lebrikizumab concentrations (Cmin) at Weeks 4, 12, 24, and 36 (Cmin,Wk4, 
Cmin,Wk12, Cmin,Wk24, and Cmin,Wk36) 
• 
Elimination half-life of lebrikizumab 
 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Change from baseline to Week 52 in radiographic findings on pulmonary HRCT, including 
QLF score 
• 
Change from screening (corresponding to timing for randomization strata) in serum and 
plasma biomarkers (e.g., periostin and CCL18) and change from baseline in serum and 
plasma biomarkers (e.g., periostin, chemokine (C-C motif) ligand 18 [CCL18], YKL40, 
COMP, OPN, CCL13) 
• 
Serum lebrikizumab concentrations during the extended treatment and the 14-week safety 
follow-up period 
• 
Exposure-response relationships (to be evaluated as warranted) 
• 
Change from baseline to Week 52 in the Borg CR10 Scale 
• 
Change from baseline to Week 52 in the ATAQ-IPF 
• 
Time from randomization to first occurrence of SGRQ individual domain worsening as 
defined by reaching MID:  Symptom = 8, Activity = 5, Impact = 7, or death from any 
cause 
• 
Change from baseline to Week 52 in the SGRQ 
 
The analysis plan for the exploratory HRCT and biomarkers will be specified in a separate 
document. 
Investigational Medicinal Products 
Test Product 
Lebrikizumab will be administered by subcutaneous injection of 250 mg every 4 weeks, with the 
first injection occurring at the randomization visit (Day 1, Visit 2).  Patients will continue to 
receive blinded study treatment every 4 weeks during the placebo-controlled treatment period 
for a total of 13 doses/26 injections of blinded treatment. 
Comparator 
For patients in Cohort A, placebo will be administered.  For patients in Cohort B, placebo plus a 
pirfenidone background dose of ≤ 2403 mg/d will be administered in divided doses three times 
per day with food. 
Statistical Methods 
Primary Analysis 
The analysis of data from the placebo-controlled period for each cohort will be performed when 
all patients have either completed the end of the placebo-controlled treatment (Week 52/EOT) 
visit or discontinued early from the study.  Treatment assignment will be unblinded to the 
personnel performing the analysis when all data through the EOT visit are in the database and 
the data have been cleaned and verified for each cohort. 
The analysis of complete data for the study, including data from the placebo-controlled period, 
open-label extension period for Cohort A, and the 14-week safety follow-up period, will be 
performed when all patients have either completed the placebo-controlled period, open-label 
extension period for Cohort A, and 14-week safety follow-up period or discontinued early from 
the study, all data from the study are in the database, and the database is locked.  An interim 
futility analysis of Cohort B was conducted. 
 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
35/Protocol GB28547, Version 7 
Efficacy Analyses 
The analysis of data from the treatment period in Cohort A will be performed when all patients 
enrolled in Cohort A have either completed the end of placebo controlled treatment visit (Week 
52), or discontinued early from the study.  Treatment assignment will be unblinded to the 
personnel performing the analysis when all data through the Week 52 visit are in the database 
and the data have been cleaned and verified. 
The analysis of data from the treatment period in Cohort B will performed when all patients 
enrolled in Cohort B have either completed the end of treatment visit (Week 52) or discontinued 
early from the study.  Treatment assignment will be unblinded to the personnel performing the 
analysis when all data through the Week 52 visit are in the database and the data have been 
cleaned and verified. 
However, the Sponsor study team directly involved in the study conduct (medical monitoring, 
clinical operations, drug safety, etc.) will not have access to individual treatment assignments 
until study completion, when all patients have completed the safety follow-up or discontinued 
the study.  All non-Sponsor personnel who are involved in the conduct of the study 
(e.g., patients, site monitors, and investigators) will remain blinded to patient-specific treatment 
assignments until all patients complete the safety follow-up period or discontinue from the study. 
Complete details of the analysis will be provided in the SAP, which will be finalized prior to 
unblinding the data. 
Safety Analyses 
Safety analyses will be based on all patients who received at least one dose of randomized 
study drug, with patients grouped according to the actual treatment received.  Safety summaries 
will be presented by treatment arm for all treated patients.  In addition, safety listings will be 
provided for any events reported during pirfenidone exposure prior to randomization. 
Safety will be assessed through the summary of adverse events, laboratory test results, 
(including antibodies to lebrikizumab), ECG, and vital signs.  These summaries will be produced 
separately for each cohort for the treatment period (placebo-controlled study treatment period, 
the Cohort A open-label lebrikizumab period). 
Pharmacokinetic Analyses 
Individual and mean serum lebrikizumab concentration−versus-time data will be reported.  
During the treatment period, mean concentrations will be reported at Weeks 4, 12, 24, 36, and 
52 (Cmin,Wk4, Cmin,Wk12, Cmin,Wk24, Cmin,Wk36, CWk52, respectively) .  Estimates for these parameters 
will be tabulated and summarized (mean, SD, coefficient of variation, median, minimum, and 
maximum).  Additional PK analyses during the treatment period or the safety follow-up period 
may be conducted as appropriate.  Population PK modeling may be performed to characterize 
inter-individual variability, which may be reported separately from the clinical study report. 
Exploratory Analyses 
Analysis of exploratory efficacy endpoints will be described in the Statistical Analysis Plan. 
Several pharmacodynamic biomarkers have been identified (e.g., periostin, CCL18, YKL40, 
COMP, OPN, CCL13) and will be measured in serum or plasma samples to assess the effect of 
lebrikizumab on these biomarkers.  Exploratory exposure-response analysis will be performed 
as appropriate. 
Determination of Sample Size 
In Cohort A, a sample size of 75 patients in each treatment group will provide approximately 
80% power to detect a change in the annualized rate of decline in percentage of predicted FVC 
over 52 weeks of a 3.7% difference in the means of the absolute change from baseline in 
percentage of predicted FVC at 52 weeks, assuming that the common standard deviation is 8% 
(as reported in the placebo group in the ASCEND trial of pirfenidone) using a two group t-test 
with a 0.05 two-sided significance level. 
In Cohort B, a sample size of 165 patients in each treatment group will provide approximately 
80% power to detect a 2.5% difference in the annualized rate of decline in percentage of 
predicted FVC over 52 weeks, assuming that the common standard deviation is 8% (as 
reported in the ASCEND trial of pirfenidone) using a two group t-test with a 0.05 two-sided 
significance level. 


 
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36/Protocol GB28547, Version 7 
Optional Interim Analyses 
The Sponsor may choose to conduct up to two interim efficacy analyses.  Interim analyses will 
involve unblinding of treatment assignments to the Sponsor for purposes of data analysis and 
interpretation.  Patients and all study site personnel will remain blinded to individual patient-level 
treatment assignments until completion of the trials.  The decision to conduct optional interim 
analyses and the timing of the analyses will be documented in the Sponsor’s trial master file 
prior to the conduct of the interim analyses.  The interim analyses will be performed and 
interpreted by members of the Sponsor study team and appropriate senior management 
personnel, who will be unblinded at the treatment group level.  Access to treatment assignment 
information will follow the Sponsor’s standard procedures. 
After the analysis of Cohort A, the Sponsor formed an IMC to perform an unplanned interim 
futility analysis of Cohort B to determine if it should be terminated for lack of sufficient 
efficacy.  Following this analysis, the decision was made to continue the study and not 
perform additional efficacy and/or futility interim analyses. 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
6MWT 
6-minute walk test 
ANA 
anti-nuclear autoantibody 
ATA 
anti-therapeutic antibody 
ATAQ-IPF 
A Tool to Assess Quality of Life in Idiopathic Pulmonary 
Fibrosis 
ATS/ERS/JRS/ALAT 
American Thoracic Society/European Respiratory 
Society/Japanese Respiratory Society/Latin American 
Thoracic Association 
Borg CR10 Scale 
Borg Category Ratio 10 Scale® 
CCL 
chemokine (C-C motif) ligand 
CCP 
anti-citrullinated protein antibody 
Cmin 
minimum serum concentration under steady-state 
conditions within a dosing interval 
COPD 
chronic obstructive pulmonary disease 
CTD 
connective-tissue disease 
CWk52 
serum concentration at Week 52 
DLCO 
diffusion capacity of the lung for carbon monoxide 
eCRF 
electronic Case Report Form 
EOT 
end of treatment 
EQ-5D 
EuroQol 5-Dimension Questionnaire 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
HRCT 
high-resolution computed tomography 
huIgG4 
humanized monoclonal antibody 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMC 
Internal Monitoring Committee 
iDCC 
independent Data Coordinating Center 
iDMC 
independent Data Monitoring Committee 
IEC 
independent Ethics Committee 
IL 
interleukin 
IL-13R 
interleukin 13 receptor 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IPF 
idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 


 
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Abbreviation 
Definition 
IV 
intravenous 
IxRS 
interactive voice/Web response system 
LPLV 
last patient, last visit 
MID 
minimal important difference 
MDD 
Multidisciplinary Discussion of Diagnosis 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
QLF 
quantitative lung fibrosis 
Q4W 
every 4 weeks 
RCR 
Roche Clinical Repository 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SGRQ 
St. George’s Respiratory Questionnaire 
RF 
rheumatoid factor 
SLB 
surgical lung biopsy 
SMT 
Study Management Team 
SpO2 
oxygen saturation 
SSc 
scleroderma 
UIP 
usual interstitial pneumonitis 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON IDIOPATHIC PULMONARY FIBROSIS 
Idiopathic pulmonary fibrosis (IPF) is a specific form of fibrosing interstitial pneumonia 
limited to the lung and has the histopathologic pattern of usual interstitial 
pneumonia (UIP) upon analysis of a surgical lung biopsy.  Historically, patients who 
receive a diagnosis of IPF required a surgical lung biopsy; however, the current 
definition allows for an IPF diagnosis through clinical and radiological methods 
(Raghu et al. 2011).  The diagnosis of IPF requires the exclusion of other known causes 
of interstitial lung disease (ILD), such as domestic and occupational environmental 
exposures, connective-tissue disease, and drug toxicity (Raghu et al. 2011).  Because it 
remains a diagnosis of exclusion, a detailed clinical assessment is required to exclude 
other diffuse parenchymal diseases. 
Most patients are over 50 years of age and report an insidious onset of progressive 
dyspnea and non-productive cough over months to years.  Inspiratory crackles are noted 
on examination of the chest, and finger clubbing is present in many patients.  
High-resolution computed tomography (HRCT) imaging shows bilateral peripheral-based 
reticular abnormalities, traction bronchiectasis, and honeycombing involving 
predominantly the lower lung zones.  Pulmonary function assessment generally reveals 
reduced lung volumes with restrictive physiology, a diminished single-breath diffusing 
capacity, and hypoxemia with exercise. 
Depending on the criteria used for identification of patients with IPF, an estimated 
29,000 to 104,000 persons in the United States are diagnosed with IPF 
(Raghu et al. 2006).  The European IPF network reports that there are probably 
200,000 patients with IPF living in the European Union (Nalysnyk et al. 2012).  The true 
prevalence of IPF worldwide is likely higher because most documented cases are 
advanced and under medical treatment, both likely to bias the sample away 
from detecting early disease (Zeki et al. 2010). 
The clinical course of the disease is challenging to predict and patient rate of decline and 
progression to death is variable, with patient deterioration occurring rapidly, slowly, or 
with periods of stability interposed with acute decline (Ley et al. 2011).  Some patients 
have gradual progression over years, followed by acute exacerbations associated 
with abrupt and often fatal hypoxemic respiratory failure (Collard et al. 2007).  
Spontaneous remissions do not occur with UIP, and 10-year survival is less 
than 15% (Lynch and Belperio 2012). 
The most recent guidelines from the American Thoracic Society/European Respiratory 
Society/Japanese Respiratory Society/Latin American Thoracic Association 
(ATS/ERS/JRS/ALAT) joint task force for the diagnosis and management of IPF 
concluded that pharmacologic therapy for IPF is without definitive, proven benefit 
(Raghu et al. 2011). 


 
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At the time of publication of Protocol Version 3, there was no approved therapy in the 
United States for the treatment of IPF.  As of October 2014, two oral therapies were 
approved by the FDA for treatment of IPF, pirfenidone (ESBRIET) and nintedanib (OFEV) 
with additional approval of nintedanib by European Commission (EC) in January 2015.  
Other commonly prescribed therapies for IPF including corticosteroid monotherapy, 
N-acetylcysteine, and combined corticosteroid (e.g., azathioprine or cyclophosphamide) 
therapy remain contraindicated (Raghu et al. 2011). 
1.2 
BACKGROUND ON LEBRIKIZUMAB 
Lebrikizumab is a humanized monoclonal antibody (huIgG4) with a mutation in the hinge 
region for increased stability.  Lebrikizumab binds specifically to soluble interleukin-13 
(IL-13) with high affinity and neutralizes its functional activities with high potency. 
Lebrikizumab does not bind to mouse IL-13, the commonly used species for animal 
models of IPF.  Therefore, there are no nonclinical data available from in vivo 
lebrikizumab pharmacology/efficacy studies in animal models of IPF; however, 
numerous nonclinical studies supporting the use of other anti−IL-13 therapies have been 
published (see Section 1.3). 
The nonclinical safety assessment of lebrikizumab includes results from eight completed 
in vitro and in vivo studies with a total of 160 cynomolgus monkeys exposed 
to lebrikizumab for up to 9 months.  Lebrikizumab was well tolerated in single- and 
multiple-dose administration studies by intravenous (IV) and subcutaneous (SC) routes.  
The no observable adverse effect level for lebrikizumab in monkeys is considered to be 
25 mg/kg given weekly by means of IV infusion or SC injection, and systemic exposure 
in the 9-month monkey toxicity study is at least 23-fold higher than the predicted 
exposure in humans with this dosing regimen. 
Lebrikizumab has been investigated in ten completed clinical studies:  five Phase I 
studies and five Phase II studies.  In those studies, more than 700 individuals were 
exposed to at least one dose of lebrikizumab.  This included 94 healthy volunteers, 
18 patients with refractory Hodgkin’s lymphoma, and more than 600 patients with 
asthma.  The studies were designed to provide proof-of-concept data and to evaluate 
the safety, tolerability, and pharmacokinetic (PK) profile of lebrikizumab.  Lebrikizumab 
has been well tolerated by patients in these clinical studies with varied levels of 
exposure. 
In Phase I clinical studies, no consistent laboratory abnormalities, clinically significant 
ECG changes, or consistent changes in vital signs were observed.  Phase II studies in 
asthma, a disease in which IL-13 also plays a key role (Hershey 2003), demonstrated 
that lebrikizumab significantly increases pulmonary function and potentially decreases 
the rate of acute exacerbations that require systemic corticosteroids (Corren et al. 2011).  
Pharmacodynamic evaluations in this and other studies provided evidence that 
lebrikizumab inhibits the activity of IL-13 supported by a reduction from baseline serum 


 
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levels of chemokines (chemokine ligand [CCL]13 and CCL17), IgE, and periostin.  The 
biomarker serum periostin was evaluated in Study ILR4646g, and baseline serum 
periostin levels of ≥ 50ng/mL were shown to be predictive in patients who have a 
clinically meaningful benefit from lebrikizumab therapy. 
The clinical data obtained to date from the Phase I and Phase II clinical studies 
supported an acceptable benefit-risk for continuing with the evaluation of lebrikizumab 
for the treatment of asthma.  
 
 
 
 
 
  Overall, no clinically important safety signals were consistently 
identified in the completed Phase II asthma studies.  Injection-site reactions were 
reported in a greater proportion of lebrikizumab-treated patients, but these were all non-
serious and in most cases did not require treatment.  The injection-site reactions 
observed to date in ongoing and completed clinical trials have been consistent with the 
rate and severity of those reported with other biological SC injectable therapies. 
Unblinded study results recently became available from three Phase III studies of 
patients with asthma, two Phase II studies of patients with atopic dermatitis and the 
current study of patients with IPF, which includes a placebo-controlled period for 
Cohort A.  A total of 1798 patients were administered at least one dose of lebrikizumab 
in all these studies combined (1536 patients with asthma, 184 patients with atopic 
dermatitis, and 78 patients with IPF).  
 
 
. 
 
  However, the safety 
profile of lebrikizumab in humans is not yet fully characterized by extensive experience 
with patient exposure.  Therefore, the potential adverse effects and the likelihood of their 
occurrence cannot be fully known at this time.  There will be continued careful 
monitoring of patients to collect this information throughout further clinical development, 
including studies in IPF. 
See the Lebrikizumab Investigator’s Brochure (IB) for details on nonclinical and clinical 
studies. 
1.3 
STUDY RATIONALE 
IPF is characterized by varying degrees of interstitial fibrosis.  Several extracellular 
matrix proteins including type I, III, and IV collagens, fibronectin, and tenascin-C are 
involved in the process of fibrosis in patients with IPF together with abnormal 
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of subepithelial fibroblastic foci.  IL-13 and IL-4 are strong inducers of tissue fibrosis.  
In nonclinical models, transgenic overexpression of IL-13 in the lungs of mice is 
sufficient to induce collagen gene expression and profound subepithelial fibrosis 
(Zhu et al. 1999; Lee et al. 2001).  Conversely, mice with targeted disruption of IL-13 and 
mice that are treated with blocking antibodies specific for IL-13 show reduced 
extracellular matrix deposition in bleomycin- and fluorescein isothiocyanate−induced 
pulmonary fibrosis models (Belperio et al. 2002; Kolodsick et al. 2004; Liu et al. 2004). 
Multiple studies have concluded that expression and activity of IL-13 is elevated 
in patients with IPF.  The expression of IL-13 and IL-13 receptors (IL-13Rs) IL-13Rα1 
and IL-13Rα2 was found to be increased in lung biopsy samples from patients with IPF 
compared with normal controls, both at the messenger RNA and protein level 
(Jakubzick et al. 2004).  IL-13 was also found to be elevated in the bronchoalveolar 
lavage fluid from patients with IPF compared with normal controls.  Importantly, the level 
of IL-13 in these samples was negatively correlated with the key measures of lung 
function, percentage of predicted forced vital capacity (FVC), and diffusion capacity 
of the lung for carbon monoxide (DLCO) (Park et al. 2009), suggesting pathogenic 
functions of IL-13 in patients with IPF. 
In addition to IL-13 itself, serum biomarkers known to be expressed downstream 
from IL-13 signaling have also been shown to be elevated in patients with IPF.  Periostin, 
an IL-13−inducible protein with a serum level that correlates with benefit from treatment 
with lebrikizumab in patients with asthma (Woodruff et al. 2007; Corren et al. 2011), is 
also elevated in the serum of patients with IPF (Okamoto et al. 2011; Naik et al. 2012).  
These elevated periostin levels have been shown to be negatively correlated with 
pulmonary function parameters (i.e., FVC and DLCO) over a 6-month period 
(Okamoto et al. 2011).  Periostin has been proposed to be a pathogenic factor in IPF on 
the basis of reduced bleomycin-induced pulmonary fibrosis observed in 
periostin-deficient mice, suggesting an additional mechanism by which IL-13 may 
contribute to disease (Uchida et al. 2012).  IL-13 signaling also induces robust 
production of chemokine (C-C motif) ligand 18 (CCL18) from macrophages in vitro, and 
alveolar macrophages isolated from patients with IPF⎯but not from normal 
controls⎯constitutively express CCL18 protein (Prasse et al. 2006).  Like periostin, 
CCL18 is increased in the serum of patients with IPF.  CCL18 levels are reported to 
correlate with disease progression and prognosis, with patients who have higher levels 
of baseline CCL18 experiencing a greater decline in FVC and higher mortality rates 
(Prasse et al. 2007, 2009).  Taken together, these data strongly suggest that IL-13 
expression is elevated in patients with IPF and that signals from this cytokine to multiple 
fibrosis-relevant cell types play a key role in driving disease pathogenesis. 
1.4 
BENEFIT-RISK ASSESSMENT 
IPF is characterized by progressive worsening of dyspnea and lung function and is 
associated with a poor prognosis (Raghu et al. 2011).  Median survival following 


 
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diagnosis is 2 to 5 years (Cottin 2012).  Two approved therapies are now available in the 
United States and Europe with the recent approval of ESBRIET and OFEV by the FDA 
and the EC in addition to the original approval of pirfenidone for IPF treatment in Japan. 
Both therapeutics provide similar effects on slowing the loss of lung function, measured 
as forced vital capacity percent (FVC)percentage of predicted; however, no benefit was 
achieved with respect to dyspnea, quality of life, or other clinically meaningful outcomes 
(King et al. 2014; Richeldi et al. 2014).  Consequently, unmet medical need for this 
condition remains high, and a need remains to develop new treatments, such as 
lebrikizumab, that may offer additional clinical benefit by interfering with a fibrotic 
pathway. 
Given the evidence supporting a key role for IL-13 in disease pathogenesis, there is a 
compelling rationale to consider targeted anti−IL-13 therapy in patients with IPF. 
The Sponsor unblinded the treatment assignment in Cohort A of the study in May 2016, 
and conducted the planned analysis of this placebo-controlled cohort to assess the 
benefit of lebrikizumab monotherapy in accordance with this protocol.  No 
clinically-meaningful treatment difference was observed between the lung function 
endpoints; however, the trends that were observed for the 6-minute walk test (6MWT) 
distance and A Tool to Assess Quality of Life in Idiopathic Pulmonary Fibrosis 
(ATAQ-IPF) were in favor of treatment with lebrikizumab.  There was no evidence of 
safety concerns in Cohort A and the cohort safety profile was generally consistent with 
the safety profile observed in previous asthma studies with lebrikizumab. 
The Sponsor performed an interim futility analysis for Cohort B in August 2016.  
Taken together, the Sponsor decided to continue the study for the Cohort A extension 
and Cohort B per the protocol. 
At this time, the benefit-risk ratio supports the continuation of this Phase II study of 
lebrikizumab in patients with IPF. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is to evaluate lebrikizumab compared with 
placebo as monotherapy or as combination therapy with pirfenidone background 
compared with placebo in patients with IPF, as measured by the annualized rate of 
decline in percentage of predicted FVC over 52 weeks. 
The secondary efficacy objectives are to evaluate lebrikizumab compared with placebo 
as monotherapy or as combination therapy with pirfenidone background therapy 
compared with placebo in patients with IPF as measured by:  
• 
The efficacy on the basis of PFS, pulmonary function, diffusion capacity, 
non-elective hospitalization for any cause, acute IPF exacerbation, proportion of 


 
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patients with at least 10% decline in percentage of predicted FVC or death, and all 
cause death 
• 
The distance walked in 6 minutes and health-related quality of life questionnaires 
 
2.2 
SAFETY OBJECTIVES 
The safety objectives for this study are the following: 
• 
To evaluate the safety of lebrikizumab as monotherapy compared with placebo in 
patients with IPF  
• 
To evaluate the safety of lebrikizumab with pirfenidone as background therapy 
compared with placebo with pirfenidone as background therapy in patients with IPF 
 
2.3 
PHARMACOKINETIC OBJECTIVE 
The PK objective for this study is to characterize the pharmacokinetics of lebrikizumab 
in patients with IPF. 
2.4 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To evaluate the efficacy of lebrikizumab compared with placebo as monotherapy or 
as combination therapy with pirfenidone compared with placebo in patients with IPF 
on the basis of changes in quantitative lung fibrosis (QLF) score on HRCT, ATAQ, 
and the BORG Category Ratio 10 Scale® (BORG CR10), and time to first 
occurrence of the St. George’s Respiratory Questionnaire (SGRQ) individual 
domain worsening as defined by reaching minimal important difference (MID; 
Swigris et al. 2010). 
• 
To evaluate potential prognostic and predictive serum, and whole blood RNA and 
DNA biomarkers associated with IPF 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study Design 
This is a randomized, multicenter, double-blind, placebo-controlled, parallel-group study 
of lebrikizumab in patients with IPF.  Approximately 480 patients with a diagnosis of IPF 
will be enrolled in the study across two cohorts (approximately 150 patients in Cohort A 
having approximately 75 patients per treatment arm and approximately 330 patients in 
Cohort B having approximately 165 patients per treatment arm) at approximately 
120 sites located globally.  The total treatment duration will be based on all patients 
receiving at least 13 doses (one dose every 4 weeks [Q4W]) of blinded treatment over 
48 weeks.  The study primary endpoint will measure the absolute change from baseline 
to Week 52 in percentage of predicted FVC. 


 
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Two cohorts of patients will be enrolled in the study; Cohort A patients will be treated in 
the absence of pirfenidone IPF background therapy; Cohort B patients will be treated 
with pirfenidone as background therapy. 
Cohort A (monotherapy) approximately 150 patients will be randomized 1:1 to 
lebrikizumab (250 mg SC) every 4 weeks or placebo in the absence of background IPF 
therapy. 
Cohort B (combination therapy) approximately 330 patients will be treated daily with the 
maximum tolerated dose of pirfenidone ≤ 2403 mg/d, and randomized 1:1 to either 
lebrikizumab (250 mg SC) every 4 weeks or placebo. 
Patients who provide written informed consent will commence a screening period, 
which will last 28 days (± 14 days) to establish entry criteria.  During the screening period, 
patients will have their IPF diagnosis (i.e., HRCT ± surgical lung biopsy [SLB]) confirmed 
by central review based upon the 2011 ATS/ERS/JRS/ALAT guidelines. 
For Cohort B/combination therapy, patients may initiate screening on a stable dose of 
pirfenidone or free of background IPF therapy.  After completing the initial screening 
assessments (28d ± 14d), eligible patients who are naive or not currently treated with 
pirfenidone will initiate the pirfenidone titration run-in period (4-6 weeks) with Visit 1.5 to 
allow for titration of pirfenidone to a dose of 2403/mg/d as per label (three 267 mg 
capsules three times a day [9 capsules daily] with food for a total of 2403 mg/day) or to 
the highest dose tolerated or recommended dose per country specific guidelines 
(see Section 4.3.4).  Patients who are unable to complete the titration run-in period will 
be considered run-in failures. 
At the end of the screening period, and applicable qualifying pirfenidone titration run-in 
period for patients requiring pirfenidone titration, eligible patients will be randomized in a 
1:1 ratio within each cohort to double-blind treatment with SC lebrikizumab 250 mg 
or placebo.  Dynamic hierarchical randomization will be performed centrally and stratified 
by region (United States, Europe/Canada, and other), lung function (FVC < 50%, 50% to 
75%, > 75% predicted), and serum periostin concentration (< 50 ng/mL, ≥ 50 ng/mL) in 
each cohort. 
Study drug will be administered by SC injection every 4 weeks, with the first injection 
occurring at the randomization visit (Day 1, Visit 2).  Patients will continue to receive 
blinded study treatment every 4 weeks during the placebo-controlled treatment period for 
a total of 13 doses/26 injections of blinded treatment.  Safety, efficacy, and patient 
reported outcomes will be assessed throughout the placebo-controlled study period as 
detailed in the schedule of assessments (see Appendix 1 and Appendix 3).  The primary 
efficacy endpoint is the absolute change from baseline to Week 52 in percentage of 
predicted FVC. 


 
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Patients in Cohort A who complete or exceed the minimum 52-week blinded 
placebo-controlled period (i.e., patients who have not prematurely discontinued study 
treatment) may continue into the 52-week open-label lebrikizumab treatment period.  All 
patients who continue into the 52-week open-label lebrikizumab treatment period will 
receive SC lebrikizumab at a dose of 250 mg every 4 weeks.  Exclusion of background 
IPF treatment is not required during this study period.  During the open-label 
lebrikizumab period, at the investigator’s discretion, a patient can start background 
therapy, including use of pirfenidone or other treatment, provided that it is an approved 
therapy for IPF in the applicable region (e.g., European Union, Canada, Mexico, Peru, or 
Japan) (see Section 4.4.1.2).  Safety and efficacy will be measured as detailed in the 
schedule of assessments (see Appendix 2). 
All patients will return to the clinic approximately 4 weeks after their last dose of study 
drug to complete follow-up assessments at the end-of-treatment (EOT) visit 
(see Appendix 1, Appendix 2, and Appendix 3).  All patients will be followed-up for 
18 weeks after the last dose including two subsequent visits during a 14-week safety 
follow-up period as indicated in schedule of assessments (see Appendix 4).  Patients 
who choose to prematurely discontinue study drug will be encouraged to remain in the 
study and complete all remaining assessments.  If this is not feasible, the patient should 
enter and complete the safety follow-up period unless consent has been withdrawn. 
Measures of safety and efficacy will be assessed throughout the study as detailed in the 
schedule of assessments (see Appendix 1, Appendix 2, Appendix 3, and Appendix 4).  
The primary efficacy outcome measure for this study is the absolute change from 
baseline to Week 52 in percentage of predicted FVC.  A key secondary outcome will be 
PFS measured as the time from randomization to disease progression or death 
(see Section 2.2 and Section 3.3.1.1 for details).  All other secondary and exploratory 
efficacy outcomes will be measured at Week 52 and at various other timepoints 
throughout the study. 
A schedule of assessments is provided in Appendix 1, Appendix 2, Appendix 3, and 
Appendix 4 and a study schema is provided in Figure 1. 


 
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Figure 1 Study Schematic 
 
 
 
3.1.2 
Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct on an ongoing basis.  Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines the iDMC roles and responsibilities.  The iDMC will 
meet approximately every 6 months to review unblinded safety and study conduct data 
provided by an independent Data Coordinating Center (iDCC).  This will include a review 
of all deaths and hospitalizations reported on the adverse events forms.  The study may 
be stopped early for safety reasons.  If the iDMC determines that a benefit-risk 
assessment is necessary, the iDMC may also review unblinded efficacy data, although 
the iDMC may not recommend stopping the study for positive efficacy. 
3.1.3 
Internal Monitoring Committee 
 
 
 
 


 
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Details with regard to the IMC were documented in an IMC agreement. 
3.2 
END OF STUDY 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  
The LPLV is expected to occur a maximum of 118 weeks after the last patient is enrolled 
and randomized into Cohort A.  This timeframe includes a 52-week placebo-controlled 
period and a maximum of an additional 52 week open-label lebrikizumab treatment 
period followed by the safety follow-up period.  In the case that enrollment in Cohort B is 
slower than anticipated, LPLV is expected occur a maximum of 66 weeks after the last 
patient is enrolled and randomized into Cohort B.  This timeframe includes a 52-weeks 
placebo-controlled period followed by the safety follow-up period.  All patients will be 
followed for safety for 18 weeks after the last dose of study treatment of lebrikizumab or 
placebo by SC injection. 
3.2.1 
Rationale for Test Product Dosage 
Lebrikizumab is a huIgG4 that inhibits IL-13 signaling.  Both nonclinical and clinical data 
suggest that IL-13 signaling plays an important role in the pathogenesis of IPF 
(see Section 1.3).  The mechanism of action of lebrikizumab is to block the interaction 
between IL-13 and its receptor and hence the intracellular signaling of IL-13.  Because 
of the fast turnover of cytokines, it is hypothesized that optimal IL-13 blockade requires 
maintaining sustained concentrations of lebrikizumab in the lung.  Assuming that IL-13 
levels in the lung are in the range reported in the literature and the serum-to-lung ratio is 
1:500 (Hart et al. 2001), a serum concentration of 10 µg/mL would be expected to 
maintain sufficiently high drug levels in the lung to neutralize IL-13.  This target 
concentration is also consistent with the lower end of the observed Week 12 trough 
concentrations in the Phase II Study ILR4646g where lebrikizumab showed efficacy 
in reducing the rate of severe asthma exacerbations in patients whose asthma was 
uncontrolled despite inhaled corticosteroid therapy.  Similar to asthmatics, patients 
with IPF have elevated levels of biomarkers associated with IL-13 biology, suggesting 
that the concentrations of lebrikizumab producing clinical benefit in asthma may also 
produce biological activity in IPF. 


 
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For the Phase II study in patients with IPF, a 250 mg Q4W dose was selected 
to maintain steady-state serum trough concentrations at or above this target 
concentration.  Under the assumption that the pharmacokinetics of lebrikizumab 
in patients with IPF are similar to those in patients with asthma, this dose/regimen would 
be expected to maintain a mean steady-state trough concentration of approximately 
30 μg/mL.  Higher serum concentrations may be maintained in patients with IPF 
because less of the drug may partition into the lungs because of reduced microvascular 
supply in the damaged fibrotic lung tissue.  In addition, a 3-fold higher concentration 
above the target allows for potentially faster clearance of lebrikizumab if autoantibodies 
are present (Dobashi et al. 2000; Magro and Crowson 2003; 
Feghali-Bostwick et al. 2007; Papiris et al. 2012).  Selection of a 250-mg dose is also 
supported by the safety experience from previous asthma clinical studies. 
Lebrikizumab is eliminated via typical IgG clearance pathways, including nonspecific 
endocytosis and catabolism to amino acid products, which do not involve CYP450 
enzymes.  Therefore, any direct drug-drug interaction with small molecule drugs, 
including pirfenidone, is unlikely.  The PK of lebrikizumab in patients with IPF will be 
characterized in the Phase II study to ensure that the properties of the molecule in this 
indication are well understood.   
3.2.2 
Rationale for Pirfenidone Dosage 
For patients in Cohort B, the background dose of pirfenidone will be ≤ 2403 mg/d 
administered in divided doses three times per day (TID) with food.  Pirfenidone has been 
selected as background therapy for IPF based upon its broad approval by health 
authorities and availability throughout much of the world including in the 28 member 
states of the European Union, Japan, Canada, and United States.  Pirfenidone 
(ESBRIET or PIRESPA) has been shown to slow the loss of lung function, measured as 
percentage of predicted FVC, in patients with IPF in three Phase III clinical trials.  The 
summary of the safety data indicates that pirfenidone is generally well tolerated.  The 
most common adverse events reported in Phase III trials were gastrointestinal disorders 
and skin disorders, typically mild to moderate, and could be managed by dose 
adjustment.  In addition, the long term safety profile of pirfenidone has been well 
established with exposure in more than 1382 pirfenidone-treated patients from 14 clinical 
trials, (PFD IB) representing the experience from 2876 patient-exposure years and 
519 patients with ≥2y exposure (some up to 10 years).  The long-term safety profile was 
consistent with observations from Phase III clinical trials. 
3.2.3 
Rationale for Patient Population 
IPF is a heterogeneous disease with variable progression characterized by deterioration 
of lung function.  There is no established method of combining clinical or biomarker 
measures to accurately determine prognosis or define the stage of disease; therefore, 
the inclusion criteria have been set to include a broad population of patients with IPF.  
The study will target patients with a confirmed diagnosis of IPF consistent with the 


 
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diagnostic criteria published in the recent international ATS/ERS/JRS/ALAT guidelines 
(Raghu et al. 2011).  Consistent with these guidelines, HRCT will be required to confirm 
the diagnosis of IPF and to exclude other possible causes of ILD in patients considered 
for enrolment.  Surgical lung biopsies are not required for eligibility; however, those 
patients who have undergone such a procedure will have their slides adjudicated by 
central review to confirm eligibility in accordance with ATS/ERS/JRS/ALAT guidelines. 
The inclusion criteria for this Phase II study were selected to allow patients with a broad 
spectrum of IPF disease the opportunity to participate, as reflected in the lung function 
(% FVC ≥ 40% and ≤ 100%, % DLCO ≥ 25% and ≤ 90%), exercise capacity 
(6MWT ≥ 100 meters), and the length of time with disease (IPF diagnosis within previous 
5 years of screening Visit 1) entry criteria.  These parameters have been proposed to 
characterize disease severity and to identify patients who are likely to be influenced by 
the study intervention. 
The primary objective of Study GB28547 is to evaluate lebrikizumab as monotherapy or 
in combination with pirfenidone background therapy compared with placebo in a Phase II 
study in patients with a confirmed diagnosis of IPF.  Two cohorts of patients will be 
studied; Cohort A (patients with no IPF background medications) and Cohort B 
(patients who were treated with pirfenidone as background medication throughout the 
study period). 
Eligibility in Cohort A excludes current use of pirfenidone and other approved, 
investigational, or other widely used therapies for IPF because of the potential 
confounding effects these therapies may have on the efficacy and safety analysis of 
lebrikizumab monotherapy.  During the open-label lebrikizumab period, at the 
investigator’s discretion, a patient can start background therapy, including use of 
pirfenidone or other treatment, provided that it is a therapy for IPF approved in the 
applicable region (e.g., European Union, Canada, Mexico, Peru, or Japan) 
(see Section 4.4.1.2). 
Eligibility for Cohort B requires that all patients be on a maximum tolerated dose of 
pirfenidone ≤ 2403 mg/day as standard background therapy.  A minimum of 4 weeks of 
exposure to pirfenidone is required prior to randomization, anticipating 52 weeks of 
background therapy.  No other therapies may be used to treat IPF (see Section 4.4.1.2). 
The Principal Investigator should notify the Medical Monitor of proposed changes in 
concomitant IPF therapy prior to starting rescue therapy throughout the study for 
patients in either Cohort A or Cohort B. 
3.2.4 
Rationale for Primary and Disease Response-Based Endpoints 
In natural history settings of IPF, it is widely accepted that a decline in absolute FVC of 
10% or more is a surrogate marker of mortality (Raghu et al. 2011), and in the absence 


 
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of an alternative explanation, disease progression.  Smaller (5%−10%) but progressive, 
sustained declines in FVC may also represent disease progression (Zappala et al. 2010). 
Changes over time in a patient’s FVC (whether analyzed continuously or categorically 
above/below a threshold value) have been correlated with survival time in multiple large 
cohorts of patients with IPF (Collard et al. 2007; Flaherty et al. 2003; du Bois 2011). 
Furthermore, the FDA approvals of pirfenidone and nintedanib were based upon similar 
measures of FVC:  the change in percentage of predicted forced vital capacity (%FVC) 
from baseline to 52 weeks for pirfenidone and annual rate of decline in FVC.  Patients 
treated with pirfenidone had a 4.5% treatment benefit relative to placebo treated patients 
and a modest improvement in survival (HR (95% HR [95% CI] = 0.75 [0.51-1.11]) 
(pirfenidone FDA label).  Similar outcomes were observed in the OFEV trials 
(NEJM 2014 and product label). 
The primary endpoint of this Phase II study will be the absolute change from baseline to 
Week 52 (end of treatment) in percentage of predicted FVC. 
A key secondary endpoint in this study is PFS, which is defined as the time from study 
treatment randomization to the first occurrence of any one of the following events: 
• 
Death from any cause 
• 
Non-elective hospitalization for any cause 
• 
Decrease from baseline of ≥ 10% in FVC (L) (relative change) 
 
The most clinically relevant domain of the proposed PFS endpoint is all-cause mortality 
(du Bois 2010; Papiris et al. 2012; Raghu et al. 2012).  It is well defined, reliable, and 
easy to measure.  All-cause mortality avoids losing clinically relevant information and 
inducing informative bias that occurs when deaths related to the study intervention are 
misclassified as “unrelated” and are censored.  The all-cause mortality endpoint also 
captures potential off-target effects that could impact risk of mortality (Raghu et al. 2012). 
Although it is commonly reported that the median survival time of those diagnosed 
with IPF is 3 to 5 years (Cottin 2012), the individual clinical course can be highly variable 
and unpredictable.  In recent clinical trials the mortality rate in the placebo arms is 
consistently low highlighting that events of death are relatively rare in IPF trials 
(Wells et al. 2012).  The current design combines all-cause mortality with additional 
parameters that have been shown to correlate with survival to increase the overall event 
rate. 
The second PFS component, non-elective all-cause hospitalization, has validity 
in capturing disease progression leading to a decrease in patient health.  
Hospitalizations for those with IPF are often significant clinical events that carry a poor 
prognosis.  The majority of hospitalizations in this population are respiratory related and 
correlates to cause of death, which is usually due to progressive fibrosis rather than 


 
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commonly occurring comorbidities (Martinez et al. 2005; Ley et al. 2011).  Limitations 
of hospitalization endpoints include a variety of non−disease-related factors that can 
influence whether hospitalization occurs, such as access to health care, social support, 
and regional practice patterns, as well as the challenge of clinical data retrieval when a 
patient is hospitalized at a facility outside the study.  Despite these limitations, 
non-elective hospitalization remains a clinically meaningful endpoint (Raghu et al. 2011).  
Similar to all-cause mortality, the all-cause hospitalization endpoint also captures 
potential off-target effects that could impact risk of hospitalization. 
As stated above, it is widely accepted that a decline of 10% in a patient’s FVC is a sign 
of disease progression and therefore a useful prognostic factor (Raghu et al. 2011).  
Using a relative (rather than absolute) change in FVC maximizes the chance of 
identifying a ≥ 10% decline without sacrificing prognostic accuracy (Richeldi et al. 2011).  
Categorical decline of ≥ 10% in FVC (relative) is the third PFS component. 
3.2.5 
Rationale for Control Group 
A placebo-treated control group will be used in Cohort A of this study and a 
pirfenidone + placebo-treated control group will be used in Cohort B to assess the 
differences in pulmonary function, PFS, IPF-specific health-related quality of life, and 
safety in patients who receive lebrikizumab compared with patients who receive placebo.  
The use of a control group is necessary given the variability in the clinical course seen 
with different IPF cohorts in other clinical studies.  Patients in the control group will 
undergo the same study assessments as the lebrikizumab-treated patients. 
During the placebo-controlled periods, N-acetylcysteine or IPF therapy approved by 
local regulatory authorities can be initiated only after a confirmed progression event 
(≥ 10% decrease in FVC or non-elective hospitalization).  No other therapies for IPF can 
be started at any time during the study. 
For patients assigned to Cohort B, other approved therapies may be initiated in the 
absence of disease progression if pirfenidone is stopped because of safety considerations 
(see Section 4.4.1.2). 
3.2.6 
Rationale for Biomarker Assessments 
The study will include a significant exploratory component focused on identification 
of biomarkers that may be prognostic for patients likely to have an accelerated rate 
of disease progression or diagnostic for identifying patients likely to benefit 
from treatment with lebrikizumab.  Periostin is an IL-13−inducible protein with a serum 
level that correlates with benefit from treatment with lebrikizumab in patients with asthma 
(Woodruff et al. 2007; Corren et al. 2011).  Periostin is also elevated in the serum 
of patients with IPF, and these levels have been shown to be negatively correlated 
with pulmonary function parameters (FVC and DLCO) over a 6-month period 
(Okamoto et al. 2011; Naik et al. 2012).  Periostin has been proposed to be a pathogenic 
factor in IPF on the basis of reduced bleomycin-induced pulmonary fibrosis observed 


 
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in periostin-deficient mice, suggesting an additional mechanism by which IL-13 may 
contribute to disease (Uchida et al. 2012). 
Serum levels of periostin appear to have a distribution in patients with IPF similar to what 
has been observed in patients with asthma.  Patients will be stratified across each 
treatment arm on the basis of periostin levels, tertiary to region, and baseline FVC.  
Patients with baseline periostin ≥ 50 ng/mL will be considered periostin high, and 
patients with baseline periostin < 50 ng/mL will be considered periostin low 
(Corren et al. 2011). 
Serum and plasma samples will be collected during screening, at baseline and 
throughout the study, and at unscheduled visits to assess the relationship between 
periostin and other IL-13− and IPF-related biomarkers, disease progression, clinical 
status, and treatment benefit.  Other IL-13− and IPF-related biomarkers that will be 
investigated may include but are not limited to CCL18, YKL40, COMP, OPN, CCL17, 
and CCL13.  If novel IL-13– or IPF−related biomarkers are identified, they may be 
measured from stored serum or plasma. 
3.3 
OUTCOME MEASURES 
3.3.1 
Efficacy Outcome Measures 
3.3.1.1 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure for this study is the annualized rate of decrease 
in percentage of predicted FVC over 52 weeks (% FVC/year). 
3.3.1.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Annualized rate of decline in 6MWT distance over 52 weeks 
• 
Time from randomization to first occurrence of a ≥ 10% absolute decline in 
percentage of predicted FVC or death from any cause 
• 
Annualized rate of decrease in percentage of predicted DLCO over 52 weeks 
• 
PFS, defined as the time from study treatment randomization to the first occurrence 
of any of the following disease progression or death events: 
Death from any cause 
All-cause hospitalization 
A decrease from baseline (relative change) of ≥ 10% in FVC (mL/year) 
• 
Annualized rate of decrease in FVC over a 52-week period (mL/year) 
• 
Annualized rate of decrease in ATAQ-IPF total score over a 52-week period 
(see Appendix 5 for a description of the instrument) 
• 
Time from randomization to first occurrence of the SGRQ (see Appendix 5 for a 
description of the questionnaire) worsening (total score) as defined by reaching 
MID (Swigris et al. 2010):  Total Score = 7 or death from any cause 


 
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• 
Time from randomization to non-elective hospitalization or death from any cause 
• 
Time from randomization to first event of acute IPF exacerbation as defined below: 
IPF exacerbation is defined as an event that meets all of the following criteria as 
determined by the investigator: 
Unexplained worsening or development of dyspnea within the previous 30 days 
And radiologic evidence of new bilateral ground-glass abnormality or 
consolidation superimposed on a reticular or honeycomb background pattern 
that is consistent with UIP 
And absence of alternative causes, such as left heart failure, pulmonary 
embolism, pulmonary infection (on the basis of endotracheal aspirate or 
bronchoalveolar lavage, if available, or investigator judgment), or other events 
leading to acute lung injury (e.g., sepsis, aspiration, trauma, reperfusion 
pulmonary edema) 
 
3.3.2 
Safety Outcome Measures 
All safety outcome measures will be assessed by comparing results from the 
lebrikizumab treatment group with the placebo group.  The safety outcome measures 
for this study are as follows: 
• 
Frequency of adverse events during the study 
• 
Severity of adverse events during the study 
• 
Incidence of anti-therapeutic antibodies (ATAs) against lebrikizumab throughout the 
study 
 
3.3.3 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Serum lebrikizumab concentration at Week 52 (Cwk52) 
• 
Predose serum lebrikizumab concentrations (Cmin) at Weeks 4, 12, 24, and 36 
(Cmin,Wk4, Cmin,Wk12, Cmin,Wk24, and Cmin,Wk36) 
• 
Elimination half-life of lebrikizumab 
 
3.3.4 
Exploratory Outcome Measures 
The exploratory outcome measures for this study include the following: 
• 
Change from baseline to Week 52 in radiographic findings on pulmonary HRCT, 
including QLF score 
• 
Change from screening (corresponding to timing for randomization strata) in 
serum and plasma biomarkers (e.g., periostin and CCL18) and change from 
baseline in serum and plasma biomarkers (e.g., periostin, CCL18, YKL40, COMP, 
OPN, CCL13) 
• 
Serum lebrikizumab concentrations during the extended treatment and the 14-week 
safety follow-up period 


 
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• 
Exposure-response relationships (to be evaluated as warranted) 
• 
Change from baseline to Week 52 in the Borg CR10 Scale 
• 
Change from baseline to Week 52 in the ATAQ-IPF 
• 
Time from randomization to first occurrence of SGRQ individual domain 
worsening as defined by reaching MID (Swigris et al. 2010):  Symptom = 8, 
Activity = 5, Impact = 7, or death from any cause 
• 
Change from baseline to Week 52 in the SGRQ 
 
The analysis plan for the exploratory HRCT and biomarkers will be specified in a 
separate document. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately 480 patients ≥ 40 years of age who have a diagnosis of IPF are enrolled 
in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Able and willing to provide written informed consent and to comply with the study 
protocol 
• 
Age ≥ 40 years at Visit 1 
• 
Have a diagnosis of IPF based on the ATS/ERS/JRS/ALAT consensus statement on 
IPF (Raghu et al. 2011) within the previous 5 years from time of screening and 
confirmed at baseline 
• 
Have a central review assessment of an HRCT performed during the screening 
period or within 12 months prior to the start of screening. 
All patients who have undergone an SLB as part of their initial workup should 
have pathology slides sent in for SLB central review assessment. 
Eligibility will be determined on the basis of assessments in Table 1. 
• 
A Multidisciplinary Discussion of Diagnosis (MDD) based on 2011 
ATS/ERS/JRS/ALAT guidelines will be utilized to finalize the diagnosis in the event 
the initial central review outcome results for HRCT and SLB are disparate 
(inconsistent with UIP/definite UIP). 
 


 
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Table 1 
Combined High-Resolution Computed Tomography and Surgical 
Lung Biopsy Eligibility Assessment 
Surgical Lung Biopsy Assessment 
HRCT 
Assessment 
Definite UIP 
Probable 
UIP 
Possible 
UIP 
Non-
Classifiable 
Fibrosis 
Inconsistent 
with UIP 
No SLB 
Definite UIP 
Eligible 
Eligible 
Eligible 
Eligible 
Not eligible 
Eligible 
Possible UIP 
Eligible 
Eligible 
Eligible 
Eligible 
Not eligible 
Eligible 
Inconsistent 
with UIP 
May be 
eligible/MDD 
Not eligible Not eligible
Not eligible 
Not eligible 
Not eligible 
HRCT = high-resolution computed tomography; MDD = Multidisciplinary Discussion of Diagnosis; 
SLB = surgical lung biopsy; UIP = usual interstitial pneumonia. 
 
Additionally, patients must meet the following criteria for study entry: 
• 
FVC ≥ 40% and ≤ 100% of predicted at screening 
• 
Stable baseline lung function as evidenced by a difference of < 10% in FVC (L) 
measurements between screening and Day 1, Visit 2 prior to randomization 
• 
DLCO ≥ 25% and ≤ 90% of predicted at screening 
• 
Ability to walk ≥ 100 meters unassisted in 6 minutes 
• 
Cohort A:  No background IPF therapy for ≥ 4 weeks allowed prior to randomization 
and throughout the placebo-controlled study period 
• 
Cohort B:  Tolerated dose of pirfenidone ≤ 2403 mg/QD for ≥ 4 weeks required prior 
to randomization and throughout the placebo-controlled study period 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
History of a severe allergic reaction or anaphylactic reaction to a biologic agent or 
known hypersensitivity to any component of the lebrikizumab injection 
• 
Evidence of other known causes of ILD (e.g., domestic and occupational 
environmental exposures, connective-tissue disease [CTD], and drug toxicity) 
• 
Lung transplant expected within 12 months of screening 
• 
Evidence of clinically significant lung disease other than IPF (e.g., asthma or COPD) 
• 
Post-bronchodilator forced expiratory volume in 1 second (FEV1)/FVC 
ratio < 0.7 at screening 
• 
Positive bronchodilator response evidenced by an increase of ≥ 12% predicted and 
200 mL increase in either FEV1 or FVC 


 
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• 
Any clinically significant medical disease (other than IPF) that is associated with an 
expected survival of < 12 months, likely to require a change in therapy during the 
study, or likely to impact the ability of the patient to participate in the study in the 
opinion of the investigator, or impact the study efficacy or safety assessments 
• 
Requirement for continuous medical care and assistance or limited ability 
to self-care that would impact the ability of patient to participate in the study or 
to perform the study-related assessments 
• 
Class IV New York Heart Association chronic heart failure or historical evidence 
of left ventricular ejection fraction < 35% 
• 
Hospitalization due to an exacerbation of IPF within 4 weeks prior to or 
during screening 
• 
Known current malignancy or current evaluation for a potential malignancy 
• 
Major episode of infection requiring any of the following: 
Admission to the hospital for ≥ 24 hours within 4 weeks prior to screening 
or during screening and run-in period 
Treatment with antibiotics (IV, IM, oral, or inhaled) within 4 weeks prior to 
screening or during screening and run-in period 
• 
An active upper or lower respiratory tract infection occurring at any time within the 
screening period prior to the randomization visit (Visit 1 to Day 1, Visit 2) 
• 
Listeria monocytogenes infection or active parasitic infection within 6 months 
prior to Day 1, Visit 2 
• 
Active tuberculosis requiring treatment within 12 months prior to screening 
• 
Known immunodeficiency, including but not limited to HIV infection 
• 
Past use of any anti–IL-13 or anti–IL-4/IL-13 therapy, including lebrikizumab 
Patients participating in a clinical trial that has not been unblinded should be 
assumed to have received the active drug 
• 
Evidence of acute or chronic hepatitis or known liver cirrhosis 
• 
AST, ALT, or total bilirubin elevation ≥ 2.0 × the upper limit of normal 
during screening 
• 
Clinically significant abnormality on ECG at screening or laboratory tests 
(hematology, serum chemistry, and urinalysis) that, in the opinion of the investigator, 
may pose an additional risk in administering study drug to the patient 
• 
Receipt of a live/attenuated vaccine within the 4 weeks prior to Visit 1 
• 
Chronic treatment with any of the following within 4 weeks or five half-lives prior to 
screening (whichever is longer) to the end of the placebo-controlled period (Day 365, 
Visit 16): 
Immunosuppressive or immunomodulatory therapies (e.g., azathioprine, 
cyclosporine A, cyclophosphamide, D-penicillamine, interferon-gamma, tumor 
necrosis factor-α antagonists) 


 
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Cytotoxic drugs (e.g., colchicine) if used for IPF indication 
Pirfenidone (Exclusion Limited to Cohort A) 
N-acetylcysteine 
Pulmonary hypertension therapies (e.g., endothelin receptor antagonist, 
phosphodiesterase type-5 inhibitor, riociguat, prostacyclin or prostacyclin 
analogue) 
Tyrosine kinase inhibitors including exclusion of nintedanib for Cohort A and 
Cohort B 
Warfarin or other anticoagulant therapy if given for IPF indication 
Any unlicensed therapy given for the indication of IPF 
Any investigational agent 
• 
Chronic oral corticosteroid therapy is not permitted within 4 weeks prior to screening 
(Visit 1), during screening and run-in, or throughout the study period 
• 
History of alcohol, drug, or chemical abuse that would impair or risk the patient’s full 
participation in the study, in the opinion of the investigator 
• 
Female patients of reproductive potential who are not willing to use a highly effective 
method of contraception (e.g., contraceptive pill or transdermal patch, spermicide 
and barrier [i.e., condoms], intrauterine device, implants for contraception, injections 
for contraception [with prolonged release], hormonal vaginal device, sterilization, 
surgical tubal ligation) for the duration of the study and for at least 18 weeks after 
the last dose of lebrikizumab or placebo study treatment) (see Appendix 9) 
• 
Pregnant or lactating 
• 
Body weight < 40 kg 
 
4.1.2.1 
Additional Exclusions Limited to Cohort B (Pirfenidone 
Background) 
• 
Known achalasia, esophageal stricture, or esophageal dysfunction sufficient to limit 
the ability to swallow oral medication 
• 
Tobacco smoking or use of tobacco-related products within 3 months of screening 
or unwillingness to avoid smoking throughout the study (e.g., cigarette, pipe, cigar) 
• 
Any condition that, as assessed by the investigator, might be significantly 
exacerbated by the known side effects associated with pirfenidone 
• 
Known or suspected peptic ulcer 
• 
Creatinine clearance < 40 mL/min, calculated using the Cockcroft-Gault formula  
• 
Ongoing use of the following therapies or agents within 4 weeks of randomization 
(Day 1, Visit 2), or during the study 
Strong inhibitors of CYP1A2 (e.g., fluvoxamine or enoxacin) 
Moderate inducers of CYP1A2, limited to tobacco smoking and 
tobacco-related products 
 


 
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4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Patients will be randomized to the treatment arms through the interactive 
voice/Web-based response system (IxRS).  After written informed consent has been 
obtained, all patients will receive a screening number, which will be assigned by the 
IxRS.  Following completion of the screening period and after all patient eligibility 
requirements are confirmed on Day 1, patients will be assigned an identification number 
(a different number from the screening number) and will be randomized in a 1:1 ratio 
to one of two treatment arms (Cohort A - lebrikizumab 250 mg SC or placebo SC every 
4 weeks; Cohort B - lebrikizumab 250 mg SC and pirfenidone ≤ 2403 mg/d or placebo 
SC every 4 weeks and pirfenidone≤ 2403 mg/d) for the 52-week placebo-controlled 
study period.  Patients will be randomized on the same day that treatment is to be 
initiated (Day 1, Visit 2).  Dynamic hierarchical randomization will be performed centrally 
and stratified by region (United States, Europe/Canada, other), lung function (FVC < 50%, 
50% to 75%, > 75% predicted), and serum periostin concentration (< 50 ng/mL, 
≥ 50 ng/mL) within each cohort.  During the placebo-controlled study period and the 
open-label lebrikizumab treatment period, the IxRS will make study treatment kit 
assignments.  IxRS will also make pirfenidone treatment kits available for patients in 
Cohort B.  At each dosing visit during the placebo-controlled period, study treatment kits 
will be assigned for administration.  The placebo and active kits are filled and packaged 
to look identical.  Patient randomization and the study treatment kit assignments will be 
verified on an ongoing basis by an external and independent statistical coordinating 
center to ensure that randomization and kit assignments are conducted correctly by 
the IxRS. 
Patients, all study site personnel, and the Sponsor and its agents (with the exception 
of the IxRS service provider, the external independent statistical coordinating center 
responsible for verifying patient randomization and study treatment kit assignments, 
PK/PD laboratory personnel, the iDMC and iDCC members) will be blinded to treatment 
assignment throughout the placebo-controlled period.  As described in Section 6, 
treatment assignment will be unblinded to the personnel performing the analysis when 
all data for the primary endpoint period are in the database and the data have been 
cleaned and verified.  
 
 
  However, patients and all study site personnel will remain 
blinded to individual treatment assignment until after the study is completed (after all 
patients have either completed the safety follow-up period or discontinued early from the 
study), the database is locked, and the study analyses are final. 
If unblinding is necessary for patient management (in the case of a serious adverse 
event), the investigator will be able to break the treatment code by contacting the IxRS.  
Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study treatment for any other reason, he 
or she should contact the Medical Monitor directly.  The investigator should document 


 
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and provide an explanation for any premature unblinding (e.g., accidental unblinding or 
unblinding because of a serious adverse event). 
As per health authority reporting requirements, Roche will break the treatment code 
for all unexpected serious adverse events (see Section 5.7) that are considered by the 
investigator to be related to study drug. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Lebrikizumab and Placebo 
 
 
 
 
 
 
 
  
 
 
 
 
 
For further details, see the Lebrikizumab IB. 
4.3.2 
Pirfenidone/Background Treatment in Cohort B  
ESBRIET (pirfenidone) is approved in a 267-mg capsule dosage form.  The 
recommended dose is 801 mg (i.e., three 267-mg capsules) TID, at the same times each 
day, taken with food (total dose, 2403 mg/d) (Section 4.3.4).  ESBRIET is packaged in a 
250-cc HDPE bottle.  For information on the formulation, packaging, and handling of 
pirfenidone see the local prescribing information for ESBRIET or PIRESPA in Japan or 
the pirfenidone IB.  For patients treated with PIRESPA (limited to Japan), dose titration 
and management of adverse effects should be based upon guidance in the marketed 
product label including a maximum recommended dose ≤1800 mg/d.  Investigators are 
advised to follow the country specific guidance for dose titration and handling. 
Pirfenidone, licensed as ESBRIET or PIRESPA, may be locally sourced for patients with 
access through their healthcare provider until it is provided by the Sponsor as IMP 
through the IxRS system. 


 
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4.3.3 
Dosage, Administration, and Compliance 
4.3.3.1 
Lebrikizumab and Placebo (Cohort A) 
Patients in Cohort A and Cohort B who meet all eligibility criteria will be randomly 
assigned to receive lebrikizumab 250 mg or placebo Q4W for the 52-week placebo 
controlled period.   
Treatment with lebrikizumab or placebo will be by SC injection in the arm, thigh, or 
abdomen.  All patients will receive a total of two injections per dosing visit.  Each 
injection should be administered in a separate location at least 10 cm from the other 
injection site at each dosing visit.  Study sites will be asked to record each injection site.  
Patients will be monitored for a minimum of 1 hour after dosing for the first three 
treatment visits and for 30 minutes for all subsequent treatment visits.  Each patient will 
receive a minimum of 13 doses (2 injections per dose) of study treatment during the 
placebo-controlled, blinded, study treatment period.  Patients in Cohort A who enrolled in 
the study prior to this amendment may receive up to 31 doses of blinded study treatment 
based upon previous version of this protocol.  No dosage modification is permitted 
during the study. 
Patients in Cohort A will receive an additional 52 weeks of open-label lebrikizumab 
(13 doses) in the open-label lebrikizumab treatment period after completion of the 
placebo controlled period. 
4.3.4 
Pirfenidone Background Treatment 
The recommended dose of pirfenidone is 2403 mg/d (or 1800 mg/d for patients in Japan) 
administered in divided doses three times per day (TID) with food.  Initial pirfenidone 
treatment should be titrated over 14 days, as tolerated, to the full dose of 9 capsules per 
day (three capsules TID), as follows: 
• 
Days 1–7: one capsule TID 
• 
Days 8–14: two capsules TID 
• 
Day 15 and continuing: three capsules TID (maximum of 9 capsules daily) 
 
Each dose should be taken with food, at approximately the same times each day.  
Patients will remain on a stable maintenance dose for the duration of the study period 
unless the dose is reduced to manage an AE.  All doses of pirfenidone are to be taken 
with food to reduce the likelihood of gastrointestinal symptoms.  The dose titration period 
of 14 days at the initiation of treatment is designed to maximize tolerability.  Exposure to 
sunlight (including sunlamps and tanning beds) should be avoided to minimize the 
possibility of photosensitivity reactions or rash.  Patients should be instructed to use 
sunscreens that have a sun protection factor (SPF) of 50 or higher as well as protection 
against ultraviolet A (UV-A) and ultraviolet B (UV-B) radiation.  Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 5.1.4.  
For patients treated with PIRESPA (limited to Japan), dose titration and management of 


 
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adverse effects should be based upon guidance in the marketed product label including 
a maximum recommended dose ≤ 1800 mg/d (Costabel et al. 2014). 
If a patient experiences significant side effects, treatment of symptoms and/or temporary 
dose modifications should be considered.  The decision to modify pirfenidone dosing is 
ultimately the responsibility of the investigator; however, occasional day-to-day variability 
in dosing due to patient initiative and preference is expected to occur. 
Patients who enter the pirfenidone titration run-in period will be monitored for a minimum 
of 4 weeks and up to 6 weeks after screening and prior to randomization, to allow for 
dose modifications due to tolerability issues and to limit the requirement for dose 
adjustment during the 52-week study period. 
Any overdose or incorrect administration of pirfenidone should be noted on the 
pirfenidone administration eCRF.  Adverse events associated with either an overdose or 
incorrect administration of pirfenidone should be recorded on the Adverse Event eCRF. 
4.3.5 
Investigational Medicinal Product Accountability 
The investigational medicinal product (IMP) required for completion of this study 
(i.e., lebrikizumab and pirfenidone) will be provided by the Sponsor.  Pirfenidone, 
licensed as ESBRIET or PIRESPA, may be locally sourced for patients with access 
through their healthcare provider until provided by the Sponsor as IMP through the IxRs 
system.  The investigational site will acknowledge receipt of the IMP, using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced. 
The IMP will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or be returned to the Sponsor with the 
appropriate documentation.  The site's method of IMP destruction must be agreed 
upon by the Sponsor.  The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form. 
Accurate records of all IMP received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.6 
Post-Study Access to Lebrikizumab and Pirfenidone 
The Sponsor will offer post-study access to the study drug lebrikizumab and/or 
pirfenidone free of charge to eligible patients in accordance with the Roche Global Policy 
on Continued Access to Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 


 
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• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any applicable legal or 
regulatory requirements 
 
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or would not 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest 
that the study drug is not effective for IPF 
• 
The Sponsor has reasonable safety concerns about the study drug as treatment 
for IPF 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following location:  
http://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_t
rials/global_standards.htm. 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy 
Concomitant therapy is defined as any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal/homeopathic remedies, and nutritional supplements) 
used by a patient from 7 days prior to screening to the study completion/early 
termination visit.  All concomitant medications should be reported to the investigator and 
recorded on the Concomitant Medications electronic Case Report Form (eCRF). 
4.4.1.1 
Corticosteroids 
Chronic maintenance oral corticosteroid therapy, defined as daily or alternate day oral 
corticosteroid maintenance therapy is not permitted within the 4 weeks prior to screening 
Visit 1, during screening and run-in, or throughout the study period.  Short-term 
treatment with corticosteroids (≤ 4 weeks) with subsequent corticosteroid dose tapering 
is permitted for patients who experience an acute IPF exacerbation as defined in 
Section 4.5.12. 
4.4.1.2 
Rescue Therapy 
Patients in Cohort A who experience confirmed disease progression (≥ 10% decline in 
FVC [mL/year; relative change] or non-elective hospitalization) during the 
placebo-controlled study period will be allowed, at the investigator’s discretion, to start 
rescue therapy, including use of pirfenidone or other IPF treatment provided that it is a 
therapy for IPF approved in the applicable region (e.g., European Union, Canada, 


 
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Mexico, Peru, or Japan).  Patients who start rescue therapy will be allowed and 
encouraged to remain in the study and continue study treatment. 
During the open-label lebrikizumab study period, at the investigator’s discretion, a 
patient can initiate additional therapy for IPF that is approved in the applicable region 
(e.g., European Union, Canada, Mexico, Peru, or Japan) without evidence of disease 
progression.  
Patients in Cohort B who experience a confirmed disease progression (≥ 10% decline in 
FVC [mL/Year; relative change] or non-elective hospitalization) during the placebo 
controlled study period should continue the study drug medication, including background 
pirfenidone.  However, at the investigator’s discretion, the initiation of rescue therapy 
that is approved by local regulatory authorities is allowed.  Combination treatment with 
pirfenidone and nintedanib is not permitted throughout the study, given lack of adequate 
safety information on this drug combination.  Patients in Cohort B may initiate other 
approved therapies in the absence of disease progression if pirfenidone is stopped 
because of safety considerations.  The Principal Investigator should notify the Medical 
Monitor of proposed changes in concomitant IPF therapy prior to starting rescue therapy 
for patients in either Cohort A or Cohort B throughout the study. 
Patients who start rescue therapy must begin appropriate monitoring per the prescribing 
information for that therapy.  All safety laboratory assessments, including those required 
for the prescribed rescue medication, should be analyzed by the central laboratory 
utilized for the GB28547 clinical study. 
4.4.2 
Prohibited Therapy 
• 
Chronic treatment with any of the following within 4 weeks or five half-lives prior to 
screening (whichever is longer) to the end of the placebo-controlled period (Day 365, 
Visit 16) 
Immunosuppressive or immunomodulatory therapies (e.g., azathioprine, 
cyclosporine A, cyclophosphamide, D-penicillamine, interferon-gamma, tumor 
necrosis factor-α antagonists) 
Cytotoxic drugs (e.g., colchicine) if used for IPF indication 
Pirfenidone (exclusion limited to Cohort A) 
N-acetylcysteine 
Pulmonary hypertension therapies (e.g., endothelin receptor antagonist, 
phosphodiesterase type-5 inhibitor, riociguat, prostacyclin, or prostacyclin 
analogue) 
Tyrosine kinase inhibitors including nintedanib for Cohort A and Cohort B 
Warfarin or other anticoagulant therapy if given for IPF indication 
Any unlicensed therapy given for the indication of IPF 
Any investigational agent 


 
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• 
Chronic oral corticosteroid therapy is not permitted within 4 weeks prior to screening 
(Visit 1), during screening and run-in, or throughout the study period. 
• 
N-acetylcysteine or IPF therapy approved by local regulatory authorities can be 
initiated in the event of disease progression as per Section 4.4.1.2.  Patients in 
Cohort B may initiate other approved IPF therapies in the absence of disease 
progression if pirfenidone is stopped because of safety considerations. 
• 
No other therapies for IPF can be started at any time during the study. 
 
4.4.2.1 
Prohibited Therapy Limited to Cohort B (Background 
Pirfenidone) 
• 
Ongoing use of the following therapies or agents within 4 weeks of randomization 
(Day 1, Visit 2) or at the initiation of pirfenidone (whichever is longer) to the end of 
the safety follow-up period 
Strong inhibitors of CYP1A2 (e.g., fluvoxamine or enoxacin) 
Moderate inducers of CYP1A2 limited to tobacco smoking and 
tobacco-related products  
• 
Concomitant administration of ESBRIET and ciprofloxacin (a moderate inhibitor of 
CYP1A2) moderately increases exposure to ESBRIET.  If ciprofloxacin at the 
dosage of 750 mg twice daily cannot be avoided, reduce ESBRIET to two capsules 
three times a day, per ESBRIET package insert instructions.  Monitor patients 
closely when ciprofloxacin is used at a dosage of 250 mg or 500 mg once daily. 
 
4.5 
STUDY ASSESSMENTS 
4.5.1 
Description of Study Assessments 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), inflammatory/autoimmune disease, 
smoking history, use of alcohol and drugs of abuse within the previous year, and 
specified conditions pre-set on the Targeted Medical History such as pulmonary 
hypertension, familial IPF, gastroesophageal reflux disease.  These conditions should all 
be addressed on the Targeted Medical History and Baseline Conditions Log eCRF.  All 
other medical history conditions, including any histories of alcoholism or drug abuse 
(except for smoking history and prior and concomitant surgeries and procedures, would 
be entered on the General Medical History and Baseline Conditions Log eCRF.  Any 
history of smoking should be entered on the Tobacco Use History eCRF. 
All concomitant medications (e.g., prescription drugs, over-the-counter drugs, 
herbal/homeopathic remedies, nutritional supplements) used by the patient within 
90 days prior to Screening/Visit 1 should be entered on the Concomitant Medications log 
eCRF.  A start date should be entered for all medication items entered on the 
Concomitant Medications eCRF, including those medications used chronically. 
Demographic data will include age (date of birth), sex, and self-reported race/ethnicity. 


 
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4.5.3 
Physical Examinations 
A complete physical examination should include the following:  an evaluation of the head, 
eyes, ears, nose, throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems.  No rectal or pelvic examination 
is required.  Any abnormality identified during screening should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
At subsequent visits, limited symptom-directed physical examinations should be 
performed.  Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened abnormalities should be recorded as adverse events on the Adverse 
Event eCRF. 
4.5.4 
Vital Signs, Resting Pulse Oximetry, Weight, and Height 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.  Pulse 
oximetry should be measured while resting.  Weight and height will also be measured at 
designated intervals (see Appendix 1, Appendix 2, Appendix 3, and Appendix 4). 
4.5.5 
Spirometry 
Spirometry, including the procedure for bronchodilator testing, will be conducted as 
per the study Pulmonary Function Manual, which is based on the ATS/ERS Consensus 
Statement (Miller et al. 2005).  The manual will include information on equipment, 
procedures, patient instructions, and precautions.  Spirometry will be performed on a 
centralized spirometry system (provided to all sites by the spirometry vendor) configured 
to the requirements of the study and in accordance with ATS/ERS guidelines.  
Spirometric measures to be collected will include FEV1 and FVC values as well as 
flow−volume and volume-time curves.  The National Health and Nutrition Examination 
Survey (NHANES) III dataset as described by Hankinson and colleagues (1999) will be 
used to calculate percent-predicted FEV1 and FVC values.  The NHANES data sets 
have been standardized on the basis of key demographic information that includes 
ethnicity and race.  It is therefore necessary to collect patient race/ethnicity to ensure 
that the most appropriate reference equation is used to establish the predicted values. 
Acceptability of the spirometry data from the computerized configured system, including 
the graphic representations of the maneuvers, will be determined by over-readers 
blinded to study drug treatment.  Calculations for the reproducibility of the acceptable 
maneuvers will be performed and reviewed centrally by over-readers blinded to study 
drug treatment and/or the Medical Monitor. 
Patients must be aware that medications containing bronchodilators may affect 
spirometry and must be withheld until assessments are completed on the day of the 
study visits.  The last dose of short-acting beta-agonists must be at least 4 hours 


 
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before testing and the last dose of long-acting beta-agonists must be at least 12 hours 
prior to testing. 
Pre-bronchodilator and post-bronchodilator spirometry will be assessed during screening 
and at subsequent visits according to the schedules of assessments in Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4. 
4.5.6 
Gas Exchange-Diffusion Capacity of the Lung for Carbon 
Monoxide Assessment 
DLCO will be conducted as per the study Pulmonary Function Manual, which is based 
on the 2005 ATS/ERS Consensus Statement (MacIntyre et al. 2005).  DLCO 
measurements corrected for serum hemoglobin concentration will be used 
for determining eligibility and endpoint assessments.  DLCO testing will be performed 
on a centralized DLCO/spirometry system (provided to all sites by the spirometry vendor) 
configured to the requirements of the study and in accordance with ATS/ERS guidelines.  
The acceptability of the data, including the graphic representations of the maneuvers, 
will be determined by over- readers blinded to study drug treatment.  Calculations for the 
reproducibility of the acceptable maneuvers will be performed and reviewed centrally. 
4.5.7 
High-Resolution Computed Tomography 
Pulmonary HRCT scans will be obtained during screening to confirm the IPF diagnosis.  
Good-quality standard–of-care scans obtained ≤ 12 months prior to screening and 
in accordance with study image acquisition guidelines can be used for eligibility 
determination.  HRCT scans will be reviewed first by the site radiologist and/or 
investigator to assess for eligibility.  If the site determines that the patient‘s HRCT meets 
IPF diagnostic criteria as specified in Table 1, the HRCT scans will be sent for central 
review to confirm eligibility.  The blinded central review radiologist will evaluate 
screening images for the UIP Pattern (Definite UIP, Possible UIP, or Inconsistent with 
UIP) in accordance with the 2011 ATS/ERS/JRS/ALAT Statement (Raghu et al. 2011).  
The HRCT assessment criteria are outlined in Appendix 10.  Final eligibility will be 
determined by the central review assessments inclusive of SLB when available.  An 
MDD based on 2011 ATS/ERS/JRS/ALAT guidelines will be utilized to finalize the 
diagnosis in the event the initial central review outcome results for HRCT and SLB are 
disparate (inconsistent with UIP/definite UIP).  The MDD process will be managed by the 
imaging vendor, who will coordinate review with an external pulmonologist expert and 
manage the services of the same external pulmonologist with regards to the 
management of IPF in addition to the study radiologist and pathologist. 
4.5.8 
Optional Quantitative High-Resolution Computed Tomography 
Scan 
An optional follow-up pulmonary HRCT scan will be obtained at Week 52 from 
consenting patients to evaluate for changes in quantitative HRCT fibrosis scores.  
The optional HRCT scan will be offered to randomized patients in the United States.  


 
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A written informed consent from each individual who has opted in to the optional 
quantitative HRCT scan will be obtained by the investigator or a person designated 
by the investigator (if acceptable by the local regulations). 
For consenting patients whose eligibility assessment was determined using a historical 
standard-of-care scan, a study specific baseline HRCT scan will be required 
prior to randomization.  Consenting patients will have a follow-up pulmonary HRCT scan 
performed at Week 52 to evaluate for qualitative and quantitative changes related 
to IPF progression.  The HRCT films will be centrally reviewed and scored on the basis 
of texture based analysis for changes in lung fibrosis on the basis of quantitative 
computer tomography.  Changes in quantitative computer tomography scores will be 
calculated as an exploratory endpoint and assessed relative to disease progression, 
spirometry parameters, and other efficacy measures. 
4.5.9 
Surgical Lung Biopsy 
Surgical lung biopsies are not required for eligibility into the study.  Patients who have 
undergone a surgical lung biopsy should have slides sent for SLB central review 
assessment to confirm eligibility in accordance with the 2011 ATS/ERS/JRS/ALAT 
consensus statement.  The central review pathologist will evaluate submitted slides 
for UIP Pattern (UIP, Probable UIP, Possible UIP, Non-classifiable, or Inconsistent 
with UIP).  The histopathologic assessment criteria are outlined in Appendix 11. 
Those with an HRCT central review assessment of “UIP” will not be required to submit 
SLB slides for central review if documentation of a “UIP” or “Probable UIP” pattern can 
be provided by a pathologist qualified in reviewing IPF biopsies. 
Assessments from the SLB central review will be entered into the eCRF, and results will 
be provided to sites for eligibility determination. 
4.5.10 
Pirfenidone Background Therapy (Cohort B) 
IPF background therapy in Cohort B is pirfenidone.  Pirfenidone licensed as ESBRIET or 
PIRESPA may be locally sourced for patients with access through their healthcare 
provider until it is provided by the Sponsor as IMP through the IxRS system.  Patients 
consenting for Cohort B who are currently on a stable dose of pirfenidone (licensed as 
ESBRIET or PIRESPA) ≤ 2403 mg/d for ≥ 4 weeks will start the standard screening 
period of 28 days (± 14 days).  Those patients who meet all eligibility criteria will then be 
randomized 1:1 to double blind treatment with SC lebrikizumab 250 mg or placebo every 
4 weeks.  Patients consenting to Cohort B who are not treated with pirfenidone at the 
time of screening will complete all screening assessments prior to initiating the 
pirfenidone titration run-in period.  The Sponsor will provide background pirfenidone IMP 
to all patients who meet eligibility criteria within the 28-day (± 14 days) screening window.  
Pirfenidone titration and optimal patient dose will be determined during the 4−6 weeks 
“run-in” period to establish pirfenidone tolerability.  A minimum period of 4 weeks from 
the first dose of pirfenidone will be required prior to randomization.  Dose titration will 


 
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proceed based upon pirfenidone label guidance (see Section 4.3.4).  If a patient 
experiences significant side effects, treatment of symptoms and/or temporary dose 
modifications should be considered (Costabel et al. 2014).  The decision to modify 
pirfenidone dosing is ultimately the responsibility of the investigator; however, occasional 
day-to-day variability in dosing due to patient initiative and preference is expected to 
occur.  Guidelines for dosage modification and treatment interruption or discontinuation 
are provided in Section 5.1.4.  For patients treated with PIRESPA (limited to Japan), 
dose titration and management of adverse effects should be based upon guidance in the 
marketed product label, including a maximum recommended dose ≤1800 mg/d.  Patients 
who fail to tolerate pirfenidone will be run-in failed and will not be randomized to this 
study. 
4.5.11 
Non-Elective Hospitalizations 
At each study visit, the investigator will ask directed questions to assess the possibility 
that the patient experienced a non-elective hospitalization(s) per protocol over the 
preceding 4 weeks.  Given that non-elective hospitalizations are a component of the 
primary endpoint in this study, a dedicated eCRF will be used to record information 
regarding a protocol-defined hospitalization event.  A hospitalization must also be 
reported as a serious adverse event as per Section 5.2.2. 
4.5.12 
Protocol-Defined Idiopathic Pulmonary Fibrosis Exacerbation 
At each study visit, the investigator will ask directed questions and review the file 
to assess the possibility that the patient experienced an acute IPF exacerbation per 
protocol over the preceding 4 weeks.  A dedicated eCRF will be used to record 
information regarding a protocol defined acute IPF exacerbation.  An acute IPF 
exacerbation should also be reported as an adverse event (or serious adverse event as 
applicable) as per Section 5.2 and Section 5.3.5.9.  A protocol-defined acute IPF 
exacerbation is defined as an event that meets all of the following criteria as determined 
by the investigator: 
• 
Unexplained worsening or development of dyspnea within the previous 30 days 
• 
Radiologic evidence of new bilateral ground-glass abnormality or consolidation, 
superimposed on a reticular or honeycomb background pattern that is consistent 
with UIP 
• 
Absence of alternative causes, such as left heart failure, pulmonary embolism, 
pulmonary infection (on the basis of endotracheal aspirate or bronchoalveolar 
lavage if available, or investigator judgment), or other events leading to acute lung 
injury (e.g., sepsis, aspiration, trauma, reperfusion pulmonary edema) 
 
4.5.13 
Six-Minute Walk Test 
The 6MWT will be conducted as per the study 6MWT Procedural Manual that is based 
on the 2002 ATS guidelines for the Six-Minute Walk Test (ATS Statement 2002). 


 
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For safety reasons, all patients should be clinically stable prior to performing any 
study-related 6MWT. 
Absolute contraindications to the 6MWT include unstable angina or myocardial infarction 
during the previous month. 
Relative contraindications to participation in the 6MWT include: 
• 
Resting heart rate > 120 or < 60 beats per minute 
• 
Systolic blood pressure > 180 mmHg 
• 
Diastolic blood pressure > 100 mmHg 
 
Prior to performing any study-related 6MWTs, patients will undergo an oxygen titration 
protocol to determine the necessary O2 flow rate (if any) for the screening 6MWT.  The 
flow rate identified during the oxygen titration procedure will also be the stable flow rate 
that the patient remains on for all subsequent 6MWTs for the entire study duration.  The 
titration procedure will be standardized as follows: 
1. 
The patient should be seated for at least 10 minutes while breathing room air. 
2. 
A room air SpO2 will be obtained. 
3. 
If the patient’s SpO2 is ≥ 88% the oxygen titration protocol can be stopped.  All 
6MWTs in this case should be performed on room air (0 L/min). 
4. 
If the patient’s SpO2 is < 88%, he or she should be started on O2 at the rate of 
2 L/min and allowed to rest for 5 minutes. 
5. 
If the patient’s SpO2 is ≥ 88% on 2 L/min after 5 minutes, the oxygen titration 
protocol can be stopped.  All 6MWTs in this case should be performed on 2 L/min. 
6. 
If the patient’s SpO2 is < 88% after 5 minutes, Steps 4 and 5 should be repeated 
on 4 L/min and 6 L/min (if necessary). 
7. 
The maximum allowed O2 flow rate for study-related 6MWTs is 6L/min.  Patients 
whose SpO2 is not ≥ 88% on 6 L/min after 5 minutes will be excluded from all 
6MWTs. 
 
Screening and all subsequent 6MWT procedures will occur with the patient receiving the 
O2 flow rate as determined by the screening oxygen titration protocol.  Patients that are 
prescribed a different oxygen requirement either at rest or with exercise should be 
placed on the flow rate determined during the titration protocol.  SpO2 should be 
measured before all study-related 6MWTs after the patient has been at rest 
for 5 minutes while receiving their titrated O2 requirement.  Any patient who has an SpO2 
of < 85% after 5 minutes should not undergo the procedure during that visit. 


 
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SpO2 should not be monitored during the 6MWT procedure.  Patients should undergo 
the procedure without any encouragement and may temporarily or permanently stop 
walking at their discretion.  Patients should immediately stop the 6MWT procedure if any 
of the following occur: 
• 
Chest pain 
• 
Light headedness 
• 
Intolerable dyspnea 
• 
Leg cramps 
• 
Staggering 
• 
Diaphoresis 
• 
Pale or ashen appearance 
• 
Mental confusion or headache 
 
Oxygen flow rate will be recorded before every 6MWT.  Heart rate, SpO2, and the 
Borg CR10 Scale will be recorded immediately before and after the procedure. 
4.5.14 
Laboratory Assessments 
Laboratory samples will be obtained according to the schedules in Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4.  Clinically significant abnormal laboratory 
findings discovered during the screening period should be recorded on the Medical 
History and Baseline Conditions eCRF as a diagnosis, rather than recording actual 
laboratory values.  On days of study drug administration, predose laboratory samples 
should be drawn 0-4 hours before the injection, unless otherwise specified. 
Samples for the following standard laboratory tests will be sent to the study sites’ local 
laboratory for analysis: 
• 
Urine pregnancy test 
 
All women of childbearing potential (including those who have had a tubal ligation) will 
have urine pregnancy tests performed prior to dosing and at other specified visits 
(see Appendix 1, Appendix 2, Appendix 3, and Appendix 4).  If a urine pregnancy test 
result is positive, study treatment will not be administered that day, and the result must 
be confirmed by a serum pregnancy test (conducted at a central laboratory; see below).  
Women with a confirmed pregnancy must discontinue study treatment. 
• 
Serum tryptase (obtained 1–6 hours after the acute onset of symptoms of an 
anaphylactic, anaphylactoid, or serious hypersensitivity reaction), whenever 
possible 
 


 
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Samples for the following standard laboratory tests will be sent to a central laboratory 
for analysis or for storage until shipped to a reference laboratory for testing: 
• 
Hematology:  RBC count, WBC count, hemoglobin, hematocrit, platelet count, and 
WBC differential count (neutrophils, bands, lymphocytes, eosinophils, basophils, 
monocytes, and other cells).  The Principal Investigator, all clinical study site staff 
and Sponsor study management team will be blinded to values of blood eosinophil 
and monocytes for randomized patients to prevent unintentional unblinding of the 
study.  These values will be monitored by an external Medical Monitor identified by 
the Sponsor to ensure patient safety is monitored. 
• 
Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total protein, 
albumin, ALT, AST, LDH, alkaline phosphatase, creatinine phosphokinase, and uric 
acid 
• 
B-type Natriuretic protein 
• 
Serum pregnancy test 
All women of childbearing potential (including those who have had a tubal 
ligation) will have a serum pregnancy test performed at screening and 
to confirm any subsequent positive urine pregnancy test result.  Women with a 
confirmed pregnancy will be excluded from study participation and must 
discontinue study treatment.  Refer to Section 5.4.3.1 for management of a 
patient with a confirmed pregnancy. 
• 
Urinalysis:  protein, blood, glucose, and microscopic examination (RBCs, WBCs, 
casts, and crystals) 
 
Samples for the following non-standard laboratory tests will be sent to the Sponsor or a 
designee for analysis: 
• 
Serum samples for antibodies and anti-PLB2 antibody testing 
• 
Serum samples for PK assessments (free lebrikizumab concentrations) 
• 
Serum and plasma samples for exploratory research on IL-13− or IPF-related 
biomarkers (e.g., periostin, CCL18, YKL40, COMP, OPN, CCL13) 
 
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling and Logistics Manual. 
4.5.14.1 
Electrocardiograms 
Single digital 12-lead ECG recordings will be obtained at screening, Week 24, and 
Week 52 of the placebo-controlled periods for Cohort A and Cohort B, and at 
Week 104/52OL for open-label lebrikizumab treatment in Cohort A, and at the last 
scheduled Safety Follow-Up Visit 14 weeks after EOT.  Standard local procedures for 
obtaining high-quality ECGs should be followed. 
ECGs for each patient will be collected on standardized equipment provided by the 
Sponsor.  To minimize variability, it is important that patients be in a resting position 


 
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for ≥ 5 minutes prior to each ECG evaluation.  Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate.  Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording.  ECGs should be performed prior to meals and 
any scheduled study procedures (e.g., vital sign measurements, blood draws, and study 
drug administration if applicable).  ECGs should be performed at least 4 hours after the 
last short-acting beta-agonist dose and at least 12 hours after the last LABA dose. 
ECG data will be captured, annotated, and centrally read by a single, blinded, 
independent cardiologist at a central ECG laboratory. 
The investigator or designee must review, sign, and date all ECG tracings.  For safety 
monitoring purposes, any abnormalities on any of the ECGs will be documented in the 
ECG file by the investigator.  Any ECG changes that are associated with symptoms or 
lead to a change in study treatment or concomitant treatment or discontinuation from 
study treatment must be reported as an adverse event on the adverse event eCRF 
(see Section 5.2).  Paper copies of the ECGs will be kept as part of the patient’s 
permanent study file at the site. 
4.5.15 
Patient-Reported Outcomes 
Patient-reported outcome (PRO) data will be elicited from the patients in this study 
to more fully characterize the clinical profile of lebrikizumab.  The PRO questionnaires, 
translated as required in the local language, will be completed in their entirety by the 
patient at specified timepoints during the study (see Appendix 1, Appendix 2, Appendix 3, 
and Appendix 4).  The ATAQ-IPF, SGRQ, and EQ-5D should be self-administered at the 
investigational site prior to all other non-PRO assessments and before the patient 
receives any disease-status information or study drug during that assessment.  The 
Borg CR10 Scale should be administered immediately before and after the 6MWT prior 
to all other non-PRO assessments and before the patient receives any disease-status 
information or study treatment during that assessment.  However, spirometry and DLCO 
may be performed during Visit 1 before 6MWT at the discretion of the investigator.  In all 
cases, each study assessment should be done in the same order at subsequent visits. 
4.5.15.1 
A Tool to Assess Quality of Life in Idiopathic Pulmonary 
Fibrosis 
The ATAQ-IPF is an IPF-specific quality-of-life questionnaire.  The original version of the 
ATAQ-IPF contains 74 items (Swigris et al. 2010).  Version 3 will be implemented in this 
study.  Version 3 of the ATAQ-IPF includes 31 items within five domains:  cough 
(6 items), dyspnea (7 items), exhaustion (6 items), emotional well-being (6 items), and 
independence (6 items).  Each item of the ATAQ-IPF is assessed on a scale ranging 
from 1 (Strongly disagree) to 4 (Strongly agree).  The ATAQ-IPF has a recall 
specification of 2 weeks.  A copy of the questionnaire is provided in Appendix 5. 


 
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4.5.15.2 
St. George’s Respiratory Questionnaire 
The SGRQ is a 50-item health-related quality-of-life instrument that measures health 
impairment (Jones et al. 1992).  The SGRQ was originally developed for use in COPD 
and asthma populations; however, it has been used to assess health impairment in IPF 
populations.  The questionnaire contains three domains:  symptoms, activity, and 
impacts.  Items are assessed on various response scales, including a 5-point Likert 
scale and True/False scale.  The SGRQ has a recall specification of 4 weeks.  A copy of 
the questionnaire is provided in Appendix 6. 
4.5.15.3 
EuroQol 5-Dimension Questionnaire 
The EQ-5D is a generic preference-based health-related quality of life questionnaire that 
provides a single index value for health status (Rabin and de Charro 2001).  This tool 
includes questions about mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression that are used to build a composite of the patient’s health status.  The 
EQ-5D questionnaire will be utilized in this study for economic modeling.  A copy of the 
questionnaire is provided in Appendix 7. 
4.5.15.4 
Borg Category Ratio 10 Scale® 
The Borg CR10 Scale is a one-item assessment that can be used to measure a variety 
of perceptions and experiences (i.e., perceived exertion, chest pain, dyspnea, and 
fatigue) (Borg and Borg 2010).  In this study, the instrument will be used to assess 
dyspnea from the patient’s perspective.  The Borg CR10 Scale ranges from 0 (Nothing 
at all) to 10 • (Absolute maximum/Highest possible).  A copy of the assessment is 
provided in Appendix 12. 
4.5.16 
Optional Samples for Roche Clinical Repository 
4.5.16.1 
Overview of the Roche Clinical Repository 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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4.5.16.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Sampling for the RCR is contingent upon the review and approval of the exploratory 
research and the RCR portion of the Informed Consent Form (ICF) by each site's 
Institutional Review Board (IRB) or independent Ethics Committee (IEC) and, if 
applicable, an appropriate regulatory body.  If a site has not been granted approval 
for RCR sampling, this section of the protocol will not be applicable at that site. 
4.5.16.3 
Sample Collection 
The following samples will be collected for identification of dynamic (non-inherited) 
biomarkers: 
• 
Residual PD and PK serum samples for research purposes, including but not limited 
to research on biomarkers related to IL-13, IPF, IPF-related diseases, or other 
respiratory diseases 
• 
Whole-blood PAXgene samples for RNA extraction for research purposes including 
but not limited to research on biomarkers related to IL-13, IPF, IPF-related diseases, 
or other respiratory diseases 
 
The following samples will be collected for identification of genetic (inherited) biomarkers: 
• 
Whole-blood samples for DNA extraction for research purposes, including but not 
limited to research on biomarkers related to IL-13, IPF, IPF-related diseases, or 
other respiratory diseases 
 
The purpose of collecting optional RNA samples is to increase the understanding 
of peripheral blood gene expression in patients with IPF with and without lebrikizumab.  
These studies may help identify biomarkers to increase understanding of disease 
severity, disease progression, and clinical heterogeneity of the disease and possible 
drug response. 
The purpose of collecting the optional DNA sample is to study genetic determinants that 
may predict response to lebrikizumab and other therapies used or that will be used 
for treatment of IPF, as well as to understand the relationship between heritable factors 
and clinical features of IPF.  These studies might also help to increase understanding 
of the disease. 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the Sample Handling and Logistics Manual. 
RCR specimens will be destroyed no later than 15 years after the date of final closure 
of the associated clinical database.  The RCR storage period will be in accordance with 
the IRB/IEC-approved ICF and applicable laws (e.g., health authority requirements). 


 
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The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below. 
4.5.16.4 
Confidentiality 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.5.16.5 
Consent to Participate in the Roche Clinical Repository 
The ICF will contain a separate section that addresses participation in the RCR.  The 
investigator or authorized designee will explain to each patient the objectives, methods, 
and potential hazards of participation in the RCR.  Patients will be told that they are free 
to refuse to participate and may withdraw their specimens at any time and for any 
reason during the storage period.  A separate, specific signature will be required 
to document a patient's agreement to provide optional RCR specimens.  Patients who 
decline to participate will not provide a separate signature. 


 
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The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.5.16.6 
Withdrawal from the Roche Clinical Repository 
 
 
 
 
 
 
 
 
 
 
4.5.16.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the ICF.  
Roche monitors and auditors will have direct access to appropriate parts of records 
relating to patient participation in the RCR for the purposes of verifying the data provided 
to Roche.  The site will permit monitoring, audits, IRB/IEC review, and health authority 
inspections by providing direct access to source data and documents related to the 
RCR samples. 
4.5.17 
Timing of Study Assessments 
4.5.17.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained 
before performing any study-specific screening tests or evaluations.  ICF completion 
must occur before any other Visit 1 procedures are initiated. 
ICFs for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
Screening tests and evaluations will be performed within 28 ± 14 days prior to 
randomization (Day 1, Visit 2) or the start of run-in (Visit 1.5), where required, unless 
otherwise specified.  For Cohort B, all screening evaluations must be completed and 
reviewed to confirm that patients meet all eligibility criteria before the pirfenidone titration 
run-in period (Visit 1.5) and/or randomization Visit 2 are scheduled.  A minimum period 
of 4 weeks may be required to establish pirfenidone tolerability prior to the randomization 


 
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visit (Day 1, Visit 2) for patients in Cohort B.  The investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure, as applicable. 
A serum sample to assess periostin must be collected and shipped to the central 
laboratory during the first 2 weeks of screening. 
Re-screening refers to repeating the entire screening process, with the exception of 
HRCT/SLB results.  Re-screening is required if a patient has not met all of the eligibility 
criteria within the screening period.  Patients are allowed to be re-screened for selected 
reasons up to two times.  Each patient must be re-consented before re-screening occurs.  
See Appendix 1 and Appendix 3 for the schedule of screening and pretreatment 
assessments. 
4.5.17.2 
Assessments during Treatment 
All assessments must be performed on the day of the specified visit, unless a time 
window is specified in the schedule of assessments (see Appendix 1, Appendix 2, and 
Appendix 3).  Assessments scheduled on the day of study treatment administration 
should be performed prior to administration of study treatment, unless otherwise noted in 
the schedule of assessments.  The ATAQ-IPF, SGRQ, and EQ-5D should be self-
administered at the investigational site prior to all other non-PRO assessments and 
before the patient receives any disease-status information or study drug during that 
assessment.  The Borg CR10 Scale should be administered immediately before and 
after the 6MWT prior to all other non-PRO assessments and before the patient receives 
any disease-status information or study treatment during that assessment.  However, 
spirometry and DLCO may be performed during Visit 1 before 6MWT at the discretion of 
the investigator.  In all cases, each study assessment should be done in the same order 
at subsequent visits.  See Appendix 1, Appendix 2, and Appendix 3 for the schedules of 
assessments performed during the minimum and maximum treatment periods. 
4.5.17.3 
Assessments at Study Completion/Early Termination Visit 
The study completion visit occurs as part of the last Safety Follow-up Visit 
(see Appendix 1, Appendix 2, and Appendix 3).  All patients will be monitored for safety 
for 18 weeks after receipt of the final dose of lebrikizumab or placebo study treatment. 
Patients who choose to prematurely discontinue study drug will be encouraged to remain 
in the study and complete all remaining assessments.  If this is not feasible, the patient 
should enter and complete the safety follow-up period unless consent has been 
withdrawn. 
Patients who withdraw from the study (regardless of the reason) and refuse safety 
follow-up will be asked to return to the clinic within 30 days (± 7 days) after the last dose 
of study treatment for an early termination visit.  Refer to Appendix 1, Appendix 2, and 


 
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Appendix 3 for the schedules of assessments performed at the study completion or early 
termination visit. 
4.5.17.4 
Follow-Up Assessments  
After the study completion/early termination visit, adverse events should be followed as 
outlined in Section 5.5 and Section 5.6.  Refer to Appendix 4 for the schedule of 
assessments performed at the follow-up visit. 
4.5.17.5 
Assessments at Unscheduled Visits 
See Appendix 1, Appendix 2, Appendix 3, and Appendix 4 for assessments that are 
required in case of an unplanned visit.  An unscheduled visit may occur at any time 
during the study. 
4.6 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug or withdrawal from the study may include but are not 
limited to the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient noncompliance, such as missing scheduled visits, non-adherence 
with medications, etc. 
 
4.6.1.1 
Discontinuation from Study Drug 
Patients must discontinue study drug if they experience any of the following: 
• 
Pregnancy 
• 
Anaphylactic, anaphylactoid, or other serious hypersensitivity reaction 
• 
Malignancy (including basal or squamous cell carcinoma of the skin or carcinoma 
in situ) 
 
Patients who discontinue study treatment should continue to complete all scheduled 
study assessments and if unable or unwilling to complete these assessments should 
at minimum enter the safety follow-up period.  All patients should be followed for safety 
for 18 weeks after the last dose of lebrikizumab or placebo study treatment.  The primary 
reason for premature study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 


 
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4.6.1.2 
Withdrawal from Study 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
• 
Patient enrollment is unsatisfactory 
• 
Data recording is inaccurate or incomplete 
 
The Sponsor will notify the investigator if the study is placed on hold or if the Sponsor 
decides to discontinue the study or development program. 
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include but are not limited to the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) 
guidelines for Good Clinical Practice 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
5.1.1 
Adverse Events of Special Interest for Lebrikizumab 
Based on data to date, the theoretical risks associated with IL-13 inhibition, and the risks 
associated with and for biologic agents in general, the following four categories of 
potential adverse events have been identified as adverse events of special interest for 
lebrikizumab (refer to the Lebrikizumab IB for more details): 
• 
Local injection-site reactions 
• 
Anaphylactic, anaphylactoid, and hypersensitivity reactions 
• 
Infections 
• 
Malignancies 
 
Collection of information about these events allows for better evaluation and 
understanding of any potential safety risk to patients (refer to the Lebrikizumab IB 
for more details). 


 
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The documentation and expedited reporting requirements for these adverse events 
of special interest are described in Section 5.2.2 (reporting of serious events) and 
Section 5.2.3 (reporting of events of special interest). 
The following risk mitigation measures apply to patients receiving the study drug.  
Adherence to the planned dose regimen of study drug is required unless dosing is held 
for safety reasons.  For study visits at which the study drug dose is withheld because 
of toxicity, all other study assessments should be performed as per the study schedule. 
Recommendations for vigilance with regard to signs and symptoms of particular safety 
events of interest are summarized in the following sections. 
5.1.1.1 
Local Injection-Site Reactions 
In recently-completed Phase III clinical trials with lebrikizumab administered to patients 
with asthma, the reported rate of injection-site reactions was comparable between the 
group of patients who were treated with lebrikizumab and the group of patients who 
were treated with placebo (117 of 1432 patients [8.2%] vs. 55 of 716 patients [7.7%], 
respectively).  In Cohort A of Study GB28547 (RIFF), injection site reactions were 
reported in 13 of 78 patients (16.7%) who were treated with lebrikizumab compared 
with 6 of 76 patients (7.9%) who were treated with placebo.  These events were all 
non-serious and in most cases did not require treatment. 
A local injection-site reaction is any local reaction occurring at the site of injection 
following study drug administration.  Local injection-site reactions including but not 
limited to erythema, induration, and pain, should be reported immediately to the Sponsor 
as adverse events of special interest and as serious adverse events if appropriate.  The 
event term should be recorded in the Adverse Event eCRF as the symptom preceded by 
or followed by “injection site” (e.g., “injection-site erythema” or “erythema at injection 
site”).  If needed, injection-site reactions should be treated and any treatment(s) should 
be reported on the eCRF.  Injection-site reactions will be monitored closely, with site 
training in the recognition and reporting of events immediately to the Sponsor as adverse 
events of special interest and as serious adverse events if appropriate.  Detailed 
information regarding injection-site reactions that occur during the study will be collected, 
regardless of whether the events are serious (see Section 5.2.2) or non-serious 
(see Section 5.2.3). 
5.1.1.2 
Anaphylactic, Anaphylactoid, and Hypersensitivity Reactions 
Anaphylactic, anaphylactoid, and hypersensitivity reactions to treatment are considered 
a potential risk with all biologic medications, including lebrikizumab.  On the basis of 
newly-available safety data from six studies that were recently unblinded to the study 
treatment, there were no reports of anaphylaxis per the Sampson's criteria assessed as 
related to lebrikizumab treatment by an independent external adjudication committee 
that was blinded to the study treatment.  Furthermore, in the study of patients with 
IPF (Study GB28547, Cohort A) and both atopic dermatitis studies (Study GS29250 


 
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and Study GS29735), there were no reported events of anaphylaxis, anaphylactoid, or 
serious hypersensitivity reactions meeting search criteria. 
Patients with a history of a severe allergic or anaphylactic reaction to a biologic agent or 
known hypersensitivity to any component of the lebrikizumab injection are excluded from 
study participation. 
Signs of a possible anaphylactic, anaphylactoid, or hypersensitivity reaction include but 
are not limited to the following: 
• 
Fever, chills, pruritus, urticaria, angioedema, and skin rash 
• 
Cardiopulmonary reactions including chest pain, dyspnea, hypotension, or 
hypertension 
• 
Persistent gastrointestinal symptoms (e.g., cramping, abdominal pain, vomiting) 
 
Investigators and health care professionals administering lebrikizumab will receive 
guidance on how to recognize and manage the signs and symptoms of a potential 
anaphylactic, anaphylactoid, or hypersensitivity reaction and should be familiar with 
Sampson’s criteria for defining anaphylaxis (Sampson et al. 2006; see Appendix 8).  
Investigators and health care professionals should also be trained to accurately and 
appropriately report these events immediately to the Sponsor as adverse events of 
special interest or as serious adverse events if appropriate (see Section 5.2).  
Health care professionals should also instruct patients on how to recognize the signs 
and symptoms of any anaphylactic, anaphylactoid, or hypersensitivity reaction and 
contact a health care provider or seek emergency care in case of any such symptoms.  
Patients will need to be clinically stable prior to each dose of study drug as assessed by 
clinical evaluations including vital signs and resting pulse oximetry. 
Patient injections will be administered by a qualified health care professional or a trained 
non-health care professional who can legally administer injections.  Patients will be 
monitored by a qualified health care professional for a minimum of 1 hour after dosing for 
the first three treatment visits and for 30 minutes after dosing for all subsequent 
treatment visits. 
If a patient experiences a suspected non-serious hypersensitivity reaction, the case 
should be discussed with the Medical Monitor prior to continued dosing.  If a patient has 
signs or symptoms of an anaphylactic, anaphylactoid, or serious hypersensitivity 
reaction, administration of the study drug must be discontinued permanently (refer to 
Appendix 8 for suggested clinical criteria for diagnosis of anaphylaxis).  The patient 
should be treated according to the standard of care for management of anaphylaxis or 
an anaphylactoid or hypersensitivity reaction.  The patient must discontinue study drug 
but, whenever possible, should continue to be followed in the study (see Section 4.6.1.1).  
A blood sample for measuring total tryptase level should be obtained 1–6 hours after the 
acute onset of symptoms, whenever possible.  The tryptase sample will be collected and 


 
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analyzed per the site’s local laboratory practice.  Blood samples for antibody testing and 
PK analysis should be obtained at the time of the event whenever possible, and a blood 
sample for antibody testing should be obtained at the first follow-up visit after the event 
(e.g., Safety Follow-Up Visit 1; see Appendix 4). 
Detailed information regarding anaphylactic, anaphylactoid, or hypersensitivity reactions 
that occur during the study will be collected, regardless of whether the events are 
serious (see Section 5.2.2) or non-serious (see Section 5.2.3). 
5.1.1.3 
Infections 
Although parasitic infections have not been observed clinically to date, experimental 
animal models suggest that IL-13 plays a role in the immune response to gastrointestinal 
nematodes.  IL-13 may also play a role in the progression from infection to the 
development of clinical disease with parasites such as Leishmania and intracellular 
pathogens, such as L. monocytogenes.  Patients and study investigators will be advised 
of this possibility, particularly if the patient has a relevant travel history (for Leishmania or 
other parasites).  Patients should be instructed in appropriate food preparation and travel 
precautions and be made aware of the need to seek attention for possible symptoms 
of L. monocytogenes infection.  Patients with an active parasitic infection or 
L. monocytogenes infection within 6 months prior to Day 1 will be excluded from study 
participation. 
The role of IL-13 in other infections is less clear.  Safety analysis data from five studies 
(with the exclusion of Study GB28547) that were recently unblinded to the study 
treatment show that lebrikizumab treatment is not associated with infections and 
overall, there were no imbalances in infections (both broad and narrow [MedDRA 
High-Level Group Term of helminthic disorders, mycobacterial infectious disorders, and 
protozoal infectious disorders, or MedDRA High-Level Term of listeria infections]).  
Analysis results from Cohort A of Study GB28547 showed higher rates of infection 
(broad) in the group of patients who were treated with lebrikizumab versus those who 
were treated with placebo (51 of 78 patients [65.4%] vs. 41 of 76 patients [53.9%], 
respectively), which was driven mainly by an imbalance in urinary tract infections 
(UTIs) between the groups of patients.  All patients who were treated with 
lebrikizumab and showed a UTI had predisposing risk factors, including a single 
serious adverse event of UTI that occurred in a patient with prostatic hyperplasia. 
In Phase III studies of patients with moderate-to-severe asthma, herpes infections 
including herpes zoster (shingles) were reported in 2.0% of patients who were treated 
with lebrikizumab compared with 0.7% of patients who were treated with placebo.  In a 
Phase II study of patients with moderate-to-severe atopic dermatitis, herpes infections 
including herpes zoster (shingles) were reported in 3.8% of the patients who were 
treated with lebrikizumab.  None of the herpes infections that were reported, including 
herpes zoster, required a hospital admission.  In Cohort A of Study GB28547, herpes 
viral infections in patients were reported but there were no imbalances noted between 


 
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patients who were treated with lebrikizumab and patients who were treated with 
placebo.  Refer to the Lebrikizumab IB for more detail. 
Patients with a history of active tuberculosis requiring treatment within the 12 months 
prior to screening will be excluded from study participation.  Patients who have 
completed treatment for tuberculosis at least 12 months prior to Visit 1 and have no 
evidence of recurrent disease are permitted. 
In addition, patients will be excluded from study participation if they experience an 
episode of infection requiring hospitalization for ≥ 24 hours or treatment with antibiotics 
(IV, oral, or inhaled) within 4 weeks prior to Day 1 or during screening. 
Patients with an active upper or lower respiratory tract infection occurring at any time 
within the screening period prior to the randomization visit (Visit 1 to Day 1, Visit 2) are 
excluded, even if the infection did not require antibiotics.  
All infections that occur during the study, including non-serious infections such as viral 
upper respiratory infections, should be reported immediately to the Sponsor as 
adverse events of special interest and as serious adverse events, if appropriate.  
Detailed information with regard to parasitic or other infections that occur during the 
study will be collected, regardless of whether the events are serious (see Section 5.2.2) 
or non-serious (see Section 5.2.3). 
Given that blockade of the effector function of IL-13 constitutes immune modulation, 
patients will be excluded if they are receiving other immunomodulatory therapies 
(because of the uncertainty of the combined effect of lebrikizumab with such therapies) 
or if they have a known immunodeficiency, including but not limited to HIV infection. 
5.1.1.4 
Malignancies 
The impact of IL-13 inhibition on the development of malignancies is not known; 
however, malignancies have been identified as a potential concern for other biologic 
agents.  In the completed Phase II asthma studies, 1 patient experienced malignant 
melanoma in situ and a basal cell carcinoma approximately 10 weeks after the initiation 
of treatment with lebrikizumab.  Both events were considered by the investigator to be 
unrelated to lebrikizumab. 
All patients with a known current malignancy or who are undergoing workup for a 
potential malignancy will be excluded from the study.  Study drug must be discontinued 
in patients who develop malignancies during the study (including basal or squamous cell 
carcinoma of the skin or carcinoma in situ). 
Malignancies should be reported immediately to the Sponsor as adverse events 
of special interest and as serious adverse events, if appropriate.  Detailed information 


 
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regarding any malignancies that occur during the study will be collected, regardless 
of whether the events are serious (see Section 5.2.2) or non-serious (see Section 5.2.3). 
 
 
 
 
  
 
 
 
 
 
 
5.1.3 
Other Area of Interest:  Immunogenicity 
As with administration of any exogenous protein, a potential exists for the development 
of ATAs to lebrikizumab, which could have neutralizing or sensitizing effects resulting 
in reduced efficacy or safety.  Data obtained to date in completed clinical trials do not 
suggest increased incidence of ATAs with lebrikizumab treatment.  In the few patients 
with positive post-treatment ATA assessments in completed trials, no clinically 
detectable response as assessed by PK, efficacy, or safety data was seen.  A positive 
antibody response to PLB2 has been observed in asthma patients treated with the 
previous clinical trial material containing higher levels of PLB2.  The clinical significance 
of the antibody response is not known, and no clinically important safety signals have 
been identified in completed studies.  Refer to the Lebrikizumab IB for more detail. 
To assess for the development of immunogenicity, antibody samples will be obtained 
at baseline, at regular intervals during treatment, and during the safety follow-up period 
(see Appendix 1, Appendix 2, Appendix 3, and Appendix 4).  Antibody response to 
lebrikizumab and PLB2 will be assessed. 
To ensure that an accurate assessment of immunogenicity is obtained, a final antibody 
sample will be obtained from all patients at the final visit, whether that occurs at study 
completion or early discontinuation.  With the exception of patients who withdraw 
from the study early, this sample will typically be obtained following completion of a 
14-week follow-up period, which will allow the drug to clear for ≥ 5 half-lives. 
Samples will be stored appropriately for further evaluation as needed. 
5.1.4 
Adverse Events of Special Interest for Pirfenidone  
Summary data from Phase III studies indicate that pirfenidone is generally well tolerated.  
The most common adverse events were gastrointestinal disorders and skin disorders, 
which are typically mild to moderate and can be managed by dose modification.  Mild or 


 
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moderate serum transaminase elevations (serum ALT or AST > 3 × ULN) occurred more 
frequently in patients who were treated with pirfenidone 2403 mg/d than in patients who 
were treated with placebo, but they were most often effectively managed with dose 
modification.  
It is the responsibility of the investigator to monitor patients for toxicities as frequently as 
clinically indicated and consistent with the instructions of the package inserts for any 
medication used to treat a study patient.  Refer to Section 6.1 on the safety data 
established in Phase III studies. 
If a patient experiences significant side effects, treatment of symptoms and/or temporary 
dose reductions, interruptions, or discontinuation of pirfenidone treatment should be 
considered.  Any such dosing modifications should be recorded in the patient eCRF.  
Contact the Roche Medical Monitor or designee to discuss the management of adverse 
events and dose modification, as needed. 
5.1.4.1 
Elevated Liver Enzymes 
Increases in ALT and AST > 3 × ULN have been reported in patients treated with 
pirfenidone.  Rarely these have been associated with concomitant elevations in bilirubin.  
Patients treated with pirfenidone 2403 mg/day in the three Phase 3 trials had a higher 
incidence of elevations in ALT or AST ≥ 3 × ULN than placebo patients (3.7% vs. 0.8%, 
respectively).  Elevations ≥ 10 × ULN in ALT or AST occurred in 0.3% of patients in the 
pirfenidone 2403 mg/day group and in 0.2% of patients in the placebo group. Increases 
in ALT and AST ≥ 3 × ULN were reversible with dose modification or treatment 
discontinuation.  No cases of liver transplant or death due to liver failure that were 
related to pirfenidone have been reported.  However, the combination of transaminase 
elevations and elevated bilirubin without evidence of obstruction is generally recognized 
as an important predictor of severe liver injury that could lead to death or the need for 
liver transplants in some patients.  
Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with 
pirfenidone in all patients, then monthly for the first 6 months and every 3 months 
thereafter, per ESBRIET package insert instructions.  Dosage modifications or 
interruption may be necessary for liver enzyme elevations.  These guidelines must be 
followed for any patient who may initiate pirfenidone treatment, whether as rescue 
therapy in Cohort A or background therapy in Cohort B. 


 
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Dosage Modification due to Elevated Liver Enzymes  
Dosage modifications or interruptions may also be necessary when liver enzyme and 
bilirubin elevations are exhibited. For liver enzyme elevations, modify the dosage as 
follows: 
If a patient exhibits > 3 but ≤ 5 × ULN ALT and/or AST without symptoms or 
hyperbilirubinemia after starting ESBRIET therapy: 
• 
Discontinue confounding medications, exclude other causes, and monitor the 
patient closely. 
• 
Repeat liver chemistry tests as clinically indicated. 
• 
The full daily dosage may be maintained, if clinically appropriate, or reduced or 
interrupted (e.g., until liver chemistry tests are within normal limits) with subsequent 
re-titration to the full dosage as tolerated. 
 
If a patient exhibits > 3 but ≤ 5 × ULN ALT and/or AST accompanied by symptoms or 
hyperbilirubinemia:  
• 
Permanently discontinue ESBRIET.  
• 
Do not rechallenge patient with ESBRIET. 
 
If a patient exhibits > 5 × ULN ALT and/or AST: 
• 
Permanently discontinue ESBRIET. 
• 
Do not rechallenge patient with ESBRIET. 
 
5.1.4.2 
Photosensitivity Reaction or Rash 
Patients treated with ESBRIET 2403 mg/day in the three Phase 3 studies had a higher 
incidence of photosensitivity reactions (9%) compared with patients treated with placebo 
(1%).  The majority of the photosensitivity reactions occurred during the initial 6 months.  
Instruct patients to avoid or minimize exposure to sunlight (including sunlamps), to use a 
sunblock (SPF 50 or higher), and to wear clothing that protects against sun exposure.  
Additionally, instruct patients to avoid concomitant medications known to cause 
photosensitivity.  Dosage reduction or discontinuation may be necessary in some cases 
of photosensitivity reaction or rash. 
5.1.4.3 
Gastrointestinal Disorders 
In the clinical studies, gastrointestinal events of nausea, diarrhea, dyspepsia, vomiting, 
gastro-esophageal reflux disease, and abdominal pain were more frequently reported by 
patients in the ESBRIET treatment groups than in those taking placebo.  Dosage 
reduction or interruption for gastrointestinal events was required in 18.5% of patients in 
the 2403 mg/day group, as compared to 5.8% of patients in the placebo group; 2.2% of 
patients in the ESBRIET 2403 mg/day group discontinued treatment due to a 
gastrointestinal event, as compared to 1.0% in the placebo group.  The most common 
(> 2%) gastrointestinal events that led to dosage reduction or interruption were nausea, 
diarrhea, vomiting, and dyspepsia.  The incidence of gastrointestinal events was highest 


 
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early in the course of treatment (with highest incidence occurring during the initial 
3 months) and decreased over time.  Dosage modifications may be necessary in some 
cases of gastrointestinal adverse reactions. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, measurement of 
protocol-specified safety laboratory assessments, measurement of protocol-specified 
vital signs, and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined 
in Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with use of a medicinal product, whether 
or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described 
in Section 5.3.5.9 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present 
at baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening procedures such 
as spirometry or biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
Life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 


 
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• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug 
• 
Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity 
of an adverse event (rated as mild, moderate, or severe; see Section 5.3.3); the event 
itself may be of relatively minor medical significance (such as severe headache 
without any further findings).  Severity and seriousness need to be independently 
assessed for each adverse event recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 
for reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following: 
• 
Adverse events of special interest for general drug development 
Cases of an elevated ALT or AST in combination with either an elevated 
bilirubin or clinical jaundice, as defined in Section 5.3.5.6 
Suspected transmission of an infectious agent by the study drug, as defined 
below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, 
is considered an infectious agent.  A transmission of an infectious agent 
may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a patient exposed to a medicinal product.  This term applies 
only when a contamination of the study drug is suspected. 
• 
Adverse events of special interest for lebrikizumab (see Section 5.1.1 for further 
information) 
Local injection-site reactions 
Anaphylaxis, anaphylactoid and hypersensitivity reactions 
Infections 


 
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Malignancies 
• 
Adverse events of special interest for pirfenidone  
Elevated liver enzymes (to report cases of elevated ALT or AST in combination 
with either an elevated bilirubin or clinical jaundice, as defined in 
Section 5.3.5.6) 
Photosensitivity reaction or rash 
Gastrointestinal disorders 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 
for definition) are recorded on the Adverse Event eCRF and reported to the Sponsor 
in accordance with instructions provided in this section and in Sections 5.4, 5.5, and 5.6.  
The investigator is also responsible for reporting medical device complaints 
(see Section 5.4.4). 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, 
serious adverse events caused only by a protocol-mandated intervention should be 
reported (e.g., serious adverse events related to procedures such as biopsies or 
spirometry) or protocol mandated washout of medications.  See Section 5.4.2 for 
reporting requirements of Serious Adverse Events. 
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until study completion.  After this period, the investigator does not 
need to actively monitor patients for adverse events.  Once the study has ended the 
Sponsor should be notified if the investigator becomes aware of any serious adverse 
events and adverse events of special interest (see Section 5.6). 
For Cohort B only:  Safety findings should be reported for patients who are 
administered background pirfenidone by their health care provider.  Safety findings 
should be collected as of date of consent for the study for patients who are naive to 
pirfenidone treatment.  Safety findings should be collected on the dates when 
pirfenidone is taken (see Section 4.5.10). 


 
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5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted to elicit 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
 
5.3.3 
Assessment of Severity of Adverse Events 
Table 2 provides guidance for assessing adverse event severity: 
Table 2 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  Refer 
to definition of a serious adverse event (see Section 5.2.2). 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known 
to increase the occurrence of the event 
• 
Presence of non−treatment-related factors that are known to be associated with the 
occurrence of the event (e.g., accident, new or intercurrent disease) 
 
For patients receiving combination therapy, causality will be assessed individually 
for each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 


 
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Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather 
than individual signs and symptoms (e.g., record only liver failure or hepatitis rather 
than jaundice, asterixis, and elevated transaminases).  However, if a constellation 
of signs or symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded on the 
Adverse Event eCRF.  If a diagnosis is subsequently established, all previously reported 
adverse events based on signs and symptoms should be nullified and replaced by one 
adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception 
of severe or serious secondary events.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously without resolution 
between patient evaluation timepoints. Such events should be recorded only once on the 
Adverse Event eCRF.  Initial adverse event intensity should be recorded at the time the 
adverse event is reported.  If a persistent adverse event becomes more severe, the most 
extreme intensity should also be recorded in the Adverse Event eCRF.  For example, a 
headache Grade 1 increases to headache Grade 2.  At the time of the intensity change, 
the Grade 2 intensity should be recorded in the Adverse Event eCRF in the most 
extreme intensity data field. 


 
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If at any time the non-serious adverse event qualifies as a serious adverse event per the 
seriousness criteria (refer to Section 5.3.3), the Adverse Event eCRF should be updated 
to reflect this and should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions).  To update the Adverse Event eCRF, change the seriousness criteria to 
“serious” from “non-serious,” provide the date the event became serious, and complete 
all subsequent data fields on the Adverse Event eCRF. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately on an Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
should be reported as an adverse event whether it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin five times the upper limit of normal [ULN] 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mq/L should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 


 
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seriousness should be updated any time the event worsens (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded 
on the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens (see Section 5.3.5.3 for 
details on recording persistent adverse events).  
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST >3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or, if a diagnosis cannot be established, the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning 
of the event), either as a serious adverse event or a non-serious adverse event of 
special interest (see Section 5.4.2). 


 
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5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of IPF. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term “sudden death” should be used only for the occurrence of an abrupt 
and unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the Adverse Event eCRF.  If the cause 
of death later becomes available (e.g., after autopsy), “unexplained death” should be 
replaced by the established cause of death. 
If the death is attributed to progression of IPF, "IPF progression” should be recorded 
on the Adverse Event eCRF. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
5.3.5.9 
Lack of Efficacy or Worsening of Idiopathic Pulmonary 
Fibrosis 
Medical occurrences or symptoms of deterioration that are anticipated as part of IPF 
should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening of IPF on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., “worsening of IPF” or “IPF progression”). 


 
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5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.2.2), except as outlined below. 
The following hospitalization scenarios are not considered to be serious adverse events: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not suffered an adverse event 
 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose studied.  An overdose, incorrect administration of study drug, or incorrect 
kit administration is not an adverse event unless it results in untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted 
on the Study Drug Administration eCRF. 
All adverse events associated with an overdose, incorrect administration, or incorrect kit 
administration of study drug should be recorded on the Adverse Event eCRF.  If the 
associated adverse event fulfills a seriousness criterium, the event should be reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2). 
5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data.  However, if any patient 
responses suggestive of a possible adverse event are identified during site review of the 
PRO questionnaires, the site staff will alert the investigator, who will determine whether 
the criteria for an adverse event have been met and will document the outcome of this 
assessment in the patient's medical record per site practice.  If the event meets the 
criteria for an adverse event, it will be reported on the Adverse Event eCRF. 


 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/IEC. 
5.4.1 
Emergency Medical Contacts:  Operations/Clinical 
Medical Monitor (Roche Medical Responsible) Contact Information is as follows: 
Primary Contact 
Medical Monitor:  
 
, M.D.  
Telephone No.:  
 
 
Mobile Telephone No.: 
 
Secondary Contact 
Medical Monitor:  
 
 M.D.  
Telephone No.:  
 
 
Mobile Telephone No.: 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 


 
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available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events Occurring prior to Initiation of Study Drug 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
A paper Serious Adverse Event/Adverse Event of Special Interest CRF and Fax 
Coversheet should be completed and faxed to Roche Safety Risk Management or its 
designee immediately (i.e., no more than 24 hours after learning of the event), with use 
of the fax numbers provided to investigators.  Patients who undergo screening 
procedures but do not enroll in the study will have serious adverse events recorded only 
in the Roche Drug Safety database and not in the study’s clinical database. 
5.4.2.2 
Events Occurring after Initiation of Study Drug 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until study completion.  Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Roche Safety Risk Management by the 
EDC system. 
For Cohort B only:  Safety findings should be reported for patients who are 
administered background pirfenidone by their health care provider.  Safety findings 
should be collected as of date of consent for the study for patients who are naive to 
pirfenidone treatment.  Safety findings should be collected on the dates when 
pirfenidone is taken (see Section 4.5.10). 
In the event that the EDC system is unavailable, a paper clinical trial Serious Adverse 
Event/Adverse Event of Special Interest reporting form and Fax Coversheet should be 
completed and faxed to Roche Safety Risk Management or its designee immediately 
(i.e., no more than 24 hours after learning of the event), with use of the fax numbers or 
email address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 18 weeks after the last 
dose of lebrikizumab or placebo study drug.  A Pregnancy Report eCRF should be 
completed by the investigator immediately (i.e., no more than 24 hours after learning of 


 
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the pregnancy) and submitted via the EDC system.  A pregnancy report will 
automatically be generated and sent to Roche Safety Risk Management.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. 
In the event that the EDC system is unavailable, a Clinical Trial Pregnancy Reporting 
form and Fax Coversheet should be completed and faxed to Roche Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning 
of the pregnancy), with use of the fax numbers or email address provided to 
investigators.  Once the EDC system is available, all information will need to be entered 
and submitted via the EDC system. 
5.4.3.2 
Abortions 
Any abortion should always be classified as serious (because the Sponsor considers 
these to be medically significant), recorded on the Adverse Event eCRF, and reported to 
the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.4.4 
Reporting Requirements for Medical Device Complaints 
The investigator must report all medical device complaints related to the prefilled syringe 
or other medical device used in the study to the Sponsor.  The investigator should 
document as much information as possible on the IMP Deviation Form, including the 
product batch number and forward the form to the Sponsor within 1 working day (refer to 
the pharmacy manual for further details).  If any medical device complaint results in an 
adverse event, to the study patient the adverse event must be reported on the Adverse 
Event eCRF and submitted through the EDC system.  If the event is serious, the 
Adverse Event eCRF must be completed and submitted through the EDC immediately 
(i.e., no more than 24 hours after learning of the event), as outlined in Section 5.4.2.  If 
the medical device complaint results in an adverse event to an individual other than the 
study patient, the device complaint must be reported on the IMP Deviation Form and the 
adverse event must be reported as a spontaneous adverse event to Roche Safety Risk 
Management via telephone. 


 
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5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost 
to follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or study-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, reporting 
instructions provided in Section 5.4.3.1 should be followed. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, or a monitoring 
visit to obtain additional case details and outcome information (e.g., from hospital 
discharge summaries, consultant reports, or autopsy reports) in order to perform an 
independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
Following the Adverse Event Reporting Period (see Section 5.3.1), the investigator does 
not need to actively monitor patients for adverse events.  The Sponsor should be notified 
if the investigator becomes aware of any serious adverse event that occurs after the end 
of the adverse event reporting period, if the event is believed to be related to prior study 
drug treatment.   
The investigator should report the event directly to Roche Safety Risk Management via 
telephone or via facsimile using the Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, IECs, and applicable 
health authorities based on applicable legislation. 


 
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
Lebrikizumab IB 
• 
Pirfenidone Core Safety Information (approved labels) 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The analysis of data from the placebo-controlled period for each cohort will be performed 
when all patients have either completed the end of the placebo-controlled treatment 
(Week 52/EOT) visit or discontinued early from the study.  Treatment assignment will be 
unblinded to the personnel performing the analysis when all data through the EOT visit 
are in the database and the data have been cleaned and verified for each cohort. 
The analysis of complete data for the study, including data from the placebo-controlled 
period, open-label extension period for Cohort A, and the 14-week safety follow-up 
period, will be performed when all patients have either completed the placebo-controlled 
period, open-label extension period for Cohort A, and 14-week safety follow-up period or 
discontinued early from the study, all data from the study are in the database, and the 
database is locked.  An interim futility analysis of Cohort B was conducted 
(see Section 6.8). 
Aggregate results of the placebo-controlled period analysis, summarized by treatment 
arm, may be reported to the public before completion of the study.  However, patients 
and study site personnel will remain blinded to individual treatment assignment 
until after the study is completed (after all patients have either completed the 
placebo-controlled period, open-label extension period for Cohort A, and 14-week safety 
follow-up period or discontinued early from the study), the database is locked, and the 
study analyses are final. 
Detailed specifications of the statistical methods will be described in the Statistical 
Analysis Plan (SAP). 
6.1 
DETERMINATION OF SAMPLE SIZE 
In Cohort A, a sample size of 75 patients in each treatment group will provide 
approximately 80% power to detect a change in the annualized rate of decline in 
percentage of predicted FVC over 52 weeks of a 3.7% difference in the means of the 
absolute change from baseline in percentage of predicted FVC at 52 weeks, assuming 


 
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that the common standard deviation is 8% (as reported in the placebo group in the 
ASCEND trial of pirfenidone) using a two group t-test with a 0.05 two-sided significance 
level. 
In Cohort B, a sample size of 165 patients in each treatment group will provide 
approximately 80% power to detect a 2.5% difference in the annualized rate of decline 
in percentage of predicted FVC over 52 weeks, assuming that the common standard 
deviation is 8% (as reported in the ASCEND trial of pirfenidone) using a two group t-test 
with a 0.05 two-sided significance level. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients randomized will be tabulated by study site and treatment arm.  
Patient disposition (the number of patients randomized, treated, and completing each 
study period) will be tabulated by treatment arm.  Premature treatment discontinuation 
and study discontinuation as well as reasons for discontinuations will be summarized.  
Eligibility criteria deviations and other major protocol deviations will be summarized. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics such as age, sex, race/ethnicity, concomitant 
IPF medication use, comorbid illnesses, and pulmonary function, will be summarized 
for all randomized patients by treatment arm and periostin group with use of descriptive 
statistics.  Exposure to study treatment (number of study drug treatments and duration 
of treatment) will be summarized by treatment arm and study period. 
6.4 
EFFICACY ANALYSES 
The analysis of data from the treatment period in Cohort A will be performed when all 
patients enrolled in Cohort A have either completed the end of placebo controlled 
treatment visit (Week 52), or discontinued early from the study.  Treatment assignment 
will be unblinded to the personnel performing the analysis when all data through the 
Week 52 visit are in the database and the data have been cleaned and verified. 
The analysis of data from the treatment period in Cohort B will performed when all 
patients enrolled in Cohort B have either completed the end of treatment visit (Week 52) 
or discontinued early from the study.  Treatment assignment will be unblinded to the 
personnel performing the analysis when all data through the Week 52 visit are in the 
database and the data have been cleaned and verified. 
However, the Sponsor study team directly involved in the study conduct 
(medical monitoring, clinical operations, drug safety, etc.) will not have access 
to individual treatment assignments until study completion (see Section 3.1.3), when all 
patients have completed the safety follow-up or discontinued the study.  All non-Sponsor 
personnel who are involved in the conduct of the study (e.g., patients, site monitors, and 


 
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investigators) will remain blinded to patient-specific treatment assignments until all 
patients complete the safety follow-up period or discontinue from the study. 
Complete details of the analysis will be provided in the SAP, which will be finalized prior 
to unblinding the data. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is annualized rate of decrease in percentage of predicted 
FVC (% FVC/year) through Week 52. 
The annualized rate of decrease in percentage of predicted FVC will be compared across 
the treatment arms with the use of a random slope model on observed cases at a 
0.05 two-sided significance level. 
The statistical model is as follows: 
FVCijk = (β0 + β0k) + (αi * β1 + β1k ) * tk + ηk + εijk 
where FVCijk is the predicted FVC for kth patient at visit j in treatment group 
i; β0 is the intercept; αi and β1 is the interaction term of the treatment effect 
(i = lebrikuzimab or placebo) and the slope; tk is the assessment time 
(continuous in year) for patient k; ηk is the effect of baseline lung function 
(defined as FVC < 50% vs. 50% to 75% vs. > 75% predicted) for the kth patient; 
β0k and β1k are the random components for intercept and slope; εijk is the 
random error for kth patient at time j; β0k, β1k and εijk are assumed to be 
independent and normally distributed with mean 0 and variance of σ02, σ12 and 
σε2 respectively. 
Note that because of a relatively large number of strata defined by the randomization 
stratification factors, the analysis will be adjusted only for baseline lung function 
because baseline FVC may impact the clinical disease course. 
From the model, least squares means for the annualized rate of decline in each 
treatment arm and the difference between the two treatment arms will be provided with 
95% CIs.  The model implicitly imputes missing data on the basis of a patient’s 
estimated rate of worsening of lung function prior to the study visit discontinuation 
(i.e., under the assumption that it is missing at random). 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy end points of this study are as follows: 
• 
PFS, defined as the time from study treatment randomization to the first occurrence 
of any of the following disease progression or death events: 
Death from any cause 
All-cause hospitalization 


 
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A decrease from baseline (relative change) of ≥ 10% in FVC (L) 
• 
Annualized rate of decrease in FVC (mL/year) over 52 weeks 
• 
Time from randomization to first occurrence of a ≥ 10% absolute decrease in 
percentage in predicted FVC or death from any cause 
• 
Annualized rate of decrease in percentage of predicted DLCO over 52 weeks 
• 
Annualized rate of decrease in the ATAQ-IPF total score over 52 weeks (see 
Appendix 5 for a description of the instrument) 
• 
Time from randomization to non-elective hospitalization or death from any cause 
• 
Annualized rate of decrease in the 6MWT distance over 52 weeks 
• 
Time from randomization to first event of acute IPF exacerbation (defined below) 
IPF exacerbation is defined as an event that meets all of the following criteria as 
determined by the investigator: 
Unexplained worsening or development of dyspnea within the previous 
30 days 
And radiologic evidence of new bilateral ground-glass abnormality or 
consolidation, superimposed on a reticular or honeycomb background pattern, 
that is consistent with UIP 
And absence of alternative causes, such as left heart failure, pulmonary 
embolism, pulmonary infection (on the basis of endotracheal aspirate or 
bronchoalveolar lavage if available or investigator judgment), or other events 
that lead to acute lung injury (e.g., sepsis, aspiration, trauma, reperfusion 
pulmonary edema) 
• 
Time from randomization to first occurrence of SGRQ (see Appendix 5 for a 
description of the questionnaire) worsening (total score) as defined by reaching 
MID (Swigris et al. 2010):  Total Score = 7 or death from any cause 
• 
Time from randomization to death from any cause 
 
All continuous endpoints will be analyzed with the use of the same methodology as the 
primary endpoint (see previous section) with specifics for models and summaries 
specified in the SAP. 
For time to event endpoints, the log rank test stratified by baseline lung function 
(FVC < 50% vs. 50% to 75% vs. > 75% predicted) will be used to compare the time to 
event endpoints between the two treatment arms.  Time will be measured relative to the 
date of randomization (Day 1).  Patients who do not experience the event will have their 
data censored on the last date during the placebo-controlled period when, on the basis 
of the assessments in accordance with this protocol, the patient can be considered to 
have been event-free.  Any patients who undergo lung transplantation will be censored 
at the date of the transplant.  Sensitivity analyses will be provided with lung 
transplant counted as an event for PFS and time from randomization to death or non-
elective hospitalization from any cause. 


 
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The primary efficacy assessments for the randomized placebo-controlled period are made 
on the study day of initiation of the open-label lebrikizumab through Week 52.  
Assessment on this day will be included for analyses of the randomized 
placebo-controlled period, but subsequent assessment during the open-label period or 
after Week 52 will be excluded. 
The hazard ratio and its 95% CI will be estimated with the use of a Cox regression 
model stratified by baseline lung function.  In fitting the Cox model, ties will be 
handled with the approximate likelihood method of Efron (1977).  Kaplan-Meyer curves 
will be provided. 
Summary statistics of the ATAQ-IPR and SGRQ endpoints and the changes from 
baseline will be calculated at each assessment time-point for each treatment group.  The 
mean, standard error, and median of the absolute scores and the mean changes from 
baseline (and 95% CIs) between treatment groups will be reported for the endpoint.  For 
scores involving change from baseline, patients without baseline values will be excluded 
from the analyses.  Line charts depicting the means and mean changes of subscales 
over time will be also provided.  Scoring for the questionnaire will be based on relevant 
user manuals. 
Frequencies and percentages of missing data for the ATAQ-IPR and SGRQ endpoints 
will be compared between the two treatment arms. 
Additional details for summarization, sensitivity analyses, and type I error control are 
provided in the SAP. 
6.5 
SAFETY ANALYSES 
Safety analyses will be based on all patients who received at least one dose of 
randomized study drug, with patients grouped according to the actual treatment received.  
Safety summaries will be presented by treatment arm for all treated patients.  In 
addition, safety listings will be provided for any events reported during pirfenidone 
exposure prior to randomization. 
Safety will be assessed through the summary of adverse events, laboratory test results, 
(including antibodies to lebrikizumab), ECG, and vital signs.  These summaries will be 
produced separately for each cohort for the treatment period (placebo-controlled study 
treatment period, the Cohort A open-label lebrikizumab period). 
6.5.1 
Adverse Events 
Verbatim descriptions of treatment-emergent adverse events will be coded and their 
incidence summarized by treatment arm. 
A treatment-emergent adverse event is defined as any new adverse event reported or 
any worsening of an existing condition reported on or after the first dose of study drug.  


 
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In addition, separate summaries will be generated for serious adverse events, deaths, 
and adverse events leading to discontinuation of study drug. 
Analyses will be performed by treatment group for events of special interest that include 
anaphylactic reactions, local injection-site reactions, infections, and malignancies: 
• 
Anaphylactic reactions will be reviewed and adjudicated by independent, external 
experts accordingly to a charter. 
• 
Local injection-site reactions will be identified with the use of the MedDRA 
high-level term of "injection site reaction". 
• 
Infections, as identified with the use of the MedDRA system organ class of 
“infections and infestations“ 
• 
Malignancies, as identified on the basis of the MedDRA SMQ of “Malignancy” 
and the subSMQ of “Malignant and unspecified tumours” 
 
6.5.2 
Electrocardiogram 
Descriptive summaries of ECG findings at baseline and throughout the study will be 
generated.  The number and percentage of patients with abnormal ECG findings 
at baseline or new on-treatment ECG changes (e.g., QTc prolongation, presence 
of U waves) will be summarized. 
6.5.3 
Laboratory Tests 
Descriptive summaries of laboratory values at baseline and throughout the study will be 
generated and listed on the basis of a graded scale for selected parameters.  For these 
selected parameters, changes from baseline and the proportion of patients experiencing 
clinically significant changes relative to baseline will be summarized by treatment arm. 
The number and percentage of patients with positive serum antibodies to lebrikizumab 
at baseline and during the study will be tabulated. 
6.5.4 
Vital Signs 
Descriptive summaries of vital signs, including the change from baseline for vital signs, 
will be generated by treatment arm.  Vital signs include respiratory rate, pulse rate, 
systolic and diastolic blood pressure, and temperature. 
6.6 
PHARMACOKINETIC ANALYSES 
Individual and mean serum lebrikizumab concentration−versus-time data will be reported.  
During the treatment period, mean concentrations will be reported at Weeks 4, 12, 24, 
36, and 52 (Cmin,Wk4, Cmin,Wk12, Cmin,Wk24, Cmin,Wk36, CWk52, respectively) .  Estimates for 
these parameters will be tabulated and summarized (mean, SD, coefficient of variation, 
median, minimum, and maximum).  Additional PK analyses during the treatment period 
or the safety follow-up period may be conducted as appropriate.  Population PK 


 
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modeling may be performed to characterize inter-individual variability, which may be 
reported separately from the clinical study report. 
6.7 
EXPLORATORY ANALYSES 
Analysis of exploratory efficacy endpoints will be described in the SAP. 
Several pharmacodynamic biomarkers have been identified (e.g., periostin, CCL18, 
YKL40, COMP, OPN, CCL13) and will be measured in serum or plasma samples to 
assess the effect of lebrikizumab on these biomarkers.  Exploratory exposure-response 
analysis will be performed as appropriate. 
6.7.1 
High-Resolution, Thin-Section Computed Tomography 
Quantitative Scores 
Baseline HRCT images will be performed using a low-dose radiation protocol 
(see study- and site-specific HRCT guidance manual).  Additionally, an optional HRCT 
scan will be performed at Week 52 for patients enrolled at sites located in the United 
States.  Scans obtained from those at Week 52 will be centrally reviewed and scored for 
changes in lung fibrosis on the basis of quantitative computer tomography.  Changes in 
quantitative computer tomography scores will be calculated as an exploratory endpoint 
and assessed relative to disease progression, spirometry parameters, and other efficacy 
measures. 
6.8 
OPTIONAL INTERIM ANALYSES 
The Sponsor may choose to conduct up to two interim efficacy analyses.  Interim 
analyses will involve unblinding of treatment assignments to the Sponsor for purposes of 
data analysis and interpretation.  Patients and all study site personnel will remain blinded 
to individual patient-level treatment assignments until completion of the trials.  The 
decision to conduct optional interim analyses and the timing of the analyses will be 
documented in the Sponsor’s trial master file prior to the conduct of the interim analyses.  
The interim analyses will be performed and interpreted by members of the Sponsor 
study team and appropriate senior management personnel, who will be unblinded at the 
treatment group level.  Access to treatment assignment information will follow the 
Sponsor’s standard procedures. 
After the analysis of Cohort A, the Sponsor formed an IMC to perform an unplanned 
interim futility analysis of Cohort B to determine if it should be terminated for lack of 
sufficient efficacy.  Following this analysis, the decision was made to continue the 
study and not perform additional efficacy and/or futility interim analyses. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
Roche will be responsible for data management of this study, including quality checking 
of the data.  Data entered manually will be collected via EDC with use of eCRFs.  Sites 


 
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will be responsible for data entry into the EDC system.  In the event of discrepant data, 
Roche will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
Roche will produce EDC study specifications that describe the quality checking to be 
performed on the data.  Central laboratory data and spirometry data will be sent directly 
to Roche, with use of the Roche’s standard procedures to handle and process the 
electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to a manual for appropriate eCRF completion.  eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance 
with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 


 
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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained 
per the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB/IEC review.  The investigational site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated 
in accordance with health authority requirements pertaining to computerized systems 
used in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution 
of IMPs, including eCRFs, ICFs, laboratory test results, and medication inventory 
records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required 
by relevant national or local health authorities, whichever is longer.  After that period 
of time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records 
to another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards 
for Expedited Reporting).  Studies conducted in the United States or under a 
U.S. Investigational New Drug (IND) application will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies 
conducted in the EU/EEA will comply with the EU Clinical Trial Directive (2001/20/EC). 


 
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8.2 
INFORMED CONSENT 
The Sponsor’s sample ICF (and ancillary sample ICFs such as a Child’s Assent or 
Caregiver's ICF, if applicable) will be provided to each site.  If applicable, it will be 
provided in a certified translation of the local language.  The Sponsor or its designee 
must review and approve any proposed deviations from the Sponsor's sample ICFs or 
any alternate consent forms proposed by the site (collectively, the “consent forms”) 
before IRB/IEC submission.  The final IRB/IEC-approved consent forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorized designee will 
explain to each patient the objectives of the exploratory research.  Patients will be told 
that they are free to refuse to participate and may withdraw their specimens at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to allow any remaining specimens to be 
used for exploratory research.  Patients who decline to participate will not need 
to provide a separate signature. 
The consent forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and 
that written informed consent was obtained prior to participation in the study. 
The consent forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/IEC-approved consent forms must be provided 
to the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the consent forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/IEC policy) during their participation in the study.  For any updated or revised 
consent forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised consent forms for continued participation in the study. 
A copy of each signed consent form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated consent forms must remain 
in each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each consent form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site 


 
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utilizes a separate Authorization Form for patient authorization for use and disclosure 
of personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/IEC by the Principal Investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.  In addition, any 
patient recruitment materials must be approved by the IRB/IEC. 
The Principal Investigator is responsible for providing written summaries of the status 
of the study to the IRB/IEC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/IEC.  Investigators are 
also responsible for promptly informing the IRB/IEC of any protocol amendments 
(see Section 9.5). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/IEC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/IEC, 
and archived in the site’s study file. 
8.4 
CONFIDENTIALITY 
Roche maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number.  This means that patient 
names are not included in data sets that are transmitted to any Roche location. 
Patient medical information obtained by this study is confidential and may be disclosed 
only to third parties as permitted by the ICF (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or 
required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities; Roche 
monitors, representatives, and collaborators, and the IRB/IEC for each study site, as 
appropriate. 


 
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8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information 
in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health 
authorities.  Investigators are responsible for providing information on financial interests 
during the course of the study and for 1 year after completion of the study (i.e., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/IEC and governmental approval.  
In addition, at the end of the study, the investigator will receive the patient data, which 
include an audit trail containing a complete record of all changes to data. 
9.2 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative 
for inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/IECs to inspect facilities and records relevant to this study. 
9.3 
ADMINISTRATIVE STRUCTURE 
This study is sponsored by F. Hoffmann-La Roche Ltd.  A total of 120 international study 
centers have participated in this study and enrolled 507 patients.  Roche will provide 
clinical operations oversight, data management support, and medical monitoring.  The 
eCRF data will be recorded via a Sponsor-designated EDC system.  An IxRS will be 
used for study drug inventory management and to randomize patients to study drug.  
Spirometry will be transmitted to a central spirometry center.  Blood samples will be sent 
to central laboratory for analysis.  Serum samples for PK and PD analysis will be sent to 
a central laboratory for sample storage.  Sample analysis will be performed by an 
external vendor or the Sponsor. 
An iDMC will be set up to monitor the safety of the study. 
9.4 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Roche prior 
to submission.  This allows Roche to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the 
investigator. 


 
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Roche will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, Roche will generally support publication 
of multicenter trials only in their entirety and not as individual center data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Roche personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Roche personnel. 
Any inventions and resulting patents, improvements, or know-how originating from the 
use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by Roche.  Protocol amendments will be 
submitted to the IRB/IEC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/IEC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary 
to eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
116/Protocol GB28547, Version 7 
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Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
117/Protocol GB28547, Version 7 
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Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
118/Protocol GB28547, Version 7 
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Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
119/Protocol GB28547, Version 7 
Appendix 1  
Schedule of Assessments:  Screening and Placebo Controlled Treatment Period - Cohort A 
Screening Rand. 
Placebo Controlled Study Treatment Period a 
EOT a, b 
ET a
UV 
Week 
⎯ 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
⎯ 
⎯ 
Day (Window) 
–28  
1 
 
8 
(± 2)
29 
(± 3) 
57 
(± 3)
85 
(± 3)
113 
(± 3) 
141 
(± 3) 
169 
(± 3) 
197 
(± 3) 
225 
(± 3) 
253 
(± 3)
281 
(± 3) 
309 
(± 3) 
337 
(± 3)
365 
(± 3) 
⎯ 
⎯ 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
⎯ 
⎯ 
Informed consent c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical 
examination d 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Weight 
x 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs e 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Resting pulse 
oximetry 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Single ECG f 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
 
Spirometry  
x g 
x 
x 
x 
 
x 
 
 
x 
 
 
x 
 
x 
 
x 
x 
x 
DLCO 
(mL CO/min-1/mmHg-1) 
x 
x 
x 
x 
 
x 
 
 
x 
 
 
x 
 
x 
 
x 
x 
x 
HRCT ± SLB central 
review for  
eligibility h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative HRCT i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 


Appendix 1  
Schedule of Assessments:  Screening and Placebo Controlled Treatment Period - Cohort A (cont.) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
120/Protocol GB28547, Version 7 
Screening Rand. 
Placebo Controlled Study Treatment Period a 
EOT a, b 
ET a
UV 
Week 
⎯ 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
⎯ 
⎯ 
Day (Window) 
–28  
1 
 
8 
(± 2)
29 
(± 3) 
57 
(± 3)
85 
(± 3)
113 
(± 3) 
141 
(± 3) 
169 
(± 3) 
197 
(± 3) 
225 
(± 3) 
253 
(± 3)
281 
(± 3) 
309 
(± 3) 
337 
(± 3)
365 
(± 3) 
⎯ 
⎯ 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
⎯ 
⎯ 
6MWT/Borg CR10 
Scale j 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
 
ATAQ-IPF k 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
SGRQk 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
EQ-5D k 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
Hematology l 
x 
x 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Chemistry m 
x 
x 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
B-type natriuretic 
peptide 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis n 
x 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
Serum pregnancy 
test o 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test o 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Serum PK sample p 
 
x 
x 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
Plasma PD 
sample p, q 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum PD 
sample p, q 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Appendix 1  
Schedule of Assessments:  Screening and Placebo Controlled Treatment Period - Cohort A (cont.) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
121/Protocol GB28547, Version 7 
Screening Rand. 
Placebo Controlled Study Treatment Period a 
EOT a, b 
ET a
UV 
Week 
⎯ 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
⎯ 
⎯ 
Day (Window) 
–28  
1 
 
8 
(± 2)
29 
(± 3) 
57 
(± 3)
85 
(± 3)
113 
(± 3) 
141 
(± 3) 
169 
(± 3) 
197 
(± 3) 
225 
(± 3) 
253 
(± 3)
281 
(± 3) 
309 
(± 3) 
337 
(± 3)
365 
(± 3) 
⎯ 
⎯ 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
⎯ 
⎯ 
Serum antibodies p 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
Serum tryptase r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional DNA 
sample s 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional RNA 
sample s 
 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
Study drug 
administration t 
 
x r 
 
x r 
x r 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events d, u  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes:  On treatment days, all assessments should be performed prior to dosing unless otherwise specified. 
6MWT = 6-minute walk test; ATAQ-IPF = A Tool to Assess Quality of Life in IPF; Borg CR10 = Borg Category Ratio 10 Scale®; DLCO = diffusion 
capacity of the lung for carbon monoxide; ECG = electrocardiogram; EOT = end of treatment; EQ-5D = EuroQol 5-Dimension Questionnaire; 
ET = early termination; HRCT = high-resolution computed tomography; IPF = idiopathic pulmonary fibrosis; Rand.  = randomization; SGRQ = St 
George’s Respiratory Questionnaire; UV = unscheduled visit. 
a Patients who discontinue study drug are encouraged to remain in the study and complete all scheduled assessments.  If this is not feasible, the 
patient should enter and complete the safety follow-up period or the early termination assessments, unless consent has been withdrawn.  If a 
patient is unable or unwilling to complete the assessment for 6MWT and/or the qtHRCT substudy assessment this will not be considered a 
protocol deviation. 
b Patients who enter the open label lebrikizumab treatment period should complete Day1 OL visit 35 on the same day. 


Appendix 1  
Schedule of Assessments:  Screening and Placebo Controlled Treatment Period - Cohort A (cont.) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
122/Protocol GB28547, Version 7 
c Informed consent may be obtained on the day of Visit 1 or prior to visit 1 at the discretion of the investigator.  The informed consent process 
 must be completed before initiating any Visit 1 assessments. 
d Record abnormalities observed at baseline on the Medical History and Baseline Conditions eCRF.  New or worsening abnormalities should be 
 recorded on the Adverse Event eCRF. 
e Respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
f ECGs should be performed prior to any scheduled study procedures (e.g., vital sign measurements, blood draws, and study drug 
 administration, if applicable). 
g Both pre- and post-bronchodilator testing are required at screening, but only pre-bronchodilator pulmonary function test is required throughout 
 other study visits. 
h A Multidisciplinary Discussion of Diagnosis (MDD) based on 2011 ATS/ERS/JRS/ALAT guidelines will be utilized to finalize the diagnosis in the 
event the initial central review outcome results for HRCT and SLB are disparate (inconsistent with usual interstitial pneumonitis (UIP)/definite UIP. 
i Optional procedure for patients who have consented to participate in the HRCT substudy limited to the United States and selected countries.  
Baseline qtHRCT scan does not need to be repeated if one was performed as part of the eligibility assessment.  All patients enrolled in the 
substudy will have an additional qtHRCT scan performed at the EoT Visit 16 at Week 52.  Assessment at ET is requested but not considered a 
protocol deviation if the patient is unable or unwilling to perform. 
j The Borg CR10 Scale will be performed immediately before and after the 6MWT.  Assessment of the 6MWT and Borg CR10 Scale at ET is 
requested but not considered a protocol deviation if the patient is unable or unwilling to perform. 
k Complete before all other non-PRO assessments and before the patient receives any disease-status information or study treatment during the 
study visit. 
l Includes RBC count, WBC count, hemoglobin, hematocrit, platelet count, and WBC differential count (neutrophils, bands, lymphocytes, 
eosinophils, basophils, monocytes, and other cells). 
m Includes sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total 
protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatinine phosphokinase, and uric acid.  Any patient who starts rescue therapy 
(including but not limited to pirfenidone) will need monitoring per the prescribing information.  All safety laboratory assessments, 
including those required for the prescribed rescue medication, should be analyzed by the central laboratory utilized for the GB28547 clinical 
study. 
n Includes protein, blood, glucose, and microscopic examination (RBC, WBC, casts, and crystals). 
o Only for women of childbearing potential see Appendix 9. 


Appendix 1  
Schedule of Assessments:  Screening and Placebo Controlled Treatment Period - Cohort A (cont.) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
123/Protocol GB28547, Version 7 
p On dosing days.  Samples for serum PK, PD, antibody (including anti-therapeutic antibody), and optional PAXgene mRNA analysis will be taken 
prior to dosing.  An additional sample for serum antibody and PK analysis must be taken in the event of an anaphylactic, anaphylactoid, or 
serious hypersensitivity reaction.  PLB2 antibody testing may be performed as appropriate using serum samples collected at pre-specified 
timepoints. 
q Includes IL-13− or IPF-related biomarkers (e.g., periostin, CCL18, YKL40, COMP, OPN, CCL13).  Screening serum periostin sample should be 
collected and shipped to the central laboratory within the first 2 weeks of screening. 
r Whenever possible, patients who experience an acute onset of symptoms of an anaphylactic, anaphylactoid, or serious hypersensitivity reaction 
should have a blood sample for total serum tryptase analysis collected 1–6 hours after the event.  The tryptase sample will be collected and 
analyzed per the site’s local laboratory practice. 
s The DNA sample and whole blood PAXgene mRNA samples are optional and should be obtained only from patients who sign the separate RCR 
Informed Consent Form. 
t Patients will remain in the clinic for 1 hour after dosing for the first three dosing visits and for 30 minutes after dosing on all other study drug 
administration days for routine safety monitoring. 
u All adverse events including serious adverse events and adverse events of special interest. 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
124/Protocol GB28547, Version 7 
Appendix 2  
Schedule of Assessments:  Open-Label Lebrikizumab Treatment Period - Cohort A 
Week 
Wk 52 
(Day1 
OL 
Wk 56 
(Wk4 
OL) 
Wk 60 
(Wk8
OL) 
Wk 64 
(Wk12 
OL) 
Wk 68 
(Wk16 
OL) 
Wk 72 
(Wk20 
OL) 
Wk 76 
(Wk24 
OL) 
Wk 80 
(Wk28 
OL) 
Wk84 
(Wk32 
OL) 
Wk 88 
(Wk36 
OL) 
Wk92 
(Wk40 
OL) 
Wk96 
(Wk44 
OL) 
Wk100
(Wk48
OL) 
Wk104
(Wk52 
OL) 
 
 
Day (Assessment 
Window) 
365 
(1OL) 
(± 3) 
393 
(29OL) 
(± 3) 
421 
(57OL) 
(± 3) 
449 
(85OL) 
(± 3) 
477 
(13OL) 
(± 3) 
505 
(141 
OL) 
(± 3) 
533 
(169 
OL) 
(± 3) 
561 
(197 
OL) 
(± 3) 
589  
(225 
OL) 
(± 3) 
617 
(253 
OL) 
(± 3) 
645 
(281 
OL) 
(± 3) 
673 
(309 
OL) 
(± 3) 
701 
(337 
OL) 
(± 3) 
729 
(365 
OL) 
(± 3) 
 
 
Visit 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
EoT b 
/SFU 
Wk4 
ETq
UV 
Limited physical 
exam a 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Weight 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
Vital signs c 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Resting Pulse 
Oximetry 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Single ECG d 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Spirometry   
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
DLco 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
6MWT/BorgCR10 e 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
 
ATAQ-PF f 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
 
SGRQ f 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
 
EQ-5D f 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 


Appendix 2  
Schedule of Assessments:  Open-Label Lebrikizumab Treatment Period - Cohort A (cont.) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
125/Protocol GB28547, Version 7 
Week 
Wk 52 
(Day1 
OL 
Wk 56 
(Wk4 
OL) 
Wk 60 
(Wk8
OL) 
Wk 64 
(Wk12 
OL) 
Wk 68 
(Wk16 
OL) 
Wk 72 
(Wk20 
OL) 
Wk 76 
(Wk24 
OL) 
Wk 80 
(Wk28 
OL) 
Wk84 
(Wk32 
OL) 
Wk 88 
(Wk36 
OL) 
Wk92 
(Wk40 
OL) 
Wk96 
(Wk44 
OL) 
Wk100
(Wk48
OL) 
Wk104
(Wk52 
OL) 
 
 
Day (Assessment 
Window) 
365 
(1OL) 
(± 3) 
393 
(29OL) 
(± 3) 
421 
(57OL) 
(± 3) 
449 
(85OL) 
(± 3) 
477 
(13OL) 
(± 3) 
505 
(141 
OL) 
(± 3) 
533 
(169 
OL) 
(± 3) 
561 
(197 
OL) 
(± 3) 
589  
(225 
OL) 
(± 3) 
617 
(253 
OL) 
(± 3) 
645 
(281 
OL) 
(± 3) 
673 
(309 
OL) 
(± 3) 
701 
(337 
OL) 
(± 3) 
729 
(365 
OL) 
(± 3) 
 
 
Visit 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
EoT b 
/SFU 
Wk4 
ETq
UV 
Hematology g 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Chemistry h 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Urinalysis i 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Urine pregnancy j 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Serum PK k 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
Plasma PD sample k,l 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Serum PD k, l 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Serum antibodiesk 
 
x 
 
x 
 
 
x 
 
 
 
 
 
 
x 
x 
 
Serum Tryptase m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional RNA n 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
x 
 
 
Study drug 
administration o,p 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Concomitant 
medications q 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Appendix 2  
Schedule of Assessments:  Open-Label Lebrikizumab Treatment Period - Cohort A (cont.) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
126/Protocol GB28547, Version 7 
Week 
Wk 52 
(Day1 
OL 
Wk 56 
(Wk4 
OL) 
Wk 60 
(Wk8
OL) 
Wk 64 
(Wk12 
OL) 
Wk 68 
(Wk16 
OL) 
Wk 72 
(Wk20 
OL) 
Wk 76 
(Wk24 
OL) 
Wk 80 
(Wk28 
OL) 
Wk84 
(Wk32 
OL) 
Wk 88 
(Wk36 
OL) 
Wk92 
(Wk40 
OL) 
Wk96 
(Wk44 
OL) 
Wk100
(Wk48
OL) 
Wk104
(Wk52 
OL) 
 
 
Day (Assessment 
Window) 
365 
(1OL) 
(± 3) 
393 
(29OL) 
(± 3) 
421 
(57OL) 
(± 3) 
449 
(85OL) 
(± 3) 
477 
(13OL) 
(± 3) 
505 
(141 
OL) 
(± 3) 
533 
(169 
OL) 
(± 3) 
561 
(197 
OL) 
(± 3) 
589  
(225 
OL) 
(± 3) 
617 
(253 
OL) 
(± 3) 
645 
(281 
OL) 
(± 3) 
673 
(309 
OL) 
(± 3) 
701 
(337 
OL) 
(± 3) 
729 
(365 
OL) 
(± 3) 
 
 
Visit 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
EoT b 
/SFU 
Wk4 
ETq
UV 
Adverse events a,q 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
6MWT = six minute walk test; ATAQ-IPF =  A Tool to Assess Quality of Life in IPF; Borg CR10 Scale = Borg Category Ratio 10 Scale®; 
CTD = connective-tissue disease; DLCO = diffusion capacity of the lung for carbon monoxide; eCRF = electronic Case Report Form; EOMT = end 
of minimum treatment; EOT = end of treatment; EQ-5D = EuroQol 5-Dimension Questionnaire; ET = early termination; FEV1 = forced expiratory 
volume in 1 second; FVC = forced vital capacity; HRCT = high-resolution computed tomography; IL-13 = interleukin 13; IPF = idiopathic pulmonary 
fibrosis; PD = pharmacodynamic; PK = pharmacokinetic; Rand. = Randomization; SGRQ = St. George’s Respiratory Questionnaire; UV = unscheduled 
visit. 
Notes:  On treatment days, all assessments should be performed prior to dosing unless otherwise specified. 
a New or worsening abnormalities should be recorded on the Adverse Event eCRF. 
b This visit replaces Safety Follow-up Visit 1 on Appendix 4.  The next visit is Safety Follow-up Visit 2 at Week 12 (12 weeks after last dose of 
study drug).  
c Respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
d ECGs should be performed prior to any scheduled study procedures (e.g., vital sign measurements, blood draws, and study drug administration, 
if applicable). 
e The Borg CR10 Scale will be performed immediately before and after the 6MWT. 
f Complete before all other non-PRO assessments and before the patient receives any disease-status information or study treatment during the 
study visit. 


Appendix 2  
Schedule of Assessments:  Open-Label Lebrikizumab Treatment Period - Cohort A (cont.) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
127/Protocol GB28547, Version 7 
g Includes RBC count, WBC count, hemoglobin, hematocrit, platelet count, and WBC differential count (neutrophils, bands, lymphocytes, 
eosinophils, basophils, monocytes, and other cells). 
h Includes sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total 
protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatinine phosphokinase, and uric acid.  Any patient who starts rescue therapy 
(including but not limited to pirfenidone) will need monitoring per the prescribing information.  All safety laboratory assessments, including  those 
required for the prescribed rescue medication, should be analyzed by the central laboratory utilized for the GB28547 clinical study. 
i Includes protein, blood, glucose, and microscopic examination (RBC, WBC, casts, and crystals). 
j Only for women of childbearing potential see Appendix 9. 
k On dosing days.  Samples for serum PK, PD, antibody (including anti-therapeutic antibody), and optional PAXgene mRNA analysis will be  taken 
prior to dosing.  An additional sample for serum antibody and PK analysis must be taken in the event of an anaphylactic, anaphylactoid, or 
serious hypersensitivity reaction.  PLB2 antibody testing may be performed as appropriate using serum samples collected at pre-specified 
timepoints. 
l Includes IL-13 or IPF-related biomarkers (e.g., periostin, CCL18, YKL40, COMP, OPN, CCL13). 
m Whenever possible, patients who experience an acute onset of symptoms of an anaphylactic, anaphylactoid, or serious hypersensitivity reaction 
should have a blood sample for total serum tryptase analysis collected 1–6 hours after the event.  The tryptase sample will be collected and 
analyzed per the site’s local laboratory practice. 
n The whole blood PAXgene mRNA samples are optional and should be obtained only from patients who sign the separate RCR Informed 
Consent Form. 
o Patients will remain in the clinic for 1 hour after dosing for the first three dosing visits and for 30 minutes after dosing on all other study drug 
administration days for routine safety monitoring. 
p Patients who discontinue study drug are encouraged to remain in the study and complete all scheduled assessments.  If this is not feasible, the 
patient should enter and complete the safety follow-up period or the early termination assessments, unless consent has been withdrawn. 
q All adverse events including serious adverse events and adverse events of special interest. 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
128/Protocol GB28547, Version 7 
Appendix 3  
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B 
Screening 
PFD 
titration
-run-in 
Rand. 
Placebo controlled Study Treatment Period a 
EOTa, b ETa
UV 
Week 
⎯ 
 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
⎯ 
⎯ 
Day (Window) 
–28 (± 14) 4-6 wks 
(28-42 
days) 
1 
 
8 
(± 2)
29 
(± 3)
57 
(± 3)
85 
(± 3)
113 
(± 3)
141 
(± 3) 
169 
(± 3) 
197 
(± 3) 
225 
(± 3) 
253 
(± 3) 
281 
(± 3) 
309 
(± 3) 
337 
(± 3) 
365 
(± 3) 
⎯ 
⎯ 
Visit 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
⎯ 
⎯ 
Informed 
consent c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical 
examination d 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Weight 
x 
x 
x 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs e 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Resting pulse 
oximetry 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Single ECG f 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
 
Spirometry 
x g 
 
x 
x 
x 
 
x 
 
 
x 
 
 
x 
 
x 
 
x 
x 
x 


Appendix 3 
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B (cont) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
129/Protocol GB28547, Version 7 
Screening 
PFD 
titration
-run-in 
Rand. 
Placebo controlled Study Treatment Period a 
EOTa, b ETa
UV 
Week 
⎯ 
 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
⎯ 
⎯ 
Day (Window) 
–28 (± 14) 4-6 wks 
(28-42 
days) 
1 
 
8 
(± 2)
29 
(± 3)
57 
(± 3)
85 
(± 3)
113 
(± 3)
141 
(± 3) 
169 
(± 3) 
197 
(± 3) 
225 
(± 3) 
253 
(± 3) 
281 
(± 3) 
309 
(± 3) 
337 
(± 3) 
365 
(± 3) 
⎯ 
⎯ 
Visit 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
⎯ 
⎯ 
DLCO 
(mL CO/min-1/m
mHg-1) 
x 
 
x 
x 
x 
 
x 
 
 
x 
 
 
x 
 
x 
 
x 
x 
x 
HRCT ± SLB 
central review 
for eligibility h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative 
HRCT i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
6MWT/Borg 
CR10 Scale j 
x 
 
x 
 
 
 
 
 
 
x  
 
 
 
 
 
 
x 
x 
 
ATAQ-IPF k 
x 
x 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
SGRQ k 
x 
x 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
EQ-5D k 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
Hematology l 
x 
 
x 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Chemistry m 
x 
xn 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
 
 
x 
x 
x 
x 


Appendix 3 
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B (cont) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
130/Protocol GB28547, Version 7 
Screening 
PFD 
titration
-run-in 
Rand. 
Placebo controlled Study Treatment Period a 
EOTa, b ETa
UV 
Week 
⎯ 
 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
⎯ 
⎯ 
Day (Window) 
–28 (± 14) 4-6 wks 
(28-42 
days) 
1 
 
8 
(± 2)
29 
(± 3)
57 
(± 3)
85 
(± 3)
113 
(± 3)
141 
(± 3) 
169 
(± 3) 
197 
(± 3) 
225 
(± 3) 
253 
(± 3) 
281 
(± 3) 
309 
(± 3) 
337 
(± 3) 
365 
(± 3) 
⎯ 
⎯ 
Visit 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
⎯ 
⎯ 
B-type 
natriuretic 
peptide 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis o 
x 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
Serum 
pregnancy test p 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test p 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Serum PK 
sample q 
 
 
x 
x 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
Plasma PD 
sample q, r 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum PD 
sample q, r 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum 
antibodies q 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 


Appendix 3 
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B (cont) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
131/Protocol GB28547, Version 7 
Screening 
PFD 
titration
-run-in 
Rand. 
Placebo controlled Study Treatment Period a 
EOTa, b ETa
UV 
Week 
⎯ 
 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
⎯ 
⎯ 
Day (Window) 
–28 (± 14) 4-6 wks 
(28-42 
days) 
1 
 
8 
(± 2)
29 
(± 3)
57 
(± 3)
85 
(± 3)
113 
(± 3)
141 
(± 3) 
169 
(± 3) 
197 
(± 3) 
225 
(± 3) 
253 
(± 3) 
281 
(± 3) 
309 
(± 3) 
337 
(± 3) 
365 
(± 3) 
⎯ 
⎯ 
Visit 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
⎯ 
⎯ 
Serum tryptase s 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional DNA 
sample t 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional RNA 
sample t 
 
 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
Study drug 
administration u 
 
 
x s 
 
x s 
x s 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
PFD dispensing 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse 
events v 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
6MWT = 6-minute walk test; ATAQ-IPF = A Tool to Assess Quality of Life in IPF; Borg CR10 = Borg Category Ratio 10 Scale®; DLCO = diffusion 
capacity of the lung for carbon monoxide; ECG = electrocardiogram; EOT = end of treatment; EQ-5D = EuroQol 5-Dimension Questionnaire; 
ET = early termination; HRCT = high-resolution computed tomography; IPF = idiopathic pulmonary fibrosis; PFD = pirfenidone, Rand.  = randomization; 
SGRQ = St. George’s Respiratory Questionnaire; UV = unscheduled visit. 
Notes:  On treatment days, all assessments should be performed prior to dosing unless otherwise specified. 


Appendix 3 
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B (cont) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
132/Protocol GB28547, Version 7 
a Patients who discontinue study drug are encouraged to remain in the study and complete all scheduled assessments.  If a patient is unable or 
unwilling to complete the assessment for 6MWT and/or the qtHRCT substudy assessment this will not be considered a protocol deviation.  If this 
is not feasible, the patient should enter and complete the safety follow-up period or the early termination assessments, unless consent has been 
withdrawn. 
b This visit replaces Safety Follow-up Visit 1 on Appendix 4.  The next visit is Safety Follow-up Visit 2 at Week 12. 
c Informed consent may be obtained on the day of Visit 1 or prior to visit 1 at the discretion of the investigator.  The informed consent process 
must be completed before initiating any Visit 1 assessments. 
d Record abnormalities observed at baseline on the Medical History and Baseline Conditions eCRF.  New or worsening abnormalities should be 
recorded on the Adverse Event eCRF. 
e Respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
f ECGs should be performed prior to any scheduled study procedures (e.g., vital sign measurements, blood draws, and study drug administration, 
if applicable). 
g Both pre- and post-bronchodilator testing are required at screening, but only pre-bronchodilator pulmonary function test is required throughout 
other study visits. 
h A Multidisciplinary Discussion of Diagnosis (MDD) based on 2011 ATS/ERS/JRS/ALAT guidelines will be utilized to finalize the diagnosis in the 
event the initial central review outcome results for HRCT and SLB are disparate (inconsistent with usual interstitial pneumonitis (UIP)/definite UIP. 
i Optional procedure for patients who have consented to participate in the HRCT substudy limited to the United States.  Baseline qtHRCT scan 
does not need to be repeated if one was performed as part of the eligibility assessment.  All patients enrolled in the substudy will have an 
additional qtHRCT scan performed at the EOT Visit16 at Week 52.  Assessment at ET visit is requested but not considered a protocol deviation if 
patient is unable or unwilling to perform.  
j The Borg CR10 Scale will be performed immediately before and after the 6MWT.  Assessment of the 6MWT and Borg CR10 Scale at ET visit is 
requested but not considered a protocol deviation if patient is unable or unwilling to perform. 
k Complete before all other non-PRO assessments and before the patient receives any disease-status information or study treatment during the 
study visit. 
l Includes RBC count, WBC count, hemoglobin, hematocrit, platelet count, and WBC differential count (neutrophils, bands, lymphocytes, 
eosinophils, basophils, monocytes, and other cells). 


Appendix 3 
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B (cont) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
133/Protocol GB28547, Version 7 
m Includes sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total 
protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatinine phosphokinase, and uric acid.  Any patient who starts rescue therapy 
(including but not limited to pirfenidone) will need monitoring per the prescribing information.  All safety laboratory assessments, 
including those required for the prescribed rescue medication, should be analyzed by the central laboratory utilized for the GB28547 
clinical study. 
n If run-in period exceeds 4 weeks, follow pirfenidone guidance provided in the ESBRIET/PIRESPA package insert for liver function test. 
o Includes protein, blood, glucose, and microscopic examination (RBC, WBC, casts, and crystals). 
p Only for women of childbearing potential see Appendix 9. 
q On lebrikizumab dosing days.  Samples for serum PK, PD, antibody (including anti-therapeutic antibody), and optional PAXgene mRNA analysis 
will be taken prior to lebrikizumab dosing.  An additional sample for serum antibody and PK analysis must be taken in the event of an 
anaphylactic, anaphylactoid, or serious hypersensitivity reaction.  Anti-PLB2 antibody testing may be performed as appropriate using serum 
samples collected at pre-specified timepoints. 
r Includes IL-13− or IPF-related biomarkers (e.g., periostin, CCL18, YKL40, COMP, OPN, CCL13).  Screening serum periostin sample should be 
collected and shipped to the central laboratory within the first 2 weeks of screening. 
s Whenever possible, patients who experience an acute onset of symptoms of an anaphylactic, anaphylactoid, or serious hypersensitivity reaction 
should have a blood sample for total serum tryptase analysis collected 1–6 hours after the event.  The tryptase sample will be collected and 
analyzed per the site’s local laboratory practice. 
t The DNA sample and whole blood PAXgene mRNA samples are optional and should be obtained only from patients who sign the separate RCR 
Informed Consent Form. 
u Patients will remain in the clinic for 1 hour after dosing for the first three dosing visits and for 30 minutes after dosing on all other study drug 
administration days for routine safety monitoring. 
v All adverse events including serious adverse events and adverse events of special interest.


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
134/Protocol GB28547, Version 7 
Appendix 4  
Schedule of Assessments: Safety Follow-Up Period 
WEEK post last dose 
4 a 
12 
18 (final visit) 
Day post last dose (assessment window) 
28 (± 3) 
84 (± 3) 
126 (± 3) 
Visit 
SFU1 
SFU2 
SFU3 
Limited physical exam b 
x 
 
x 
Weight 
x 
 
x 
Vital signs c 
x 
x 
x 
Resting pulse oximetry 
x 
x 
x 
Single ECG (all patients) d 
x 
 
x 
Spirometry i 
x 
x 
x 
DLco 
x 
x 
x 
6MWT/BorgCR10 e 
x 
 
 
ATAQ-IPF f 
x 
 
x 
SGRQ f 
x 
 
x 
EQ-5D f 
x 
 
x 
Hematology g 
x 
x 
x 
Chemistry h 
x 
x 
x 
Urinalysis i 
x 
 
 
Urine pregnancy test j 
x 
 
 
Serum PK sample k 
x 
x 
x 
Plasma PD sample k,l 
x 
x 
x 
Serum PD sample k,l 
x 
x 
x 
Serum antibodies k 
x 
 
x 


Appendix 4 
Schedule of Assessments: Safety Follow-Up Period (cont) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
135/Protocol GB28547, Version 7 
WEEK post last dose 
4 a 
12 
18 (final visit) 
Day post last dose (assessment window) 
28 (± 3) 
84 (± 3) 
126 (± 3) 
Visit 
SFU1 
SFU2 
SFU3 
Optional RNA sample m 
x 
 
 
Concomitant medications 
x 
x 
x 
Adverse events a,n  
x 
x 
x 
PFD dispensing (Cohort B only) 
x 
x 
 
6MWT = 6-minute walk test; ATAQ-IPF = A Tool to Assess Quality of Life in IPF; Borg CR10 = Borg Category Ratio 10 
Scale®; DLCO = diffusion capacity of the lung for carbon monoxide; ECG = electrocardiogram; EOT = end of treatment; 
EQ-5D = EuroQol 5-Dimension Questionnaire; ET = early termination; HRCT = high-resolution computed tomography; 
IPF = idiopathic pulmonary fibrosis; SGRQ = St. George’s Respiratory Questionnaire; UV = unscheduled visit. 
a For patients in Cohort A who only complete the placebo controlled study period at Week 52 and choose to 
discontinue, the Week 52 visit will count as this visit.  For patients in Cohort A who complete the open-label 
lebrikizumab study period at week 52OL, the Week 52OL will count as this visit.  For patients in Cohort B who 
complete the placebo controlled study period at Week 52, the Week 52 visit will count as this visit. 
b New or worsening abnormalities should be recorded on the Adverse Event eCRF. 
c Respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature. 
d ECGs should be performed prior to any scheduled study procedures (e.g., vital sign measurements, blood draws, 
and study drug administration, if applicable). 
e The Borg CR10 Scale will be performed immediately before and after the 6MWT. 
f Complete before all other non-PRO assessments and before the patient receives any disease-status information or 
study treatment during the study visit. 
g Includes RBC count, WBC count, hemoglobin, hematocrit, platelet count, and WBC differential count (neutrophils, 
bands, lymphocytes, eosinophils, basophils, monocytes, and other cells). 


Appendix 4 
Schedule of Assessments: Safety Follow-Up Period (cont) 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
136/Protocol GB28547, Version 7 
h Includes sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, 
total and direct bilirubin, total protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatinine phosphokinase, 
and uric acid.  Any patient who starts rescue therapy (including but not limited to pirfenidone) will need 
monitoring per the prescribing information.  All safety laboratory assessments, including those required for the 
prescribed rescue medication, should be analyzed by the central laboratory utilized for the GB28547 clinical study. 
i Includes protein, blood, glucose, and microscopic examination (RBC, WBC, casts, and crystals). 
j Only for women of childbearing potential see Appendix 9.  
k On lebrikizumab dosing days.  Samples for serum PK, PD, antibody (including anti-therapeutic antibody), and 
optional PAXgene mRNA analysis will be taken prior to lebrikizumab dosing.  An additional sample for serum 
antibody and PK analysis must be taken in the event of an anaphylactic, anaphylactoid, or serious hypersensitivity 
reaction.  Anti-PLB2 antibody testing may be performed as appropriate using serum samples collected at pre-
specified timepoints. 
l Includes IL-13− or IPF-related biomarkers (e.g., periostin, CCL18, YKL40, COMP, OPN, CCL13).   
m The whole blood PAXgene mRNA samples are optional and should be obtained only from patients who sign the 
separate RCR Informed Consent Form. 
n All adverse events including serious adverse events and adverse events of special interest. 
 






























 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
151/Protocol GB28547, Version 7 
Appendix 8  
Clinical Criteria for Diagnosing Anaphylaxis 
These criteria are taken from a summary report from the second symposium on the 
definition and management of anaphylaxis, conducted by the National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network (Sampson et al. 2006). 
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled: 
• 
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula) 
And at least one of the following: 
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia) 
Reduced blood pressure or associated symptoms of end-organ 
dysfunction (e.g., hypotonia, syncope, incontinence) 
• 
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours): 
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia) 
Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope, 
incontinence) 
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
• 
Reduced blood pressure after exposure to known allergen for that patient (minutes 
to several hours): 
Infants and children:  low systolic blood pressure (age specific) or greater 
than 30% decrease in systolic blood pressure 
Adults:  systolic blood pressure of < 90 mmHg or greater than 30% decrease from that 
person’s baseline 


 
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd 
152/Protocol GB28547, Version 7 
Appendix 9  
Childbearing Potential, Pregnancy Testing, and Contraception 
All women of childbearing potential (including those who have had a tubal ligation) will 
have a serum pregnancy test at screening and a urine pregnancy test prior to 
administration of study drug at subsequent visits.  If a urine pregnancy test is positive, 
study drug will not be administered that day.  The result must be confirmed by a serum 
pregnancy test (conducted by the central laboratory).  Refer to Section 5.4.3.1 of the 
protocol for management of a patient with a confirmed pregnancy. 
All female patients are considered to be of childbearing potential unless they meet one 
of the following criteria: 
• 
The patient has been postmenopausal (amenorrheic) for at least 1 year 
• 
The patient had a surgical bilateral oophorectomy (with or without hysterectomy) 
more than 6 weeks prior to enrollment 
• 
The patient had a hysterectomy 
 
Female patients of reproductive or childbearing potential who are unwilling to use a 
highly effective method of contraception for the duration of the study and for at least 
18 weeks after the last dose of study treatment are excluded from study participation. 
Examples of highly effective contraception include the following: 
• 
Contraceptive pill or transdermal patch 
• 
Single barrier plus spermicide 
• 
Intrauterine device 
• 
Implants for contraception 
• 
Injections for contraception (with prolonged release) 
• 
Hormonal vaginal device 
• 
Sterilization, surgical tubal ligation 
• 
Sole sexual partner consisting of surgically sterilized male partner with appropriate 
postsurgical verification of the absence of spermatozoa in the ejaculate 
 
Patients may provide verbal confirmation that the partner completed appropriate 
follow-up after vasectomy.  Sites are not required to obtain partner medical records. 
 


 
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153/Protocol GB28547, Version 7 
Appendix 10  
High-Resolution Computed Tomography Criteria for UIP Pattern 
 
 


 
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154/Protocol GB28547, Version 7 
Appendix 11  
Histopathological Criteria for UIP Pattern 
 
 






STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan GB28547
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, STUDY TO ASSESS THE EFFICACY
AND SAFETY OF LEBRIKIZUMAB IN PATIENTS WITH
IDIOPATHIC PULMONARY FIBROSIS
PROTOCOL NUMBER:
GB28547
STUDY DRUG:
Lebrikizumab (RO5490255)
VERSION NUMBER:
2
IND NUMBER:
117,062
EUDRACT NUMBER:
2013-001163-24
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
, Ph.D.
DATE FINAL:
DATE AMENDED:
Version 1:16 May 2016.
Version 2: See electronic date stamp below
Name
Reason for Signing
Date and Time
(UTC)
13-Sep-2017 12:21:00
Company Signatory


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2/Statistical Analysis Plan GB28547
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
The Statistical Analysis Plan GB28547 Version 2 was amended as follows:

Respiratory hospitalization was added as a secondary endpoint due to a publication 
(Paterniti et al. 2017) that supports respiratory hospitalization is a clinically relevant 
endpoint and was a strong predictor of mortality in an analysis of pooled data from 
the placebo arms of the Esbriet and OFEV Phase III studies.

The secondary endpoints hierarchy was reordered
 

Time from randomization to first occurrence of a 15% absolute decrease in 
percentage of predicted DLCO or death from any cause was added as an endpoint to 
parallel a similar analysis for FVC.

An endpoint of annualized rate of decline in SpO2 was added as an exploratory 
endpoint based on review of the Phase II OFEV study results and post hoc 
examination of GB28547 Cohort A results.

The number of imputations for multiple imputation was changed from 1000 to 100 to 
reduce the computational burdens because it was realized that 100 is sufficient for 
estimation.

Additional minor changes have been made to improve clarity and consistency.


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3/Statistical Analysis Plan GB28547
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 8
2.2
Outcome Measures ................................................................. 8
2.2.1
Primary Efficacy Outcome Measures ...................................... 8
2.2.2
Secondary Efficacy Outcome Measures.................................. 8
2.2.3
Exploratory Efficacy Outcome Measures................................. 9
2.2.4
Pharmacokinetic Efficacy Outcome Measures ...................... 10
2.2.5
Safety Outcome Measures .................................................... 10
2.3
Determination of Sample Size ............................................... 10
2.4
Analysis Timing ..................................................................... 11
3.
STUDY CONDUCT..................................................................................... 11
3.1
Randomization....................................................................... 11
3.2
Independent Review Facility.................................................. 13
3.3
Data Monitoring ..................................................................... 13
3.3.1
Independent Data Monitoring Committee .............................. 13
3.3.2
Independent Anaphylaxis Adjudication 
Committee ............................................................................. 13
3.3.3
Internal Monitoring Committee............................................... 13
4.
STATISTICAL METHODS .......................................................................... 14
4.1
Analysis Populations ............................................................. 14
4.1.1
Intent-to-Treat Population...................................................... 14
4.1.2
Per Protocol Population......................................................... 14
4.1.3
Pharmacokinetic-Evaluable Population ................................. 14
4.1.4
Safety Population .................................................................. 14
4.2
Analysis of Study Conduct..................................................... 15
4.3
Analysis of Treatment Group Comparability .......................... 15
4.4
Efficacy Analysis.................................................................... 15
4.4.1
Type I Error Control Plan....................................................... 15


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4.4.2
Primary Efficacy Endpoint...................................................... 16
4.4.3
Secondary Efficacy Endpoints............................................... 17
4.4.4
Exploratory Efficacy Endpoints.............................................. 19
4.4.5
Sensitivity Analyses............................................................... 19
4.4.6
Subgroup Analyses ............................................................... 20
4.5
Pharmacokinetic Analyses..................................................... 22
4.6
Biomarker Analyses............................................................... 22
4.6.1
Pharmacodynamic Biomarker Analyses ................................ 22
4.7
Safety Analyses..................................................................... 22
4.7.1
Exposure of Study Drug......................................................... 23
4.7.2
Adverse Events ..................................................................... 23
4.7.3
Laboratory Data..................................................................... 23
4.7.4
Vital Signs.............................................................................. 23
4.7.5
ECG Results.......................................................................... 24
4.8
Missing Data.......................................................................... 24
4.9
Interim Analyses .................................................................... 24
5.
REFERENCES ........................................................................................... 25
LIST OF TABLES
Table 1
Subpopulation Definitions ........................................................... 21
LIST OF FIGURES
Figure 1
Cohort A Study Schematic............................................................ 7
Figure 2
Cohort B Study Schematic............................................................ 8
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 26
Appendix 2
Schedule of Assessments:  Screening and Placebo 
Controlled Treatment Period - Cohort A...................................... 34
Appendix 3
Schedule of Assessments:  Open-Label Lebrikizumab 
Treatment Period - Cohort A....................................................... 39
Appendix 4
Schedule of Assessments:  Screening, Pirfenidone Titration 
Run-In, and Placebo-Controlled Treatment Period - Cohort B.... 43
Appendix 5
Schedule of Assessments: Safety Follow-Up Period .................. 49


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Appendix 6
GAP Index and Staging System for IPF...................................... 52
Appendix 7
Clinical Criteria for Diagnosing Anaphylaxis................................ 53


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1.
BACKGROUND
This statistical analysis plan (SAP) provides details on the study design, outcome 
measures, and statistical analysis plan for Study GB28547.  The outcome measures and 
the statistical analysis plan in this SAP supersede those specified in the protocol.  The 
SAP was finalized prior to Cohort A unblinding and is currently being amended prior to 
unblinding Cohort B.
 
  Since then, two 
agents have been approved for the treatment of idiopathic pulmonary fibrosis (IPF) 
(Esbriet [pirfenidone], Ofev [nintedanib]), and Study GB28547 has been re-designed 
to support registration and labeling.  Key changes to study design since 2013 have 
included:

Revision of primary endpoint from progression free survival (PFS) to annual rate of 
decrease in percentage of predicted forced vital capacity (FVC, reflected in this SAP)

Addition of PFS as a key secondary endpoint

Broadening of the eligibility criteria

Addition of an independent Cohort B, to evaluate the effect of lebrikizumab in 
adjunct to/combination with pirfenidone background therapy compared with 
pirfenidone alone
After the analysis of Cohort A, the Sponsor formed an Internal Monitoring Committee 
(IMC) to perform an unplanned interim futility analysis of Cohort B to determine if the 
study should be terminated for lack of sufficient efficacy.  Following this analysis, the 
decision was made to continue the study and not perform additional efficacy and/or 
futility interim analyses.   The study continued to be monitored for safety by an external 
iDMC.
2.
STUDY DESIGN
Study GB28547 is comprised of Cohort A and Cohort B.  Each Cohort is a randomized, 
multicenter, double-blind, placebo-controlled, parallel-group study of lebrikizumab in 
patients with IPF.  Cohort A patients were treated in the absence of pirfenidone IPF 
background therapy during the placebo controlled period of the study.  Cohort B patients 
were treated with pirfenidone as background therapy.  The two cohorts of patients are 
independent and enrolled sequentially:  Cohort B enrollment initiated after the 
completion of enrollment in Cohort A on 8 April 2015.  See Study Schemas in Figure 1
and Figure 2.
Cohort A (Monotherapy) 
Approximately 150 patients were to be randomized 1:1 to lebrikizumab monotherapy at a 
dose of 250 mg or placebo every 4 weeks for a total of 52 weeks. 


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7/Statistical Analysis Plan GB28547
Patients who provided written informed consent would commence a screening period, 
which lasted approximately 28 days to establish entry criteria.  Study treatment was
administered by subcutaneous (SC) injection every 4 weeks, with the first injection 
occurring at the randomization visit (Day 1/Visit 2).  Patients continued to receive blinded 
study treatment every 4 weeks during the placebo-controlled treatment period for a total 
of 13 doses/26 injections of blinded treatment.
Patients in Cohort A who had not prematurely discontinued study treatment could
continue into the 52-week open-label lebrikizumab treatment period.  All patients who 
continued into the 52-week open-label lebrikizumab treatment period would receive SC 
lebrikizumab at a dose of 250 mg every 4 weeks.  All patients were followed for safety 
for 18 weeks after the last dose of study treatment.
See the protocol for details in eligibility criteria and study assessments.
Figure 1
Cohort A Study Schematic
dday; EOTend of treatment; FVCforced vital capacity; Lebrilebrikizumab; nnumber of patients; 
PBOplacebo; SFUsafety follow-up; wkweek.
Cohort B (Combination Therapy) 
Approximately 330 patients were to be randomized 1:1 to either lebrikizumab 250 mg or 
placebo every 4 weeks in combination with pirfenidone for a total of 52 weeks.  Patients 
were to be treated daily with the maximum tolerated dose of pirfenidone 2403 mg/d.
Patients who provided written informed consent would commence a screening period, 
which would last approximately 28 days to establish entry criteria.  Study treatment 
would be administered by SC injection every 4 weeks, with the first injection occurring at 
the randomization visit (Day 1/Visit 2).  Patients would continue to receive blinded study 
treatment every 4 weeks during the placebo-controlled treatment period for a total of 
13 doses (26 injections) of blinded treatment.  All patients would be followed for safety 
for 18 weeks after the last dose of study treatment. 


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See the protocol for details in eligibility criteria and study assessments.
Figure 2
Cohort B Study Schematic
ddays; EOTend of treatment; FVCforced vital capacity; Lebrilebrikizumab; nnumber of patients; 
pboplacebo; PFDpirfenidone; SFUsafety follow-up; wksweeks.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2, Appendix 3, Appendix 4, and Appendix 5.
2.2
OUTCOME MEASURES
2.2.1
Primary Efficacy Outcome Measures
The primary efficacy outcome measure for this study is the annualized rate of decrease
in percentage of predicted FVC over 52 weeks (% FVC/year).  See protocol for 
description of spirometry.
2.2.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures of this study are as follows:

Annualized rate of decrease in 6-Minute Walk Test (6MWT) distance over 52 weeks

Time from randomization to first occurrence of a 10% absolute decrease in 
percentage of predicted FVC or death from any cause

Annualized rate of decrease in percentage of predicted diffusion capacity of the lung 
for carbon monoxide (DLCO) over 52 weeks

PFS, defined as the time from study treatment randomization to the first occurrence 
of any of the following disease progression or death events:
Death from any cause
All-cause hospitalization
A decrease from baseline (relative change) of 10% in FVC (L)


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
Annualized rate of decrease in FVC (mL/year) over 52 weeks

Annualized rate of change in A Tool to Assess Quality of Life in IPF (ATAQ-IPF) 
total score over 52 weeks (see protocol for description of the instrument)

Time from randomization to first occurrence of St. George’s Respiratory 
Questionnaire (SGRQ; see protocol for description of the questionnaire) worsening 
(total score) as defined by reaching Minimal Important Difference (MID; 
Swigris et al. 2010)
Total Score7 or death from any cause

Time from randomization to non-elective hospitalization or death from any cause

Time from randomization to first event of acute IPF exacerbation (defined below)
IPF exacerbation is defined as an event that meets all of the following criteria as 
determined by the investigator:
Unexplained worsening or development of dyspnea within the previous 30 days
And radiologic evidence of new bilateral ground-glass abnormality or 
consolidation, superimposed on a reticular or honeycomb background pattern, 
that is consistent with UIP
And absence of alternative causes, such as left heart failure, pulmonary 
embolism, pulmonary infection (on the basis of endotracheal aspirate or 
bronchoalveolar lavage if available, or investigator judgment), or other events 
leading to acute lung injury (e.g., sepsis, aspiration, trauma, reperfusion 
pulmonary edema)

Time from randomization to death from any cause

Time from randomization to Respiratory hospitalization

Time from randomization to first occurrence of a 15% absolute decrease in 
percentage of predicted DLCO or death from any cause
2.2.3
Exploratory Efficacy Outcome Measures
The exploratory outcome measures for this study are as follows:

Change from baseline to Week 52 in radiographic findings on pulmonary 
high-resolution computed tomography (HRCT), including quantitative lung fibrosis 
(QLF) score (see protocol)

Change from screening (corresponding to timing for randomization strata) in serum 
and plasma biomarkers (e.g., periostin and CCL18) and change from baseline in 
serum and plasma biomarkers (e.g., periostin, CCL18, YKL40, COMP, OPN, CCL13)

Serum lebrikizumab concentrations during the extended treatment and the 14-week 
safety follow-up period

Exposure-response relationships (to be evaluated as warranted)

Change from baseline to Week 52 in the Borg CR10 Scale

Change from baseline to Week 52 in the ATAQ-IPF


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
Time from randomization to first occurrence of SGRQ individual domain worsening
as defined by reaching MID (Swigris et al. 2010).
Symptom8
Activity5
Impact7
or death from any cause

Change from baseline to Week 52 in the SGRQ

Annualized rate of decrease in oxygen saturation levels (SpO2) (%) over 52 weeks
The analysis plan for the exploratory HRCT and biomarkers will be specified in a 
separate document. 
2.2.4
Pharmacokinetic Efficacy Outcome Measures
The pharmacokinetic (PK) outcome measures for this study are as follows:

Serum lebrikizumab concentration at Week 52 (CWk52)

Predose serum lebrikizumab concentrations (Cmin) at Weeks 4, 12, 24, and 36 
(Cmin,Wk4, Cmin,Wk12, Cmin,Wk24, and Cmin,Wk36)
2.2.5
Safety Outcome Measures
The safety outcome measures are the same as those specified in the Protocol Synopsis 
(see Appendix 1).
2.3
DETERMINATION OF SAMPLE SIZE
Cohort A
Approximately 150 patients were to be enrolled.  A sample size of 75 patients in each 
treatment group would provide over 85% power to detect a mean change from baseline 
in percentage of predicted FVC at 52 weeks from 6.6% to 3.0% (a 3.6% absolute 
difference or 54% relative reduction) under the assumption that the common standard 
deviation is 7% (as reported in the placebo group in the PIPF-016 [ASCEND] trial of 
pirfenidone).  Power was estimated with use of a two group t-test at a 0.05 two-sided 
significance level.
A sample size of 75 patients in each treatment group will provide approximately 80% 
power to detect a change in the annualized rate of decrease in percentage of predicted 
FVC over 52 weeks from 7.2% to 3.5% (a 3.7% absolute difference or 51% relative 
reduction) under the assumption that the common standard deviation is 8% (as reported 
in the placebo group in the ASCEND trial of pirfenidone).  Power was estimated with use 
of a two group t-test at a 0.05 two-sided significance level. 
Cohort B
Approximately 330 patients were to be enrolled.  A sample size of 165 patients in each 
treatment group would provide over 85% power to detect a mean change from baseline 


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in percentage of predicted FVC at 52 weeks from 3.7% to 1.3% (a 2.4% absolute 
difference or 64% relative reduction) under the assumption that the common standard 
deviation is 7% (as reported in the pirfenidone group in the ASCEND trial of pirfenidone).  
Power was estimated with use of a two group t-test at a 0.05 two-sided significance level.
A sample size of 165 patients in each treatment group will provide approximately 80% 
power to detect a change in the annualized rate of decrease in percentage of predicted 
FVC over 52 weeks from 4.1% to 1.6% (a 2.5% absolute difference or 60% relative 
reduction) under the assumption that the common standard deviation is 8% (as reported 
in the pirfenidone group in the ASCEND trial of pirfenidone).  Power was estimated with 
use of a two group t-test at a 0.05 two-sided significance level. 
2.4
ANALYSIS TIMING
The primary analysis for Cohort A was performed after all patients enrolled in Cohort A 
had either completed the placebo-controlled treatment visit (Week 52) or discontinued 
early from the study.  Treatment assignment was unblinded when all data through the 
Week 52 visit were in the database and the data were cleaned and verified.  The 
independent Data Coordinating Center (iDCC) that prepares the safety analyses for 
independent Data Monitoring Committee (iDMC) review prepared the unblinding data of 
Cohort A for the Sponsor to ensure that the Cohort B was not inadvertently unblinded, 
when Cohort A was unblinded.
The primary analysis for Cohort B will be performed after all patients enrolled in Cohort B 
have either completed the placebo-controlled treatment visit (Week 52) or discontinued 
early from the study.  Treatment assignment will be unblinded when all data through the 
Week 52 visit are in the database and the data have been cleaned and verified.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
Patients were randomized to the treatment arms through the interactive 
voice/Web-based response system (IxRS).  After written informed consent is obtained, 
patients received a screening number, which was assigned by the IxRS.  Following 
completion of the screening period and after all patient eligibility requirements were
confirmed on Day 1, patients were to be assigned an identification number (a different 
number from the screening number) and randomized in a 1:1 ratio to one of two 
treatment arms for the 52-week placebo-controlled study period:

Cohort A - lebrikizumab 250 mg SC or placebo SC every 4 weeks

Cohort B - lebrikizumab 250 mg SC every 4 weeks and pirfenidone2403 mg/d or 
placebo SC every 4 weeks and pirfenidone2403 mg/d
Patients were to be randomized on the same day that treatment was to be initiated 
(Day 1/Visit 2).


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Dynamic hierarchical randomization was performed centrally and stratified by the 
following factors:

Cohort A: region (United States, Europe/Canada, other), lung function (FVC50%, 
50% to 75%,75% predicted), and serum periostin concentration 
(50 ng/mL,50 ng/mL)

Cohort B: region (United States, Europe/Canada, other), lung function (FVC50%, 
50% to 75%,75% predicted), and serum periostin concentration 
(50 ng/mL,50 ng/mL).  Although in the protocol amendment version 6 
(2 December 2015) the region strata was to be replaced by prior perfenidone 
exposure but due to faster than anticipated accrual and logistic challenges this 
change was not implemented.
During the placebo-controlled study period and the open-label lebrikizumab treatment 
period, IxRS assigned study treatment kits for patients in Cohort A. During the 
placebo-controlled study period, IxRS will assign study treatment kits and pirfenidone 
treatment kits for patients in Cohort B.  At each dosing visit during the placebo-controlled 
period, study and/or pirfenidone treatment kits will be distributed for administration.  The 
placebo and active kits are filled and packaged to look identical.  Patient randomization 
and treatment kit assignments will be verified on an ongoing basis by an external and 
independent statistical coordinating center to ensure that randomization and kit 
assignments are conducted correctly by IxRS.
The dynamic randomization scheme was employed with a biased-coin assignment 
whenever an imbalance at a given hierarchical level exceeds pre-specified thresholds.
The dynamic randomization parameters (i.e., the allocation probabilities and the 
imbalance thresholds that lead to a biased-coin assignment at each level) will be 
provided in the Clinical Study Report (CSR).
Patients, all study site personnel, and the Sponsor and its agents (with the exception 
of the IxRS service provider, the external independent statistical coordinating center 
responsible for verifying patient randomization and study treatment kit assignments, 
PK/PD laboratory personnel, and the iDMC, iDCC, and IMC members) will be blinded to 
treatment assignment for each cohort until the unblinding for each primary analysis.
If unblinding is necessary for patient management (in the case of a serious adverse 
event [SAE]), the treatment code is available to the investigator through the IxRS.  
Treatment codes are not to be disclosed except in emergency situations.  If the 
investigator wishes to know the study treatment assignment for any other reason, he or 
she is to contact the Medical Monitor directly.  The investigator should document and 
provide an explanation for any premature unblinding (e.g., accidental unblinding or 
unblinding because of a SAE).


 
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13/Statistical Analysis Plan GB28547 
As per health authority reporting requirements, Roche will break the treatment code 
for all unexpected SAEs (see protocol) that are considered by the investigator to be 
related to study drug. 
3.2 
INDEPENDENT REVIEW FACILITY 
See protocol for details on planned independent reviews for HRCT, surgical lung biopsy, 
and ECG. 
3.3 
DATA MONITORING 
3.3.1 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct on an ongoing basis.  Members of the iDMC will be external to the Sponsor, and 
will follow a charter that outlines the iDMC roles and responsibilities.  The iDMC will 
meet approximately every 6 months to review unblinded safety and study conduct data 
provided by an iDCC.  This will include a review of all deaths and hospitalizations 
reported on the adverse event (AE) forms.  The study may be stopped early for safety 
reasons.  If the iDMC determines that a benefit-risk assessment is necessary, the iDMC 
may also review unblinded efficacy data, although the iDMC may not recommend 
stopping the trial for positive efficacy.  Full details of the meeting schedule and flow of 
information between iDCC and iDMC can be found in the iDMC charter. 
3.3.2 
Independent Anaphylaxis Adjudication Committee  
An independent Anaphylaxis Adjudication Committee (iAAC) reviews AEs or groups of 
AEs that are identified as potential cases of anaphylactic, anaphylactoid, or 
hypersensitivity reactions.  Members of the iAAC are external to the Sponsor and review 
blinded data to adjudicate cases as anaphylaxis per Sampson’s criteria (see Appendix 7; 
Sampson et al. 2006).  
A detailed description of the procedures and data flow of the AAC is maintained in a 
separate AAC Charter. 
3.3.3 
Internal Monitoring Committee 
 
 
 
 
 
 
 
 
 
 


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Details with regard to the IMC were documented in an IMC agreement.
4.
STATISTICAL METHODS
Cohort A and Cohort B are two independent studies under the same protocol; patients 
were enrolled with the same entry criteria.  The effect of lebrikizumab in the treatment of 
IPF was assessed as a monotherapy in Cohort A and in combination with pirfenidone in 
Cohort B.  Cohort B was initiated after the completion of the enrollment in Cohort A; 
Cohort A patients are not allowed to enter Cohort B.  Analyses will be performed for 
each study separately. 
The primary analysis will be performed after the completion of the 52-week randomized 
placebo-controlled period.  Analyses will include all assessments up to Week 52.
Descriptive summaries will include mean, standard deviation, median and range for 
continuous variables, and counts and percentages for categorical variables.
All analyses will be performed using SAS software (Version 9.2 or higher).
4.1
ANALYSIS POPULATIONS
4.1.1
Intent-to-Treat Population
The intent-to-treat (ITT) population will be comprised of all patients who were 
randomized in the study. All efficacy analyses will be performed on this population with 
patients grouped according to the treatment assignment at randomization. 
4.1.2
Per Protocol Population
A per-protocol population is not deemed necessary for this study and is not defined.  
However, ongoing monitoring throughout the study course will track the number of 
patients who violate protocol-defined eligibility or study conduct criteria.  
4.1.3
Pharmacokinetic-Evaluable Population
The PK-evaluable population will include all patients who have received at least one 
dose of study drug, and have at least one non-missing PK observation.  Data from these 
patients will be included in PK analyses, as appropriate, depending on the available time 
points.
4.1.4
Safety Population
Safety analyses will be based on all patients who received at least one dose of study 
drug, with patients grouped according to the actual treatment received.


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4.2
ANALYSIS OF STUDY CONDUCT
For each cohort, the number of patients randomized will be tabulated by study site and 
treatment arm.  Patient disposition (the number of patients treated and completing each 
study period) will be tabulated by treatment arm.  Premature treatment discontinuation 
and study discontinuation, as well as reasons for discontinuations, will be summarized.  
Eligibility criteria deviations and other major protocol deviations will be summarized.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics such as age, gender, race, ethnicity, 
measures of disease severity, comorbid illnesses, baseline pulmonary function 
(percentage of predicted FVC and DLCO) and screening biomarker levels (periostin and
CXCL13) will be summarized for all randomized patients by treatment arm with use of 
descriptive statistics.  Continuous variables will be summarized with the number, mean, 
median, standard deviation, minimum, and maximum.  Categorical variables will be 
summarized with patient counts and percentages.  Baseline data will be defined as the 
last observation before randomization.
4.4
EFFICACY ANALYSIS
All efficacy analyses will be performed on the Randomized Population.  Unless 
otherwise specified, data collected during the 52-week placebo-controlled period will be 
used, regardless of whether the patient remained on treatment or discontinued the study 
drug early (but remained in the study).  Analyses will be performed for Cohort A and 
Cohort B separately.  For hypothesis testing, each cohort will be considered as a 
separate study and no type I error control will be done across the two cohorts.
For change-from-baseline endpoints, the baseline value will be defined as the 
measurement at randomization (Visit 2).  If the randomization value is not available, the 
screening (Visit 1) value can be used in its place (last measurement prior to Day 1).  For 
each subject, relative and absolute changes from baseline will be defined as follows:

Absolute change from baseline(post-baseline valuebaseline value)

Relative (%) change from baseline100 * (post-baseline valuebaseline 
value)/(baseline value)
4.4.1
Type I Error Control Plan
The fixed-sequence testing procedure (Westfall and Krishen, 2001) will be used to 
control the overall type I error rate for statistical testing of the primary and key secondary 
efficacy endpoints. 


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Contingent upon statistical significance in the primary efficacy endpoint—annualized rate 
of decrease in percentage of predicted FVC over 52 weeks, the key secondary 
endpoints will be tested at a two-sided significance level of 5% in the order as shown 
below:

Time from randomization to death from any cause 

Annualized rate of decrease in percentage of predicted DLCO over 52 weeks

Time from randomization to first respiratory-related hospitalization

Time from randomization to first acute exacerbation or death from any cause 

Annualized rate of change in the ATAQ-IPF total score over 52 weeks

Annualized rate of decrease in 6MWT distance over 52 weeks

Time from randomization to first occurrence of a 15% absolute decrease in 
percentage of predicted DLCO or death from any cause

Time from randomization to first occurrence of a 10% absolute decrease in 
percentage of predicted FVC or death from any cause

PFS defined as time to all-cause death, all-cause hospitalization or 10% relative 
decrease in FVC (L), whichever occurs first
If a test is not significant at 0.05 level, then the subsequent test(s) will not be considered 
significant regardless of the associated p-value(s).
4.4.2
Primary Efficacy Endpoint
The primary endpoint is annualized rate of decrease in percentage of predicted FVC 
through Week 52, which will be compared across treatment arms with use of a random 
slope model on observed cases at a 0.05 two-sided significance level.  
The statistical model is as follows:
        FVCijk (β0β0k)(αi * β1β1k ) * tkηkεijk
where FVCijk is the predicted FVC for kth patient at visit j in treatment group i; β0 is the 
intercept; αi and β1 is the interaction term of the treatment effect (ilebri or placebo) and 
the slope; tk is assessment time (continuous in year) for patient k; ηk is the effect of
baseline lung function (defined as FVC50% vs. 50% to 75% vs. 75% predicted) for 
the kth patient; β0k and β1k are the random components for intercept and slope; εijk is the 
random error for kth patient at time j; β0k, β1k, and εijk are assumed to be independent 
and normally distributed with mean 0 and variance of σ0
2, σ1
2, and σε
2 respectively.
Of note, because of a relatively large number of strata defined by the randomization 
stratification factors, the analysis will be adjusted for baseline lung function only because 
baseline FVC may impact the clinical disease course.
From the model, least squares means for the annualized rate of decrease in each
treatment arm and the difference between the two treatment arms will be provided with 


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95% CIs.  The model implicitly imputes missing data based on an individual’s estimated 
rate of worsening of lung function prior to study visit discontinuation (i.e., assuming 
missing at random). 
There are several different approaches to summarizing the treatment effect which are 
ways of understanding the results rather than independent endpoints.  For summarizing 
treatment effect the following will be provided but not considered as separate endpoints 
or hypotheses.

Change from baseline to landmark visit time expressed as absolute and relative 
difference

Difference in annual rate of decrease expressed as absolute and relative difference

Categorical absolute change from baseline to each visit time with categories of 
decrease of 10% or death before the visit, decrease of 10% to 0%, stability or 
improvement of change 0%
Change from baseline in percentage of predicted FVC at Week 52 will be analyzed as a 
sensitivity analysis with use of a mixed-effects model for repeated measures (MMRM) on 
observed cases at a 0.05 two-sided significance level. 
The statistical model is as follows:
        Chgijk β0 αi * βjηk εijk
where Chgijk is the change in percentage of predicted FVC for kth patient at visit j in 
treatment group i; β0 is the intercept; αi * βj is the interaction term of the treatment and 
categorical visit effect (ilebri or placebo, jWeeks 1, 4, 12, 24, 36, 44, and 52; αplacebo * 
β120); ηk is the effect of baseline lung function (defined as FVC50% vs. 50% to 75% 
vs. 75% predicted) for the kth patient; εijk is the random error for kth patient at time j 
and is assumed to be independent and normally distributed with mean 0 and 
unstructured variance-covariance V.  If this analysis fails to converge, analyses using 
compound symmetry or first order autoregressive structures as alternatives will be 
investigated.
From the model, least squares means for the absolute change from baseline as well as 
placebo corrected absolute changes with 95% CIs for each treatment arm at each 
post-baseline visit will be estimated.  
Other sensitivity analyses using various imputation/analysis strategies will also be 
performed.  See Section 4.4.5 for details.
4.4.3
Secondary Efficacy Endpoints
Time-to-Event Endpoints
The log rank test stratified by baseline lung function (FVC50% vs. 50% to 75% vs.75% 
predicted) will be used to compare the time to event endpoints between two treatment 
arms. The hazard ratio and its 95% CI will be estimated using a Cox regression model 


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stratified by baseline lung function.  In fitting the Cox model, ties will be handled with the 
approximate likelihood method of Efron (1977).  Kaplan-Meier plots will be provided.
Time-to-event will be measured in reference to the date of randomization. The primary 
efficacy assessments for the randomized placebo-controlled period are made on through 
the Week 52 visit, assessment on this day will be included for analyses of the 
randomized placebo-controlled period, but subsequent assessment during the 
open-label period or after Week 52 will be excluded. Patients are considered to be in 
the placebo controlled period even if they have discontinued study treatment if they 
would still be receiving placebo controlled study treatment had they not discontinued. 
For time to non-elective hospitalization or death from any cause, time to first event of 
acute IPF exacerbation, time from randomization to death from any cause, and time to 
respiratory hospitalization, patients not experiencing an event will be censored at the 
earlier of last known alive day, study day 368 or the last date during the 
placebo-controlled period.
For time to first occurrence of a 10% absolute decrease in percentage of predicted 
FVC or death from any cause, time to PFS, time to first occurrence of a 15% decrease 
in percentage of predicted DLCO or death from any cause, and time to first SGRQ Total 
Score≥7 or death from any cause, deaths which occur within 168 days after the last 
clinic assessment and before the week 52 visit (and before start of open label treatment) 
will be counted as events. For the PFS analysis, hospitalization will be counted as 
events following the same rule as for death. Patients without an event will be censored 
at the last clinic assessment during the placebo controlled period.  Any patients who 
undergo lung transplantation will be censored at the date of the transplant.  Sensitivity 
analyses will be provided with lung transplant counted as an event for PFS and time 
from randomization to death or non-elective hospitalization from any cause. For the 
sensitivity analyses, only lung transplant, death, or non-elective hospitalization which 
occur within 168 days after the last clinic assessment and before the week 52 visit (and 
before start of open label treatment) will be counted as events.
Annualized Rate of Decrease Endpoints
The annualized rate of decrease in FVC (mL/year) will be analyzed and summarized 
with use of the same method as for the annualized rate of decrease in percentage of
predicted FVC.  Diffusing capacity, 6MWT distance, and the ATAQ-IPF score will also be 
analyzed and summarized with the same methods. For the annualized rate of decrease
in FVC (mL/year) height, sex, and age will be included in the model as covariates.
Categorical summaries will be provided with categories of decrease of 50 meters or 
death before the visit, decrease of 50 to 0 meters, and stability or improvement of 0 
meters for the 6MWT distance; summaries will be provided with categories of decrease
of 15% or death before visit, decrease of 15% to 0 %, stability or improvement of 0% 
for percentage of predicted DLCO. 


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Rules for missing ATAQ-IPF V3 and SGRQ data are described in Section 4.8.
4.4.4
Exploratory Efficacy Endpoints
Time-to-Event Endpoints
These endpoints will be analyzed and summarized with use of the same methods for the 
time-to-event secondary endpoints. 
Change-from-Baseline Endpoints
These endpoints will be analyzed and summarized with use of the same methods as the 
endpoint—change from baseline in percentage of predicted FVC in Section 4.4.2.
Annualized Rate of Decrease Endpoints
The annualized rate of decrease in SpO2 (%) over 52 weeks will be analyzed and 
summarized with use of the same method as for the annualized rate of decrease in 
percentage of predicted FVC.
4.4.5
Sensitivity Analyses
The following additional sensitivity analyses will be performed:  
A.
A Rank ANCOVA analysis of change from baseline to week 52 in percentage of
predicted FVC stratified by baseline lung function (FVC50% vs. 50% to 75% 
vs.75% predicted) will be performed with death ranked as worst according to time 
until death (patient with the shortest survival time will be assigned the worst rank) 
and other missing results imputed the last observation carried forward method.  
These analyses will be performed as described in Stokes et al. 2000.
B.
The annualized rate of decrease in percentage of predicted FVC over 52 weeks and 
the annualized rate of decrease in percentage of predicted DLCO over 52 weeks will 
be performed using the random slope model with missing due to death imputed with 
the worst value observed in the study during the randomized treatment period, 
through week 52, among any Cohort A patient.  Other missing data will be implicitly 
imputed by the model based on an individual’s estimated rate of worsening of lung 
function prior to study visit discontinuation (i.e., assuming missing at random).
C.
The annualized rate of decrease in percentage of predicted FVC over 52 weeks will 
be performed using the random slope model with missing data imputed with the 
multiple imputation method only from placebo patients.  The multiple imputation 
method will be implemented with the following specifications.
1.
100 imputation datasets will be created separately from steps a and b
a)
The MCMC method will be used for partial imputation of non-monotone 
missingness, only to produce a monotone missing pattern.  The seed will be 
5815733. 
b)
The monotone method will then be used with regression method. The 
baseline lung function (FVC50% vs. 50% to 75% vs.75% predicted), 
treatment group, and all prior visits will be included in the model to impute 
the following visit.  The seed will be 8246205


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2.
The random slope analysis will be performed for each imputation dataset and 
the results will be combined following the methodology developed by Rubin 
(1978, 1987). 
D.
The absolute change from baseline to Week 52 in percent (%) predicted FVC and 
the absolute change from baseline to Week 52 in percentage of predicted DLCO will 
be performed using the MMRM model with missing due to death imputed with the 
worst value observed in the study during the randomized treatment period, through 
Week 52 ,among any Cohort A patient.  Other missing data will be implicitly imputed 
by the model (i.e. assuming missing at random).
4.4.6
Subgroup Analyses
Subgroup analyses will be performed to assess the impact of select baseline 
characteristics (see Table 1 ) on the change from baseline in percentage of FVC at 
52 weeks, by examining the interaction with the study drug with use of the MMRM model.  
Each baseline factor will be analyzed separately.  Some categories may be grouped to 
allow sufficient sample size for interpretation.


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Table 1
Subpopulation Definitions
Baseline Characteristics
Categories
Geographic region
U.S.
ROW
Age at randomization
65 years
65 to 75 years
75 years
Sex
Female
Male
Race/ethnicity
White
Nonwhite
Time from IPF diagnosis 
to randomization
1 year
1 year
Baseline %FVC
55% predicted
55% to 75% predicted
75% predicted
FEV1/FVC
<0.80
0.80
Hgb-corrected DLCO
(% predicted)a
35%
35% to 50%
50%
GAP Index (see Appendix 6 )
I/II or III
Extent of fibrosis on HRCT at 
baseline, expressed as a QLF 
score
Divided at the median for initial summary
Periostin
50 ng/mL
50 ng/mL
Duration of prior pirfenidone 
exposure (for Cohort B only)
0 (started after informed consent) 
1 year
1 year
FEV1forced expiratory volume in 1 second; FVCforced vital capacity; 
HRCT high-resolution computed tomography; QLF quantitative lung fibrosis; ROW rest 
of world.
Note:  Hispanic/Latino ethnicity grouped with nonwhite for subgroup analyses.


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4.5
PHARMACOKINETIC ANALYSES
Individual and mean serum lebrikizumab concentration-versus-time data will be reported.  
During the treatment period, mean concentrations will be reported at Weeks 1, 4, 12, 24, 
36, and 52 (Cmin,Wk1, Cmin,Wk4, Cmin,Wk12, Cmin,Wk24, Cmin,Wk36, CWk52, respectively).  Estimates 
for these parameters will be tabulated and summarized (mean, standard deviation, 
coefficient of variation, median, minimum, and maximum).  Additional PK analyses 
during the treatment period or the 18-week safety follow-up period may be conducted as 
appropriate.  Population PK modeling may be performed to characterize inter-individual 
variability, which may be reported separately from the CSR.
Pharmacokinetic analysis will use actual times, if available.  If actual times are missing, 
nominal times may be used or data with missing collection times may be excluded.
4.6
BIOMARKER ANALYSES
4.6.1
Pharmacodynamic Biomarker Analyses 
The pharmacodynamic (PD) effect of lebrikizumab in IPF will be explored by measuring 
the levels of biomarkers, focusing on serum levels of chemokines (chemokine ligand 
[CCL]13, CCL17, and CCL18), and periostin.  Other biomarkers of interest may be 
explored depending on data availability.  All PD analyses will be conducted on the ITT 
population.
Pharmocodynamic marker measurements over time will be summarized graphically and 
will include median measurements, median absolute changes from baseline, and 
median percent changes from baseline by treatment group.
4.7
SAFETY ANALYSES
Safety analyses will be based on all patients who received at least one dose of 
randomized study drug, with patients grouped according to the actual treatment received.  
Safety summaries will be presented by treatment arm for all treated patients.  In addition, 
safety listings will be provided for any events reported during pirfenidone exposure
following informed consent on this study but prior to randomization.
Safety will be assessed through the summary of AEs, laboratory test results (including 
antibodies to lebrikizumab), ECG, and vital signs.  These summaries will be produced 
separately for each cohort for the treatment period (placebo-controlled study treatment 
period including safety follow-up period for Cohort B patients or Cohort A patients not 
entering open label extension period and Cohort A open-label lebrikizumab period
including the subsequent safety follow-up period).


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4.7.1
Exposure of Study Drug
Exposure of study drug (lebrikizumab or placebo) will be summarized descriptively 
(mean, standard deviation, median, and range) for the following measures:

Treatment duration [days](date of last administrationdate of first administration 
1), where the date of first administration is the Visit 2 date

Number of dosestotal number of non-zero doses
4.7.2
Adverse Events
Verbatim descriptions of treatment-emergent adverse events (TEAEs) will be coded with 
use of the latest version of Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary, and their incidence summarized for each treatment arm by system organ 
class (SOC) and preferred term.  A TEAE is defined as any new AE reported, or any 
worsening of an existing condition reported on or after the first dose of study drug.  In 
addition, separate summaries will be provided for TESAEs, deaths, and AEs leading to 
discontinuation of study drug.
Analyses will be performed by treatment group for events of special interest that include 
anaphylactic reactions, local injection-site reactions, infections, and malignancies.

Anaphylactic reactions will be reviewed and adjudicated by the iACC.

Local injection-site reactions will be identified with use of the MedDRA high-level 
term of “injection site reaction”.

Infections, as identified with use of the MedDRA SOC of “infections and infestations”.

Malignancies, as identified on the basis of the Standardized MedDRA Queries 
(SMQ) of “Malignancy”.
4.7.3
Laboratory Data
Serum chemistry and hematology, evaluations will be summarized by descriptive 
statistics for each treatment group, together with changes from baseline (Visit 2 value).  
In addition, all chemistry, hematology, urinalysis, and coagulation data outside the 
normal reference ranges will be tabulated in terms of the number and proportion of 
patients with values that are out of range.  The toxicity grade at baseline and the highest
toxicity grade during the placebo-controlled treatment phase for select labs (eosinophils 
absolute count, hemoglobin, WBC, platelets, alanine aminotransferase, aspartate 
aminotransferase, bilirubin, creatine kinase) will be summarized by treatment group.
The number and percentage of patients with positive serum antibodies at baseline and 
during the study will be tabulated.
4.7.4
Vital Signs
Vital signs data including temperature, systolic and diastolic blood pressure, pulse, and 
respiratory rate together with changes from baseline (Visit 2, pre-dose value) in these 
parameters will be summarized by treatment arm.


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4.7.5
ECG Results
Descriptive summaries of ECG findings at baseline and throughout the study will be 
generated.  The number and percentage of patients with abnormal ECG findings 
at baseline or new on-treatment ECG changes (e.g., QTc prolongation, presence 
of U waves) will be summarized.
4.8
MISSING DATA
Missing data will be handled as specified in the analysis method Section 4.4.
Missing individual items for the scoring of the SGRQ will be handled as follows:  The 
symptoms component will be considered missing if more than two of the items are 
missing.  The activity component will be considered missing if more than four of the 
items are missing.  The impacts component will be considered missing if more than six 
of the items are missing.  The total score will be considered missing if any component is 
missing.  For a valid component questionnaire with unanswered questions, the 
predefined weight and score for a particular missing question will be used to calculate 
the aggregated score for the component (St George’s Respiratory Questionnaire Manual, 
Version 2.3).  Missing data will not be imputed.
Missing individual items for the scoring of the ATAQ-IPF will be handled as follows.  If 
more than half of the items in a domain have responses, then scores for missing items 
may be imputed using the mean score from non-missing items.  If half or more items are 
missing, then the domain is not scored.
4.9
INTERIM ANALYSES
It was not planned to conduct interim efficacy analyses.  However, after the analysis of 
Cohort A, the Sponsor formed an IMC to perform an unplanned interim futility analysis of 
Cohort B to determine if the study should be terminated for lack of sufficient efficacy.  
Following this analysis, the decision was made to continue the study and not perform 
additional efficacy and/or futility interim analyses.


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5.
REFERENCES
Efron B. The efficiency of Cox's likelihood function for censored data. J Am Stat Assoc 
1977;72:557–65.
Paterniti MO, Bi Y, Rekić D, et al. Acute Exacerbation and Decline in Forced Vital 
Capacity Are Associated with Increased Mortality in Idiopathic Pulmonary Fibrosis 
Ann Am Thorac Soc 2017
Raghu G, Collard HR, Egan JJ, et al. An Official ATS/ERS/JRS/ALAT Statement: 
Idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and 
management. Am J Respir Crit Care Med 2011;183:788824.
Rubin DB. Multiple imputation in sample surveys – a phenomenological Baysian 
approach to non response. Proceedings of the survey research methods section of 
the American statistical association, 1978:1:20-34. 
Rubin DB. Multiple imputation for nonresponse in surveys. John Wiley and Sons, New 
York, 1987. 
Sampson HA, Munoz-Furlong A, Campbell Rl, et al. Second symposium on the definition 
and management of anaphylaxis. Summary report—Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. 
J Allergy Clin Immunol 2006;117:3917.
Stokes ME, Davis CS, Koch GG. Categorical Data Analysis Using the SAS System, 
Cary, NC: SAS Institute, Inc. 2000; 7.7:1747.
Swigris JJ, Brown KK, Behr J, et al. The SF-36 and SGRQ:  validity and first look at 
minimum important differences in IPF. Respiratory Medicine 2010;104:296-304.
Westfall and Krishen. Optimally weighted, fixed sequence, and gatekeeping multiple 
testing procedures. J Stat Plan Inference 2001;99:25-40.


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Appendix 1
Protocol Synopsis
TITLE:
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, STUDY TO ASSESS THE EFFICACY 
AND SAFETY OF LEBRIKIZUMAB IN PATIENTS 
WITH IDIOPATHIC PULMONARY FIBROSIS
PROTOCOL NUMBER:
GB28547
VERSION NUMBER:
7
EUDRACT NUMBER:
2013-001163-24
IND NUMBER:
117,062
TEST PRODUCT:
Lebrikizumab (RO5490255)
PHASE:
II
INDICATION:
Idiopathic Pulmonary Fibrosis
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
The primary efficacy objective for this study is to evaluate lebrikizumab compared with placebo 
as monotherapy or as combination therapy with pirfenidone background compared with placebo 
in patients with idiopathic pulmonary fibrosis (IPF), as measured by the annualized rate of 
decline in percentage of predicted forced vital capacity (FVC) over 52 weeks.
The secondary efficacy objectives are to evaluate lebrikizumab compared with placebo as 
monotherapy or as combination therapy with pirfenidone background therapy compared with 
placebo in patients with IPF as measured by: 

The efficacy on the basis of Progression Free Survival (PFS), pulmonary function, diffusion 
capacity, non-elective hospitalization for any cause, acute IPF exacerbation, proportion of 
patients with at least 10% decline in percentage of predicted FVC or death, and all cause 
of death

The distance walked in 6 minutes and health-related quality of life questionnaires
Safety Objectives
The safety objectives for this study are the following:

To evaluate the safety of lebrikizumab as monotherapy compared with placebo in patients 
with IPF

To evaluate the safety of lebrikizumab with pirfenidone as background therapy compared 
with placebo with pirfenidone as background therapy in patients with IPF
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is as follows:

To characterize the PK of lebrikizumab in patients with IPF


Appendix 1
Protocol Synopsis (cont.)
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Exploratory Objectives
The exploratory objectives for this study are as follows:

To evaluate the efficacy of lebrikizumab compared with placebo as monotherapy or as 
combination therapy with pirfenidone compared with placebo in patients with IPF on the 
basis of changes in quantitative lung fibrosis (QLF) score on HRCT, A Tool to Assess 
Quality of Life in IPF (ATAQ), and the BORG Category Ratio 10 Scale(BORG CR10), 
and time to first occurrence of St. George’s Respiratory Questionnaire (SGRQ) 
individual domain worsening as defined by reaching minimal important difference (MID).

To evaluate potential prognostic and predictive serum and whole blood RNA and DNA 
biomarkers associated with IPF
Study Design
Description of Study
This is a randomized, multicenter, double-blind, placebo-controlled, parallel-group study of 
lebrikizumab in patients with IPF.  Approximately 480 patients with a diagnosis of IPF will be 
enrolled in the study across two cohorts (approximately 150 patients in Cohort A having 
approximately 75 patients per treatment arm and approximately 330 patients in Cohort B having 
approximately 165 patients per treatment arm) at approximately 120 sites located globally.  The 
total treatment duration will be based on all patients receiving at least 13 doses (one dose every 
4 weeks [Q4W]) of blinded treatment over 48 weeks.  The study primary endpoint will measure 
the absolute change from baseline to Week 52 in percent predicted FVC.
Two cohorts of patients will be enrolled in the study; Cohort A patients will be treated in the 
absence of pirfenidone IPF background therapy; Cohort B patients will be treated with 
pirfenidone as background therapy.
Number of Patients
Approximately 480 patients with a diagnosis of IPF will be enrolled in the study across two 
cohorts (approximately 150 patients in Cohort A having approximately 75 patients per treatment 
arm and approximately 330 patients in Cohort B having approximately 165 patients per 
treatment arm) at approximately 120 sites located globally.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Able and willing to provide written informed consent and to comply with the study protocol

Age 40 years at Visit 1

Have a diagnosis of IPF based on the ATS/ERS/JRS/ALAT consensus statement on IPF 
within the previous 5 years from time of screening and confirmed at baseline.

Have a central review assessment of an HRCT performed during the screening period or 
within 12 months prior to the start of screening.
All patients who have undergone a SLB as part of their initial workup should have 
pathology slides sent in for SLB central review assessment.
Eligibility will be determined on the basis of assessments in Table 1.

A Multidisciplinary Discussion of Diagnosis (MDD) based on 2011 ATS/ERS/JRS/ALAT 
guidelines will be utilized to finalize the diagnosis in the event the initial central review 
outcome results for HRCT and SLB are disparate (inconsistent with UIP/definite UIP).
Additionally, patients must meet the following criteria for study entry:

FVC 40% and 100% of predicted at screening


Appendix 1
Protocol Synopsis (cont.)
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
Stable baseline lung function as evidenced by a difference of 10% in FVC (L) 
measurements between screening and Day 1, Visit 2 prior to randomization

Diffusion capacity of the lung for carbon monoxide (DLCO) 25% and 90% of predicted at 
screening

Ability to walk 100 meters unassisted in 6 minutes

Cohort A:  No background IPF therapy for 4 weeks allowed prior to randomization and 
throughout the placebo-controlled study period

Cohort B:  Tolerated dose of pirfenidone 2403 mg/QD for 4 weeks required prior to 
randomization and throughout the placebo-controlled study period
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known 
hypersensitivity to any component of the lebrikizumab injection

Evidence of other known causes of interstitial lung disease (ILD) (e.g., domestic and 
occupational environmental exposures, connective-tissue disease (CTD), and drug toxicity)

Lung transplant expected within 12 months of screening

Evidence of clinically significant lung disease other than IPF (e.g., asthma or chronic 
obstructive pulmonary disease [COPD])

Post-bronchodilator forced expiratory volume in 1 second (FEV1)/FVC ratio 0.7 at 
screening

Positive bronchodilator response evidenced by an increase of 12% predicted and 200 mL 
increase in either FEV1 or FVC

Any clinically significant medical disease (other than IPF) that is associated with an 
expected survival of 12 months, likely to require a change in therapy during the study, or 
likely to impact the ability of the patient to participate in the study in the opinion of the 
investigator, or impact the study efficacy or safety assessments

Requirement for continuous medical care and assistance, or limited ability to self-care that 
would impact the ability of patient to participate in the study or to perform the study-related 
assessments

Class IV New York Heart Association chronic heart failure or historical evidence of left 
ventricular ejection fraction 35%

Hospitalization due to an exacerbation of IPF within 4 weeks prior to or during screening

Known current malignancy or current evaluation for a potential malignancy

Major episode of infection requiring any of the following:
Admission to the hospital for24 hours within 4 weeks prior to screening or during 
screening and run-in period
Treatment with antibiotics (IV, IM, oral, or inhaled) within 4 weeks prior to screening or 
during screening and run-in period

An active upper or lower respiratory tract infection occurring at any time within the 
screening period prior to the randomization visit (Visit 1 to Day 1, Visit 2)

Listeria monocytogenes infection or active parasitic infection within 6 months prior to Day 1, 
Visit 2

Active tuberculosis requiring treatment within 12 months prior to screening

Known immunodeficiency, including but not limited to HIV infection


Appendix 1
Protocol Synopsis (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
29/Statistical Analysis Plan GB28547

Past use of any anti–IL-13 or anti–IL-4/IL-13 therapy, including lebrikizumab
Patients participating in a clinical trial that has not been unblinded should be assumed 
to have received the active drug

Evidence of acute or chronic hepatitis or known liver cirrhosis

AST, ALT, or total bilirubin elevation 2.0the upper limit of normal during screening

Clinically significant abnormality on ECG at screening or laboratory tests (hematology, 
serum chemistry, and urinalysis) that, in the opinion of the investigator, may pose an 
additional risk in administering study drug to the patient

Receipt of a live/attenuated vaccine within the 4 weeks prior to Visit 1

Chronic treatment with any of the following within 4 weeks or five half-lives prior to 
screening (whichever is longer) to the end of the placebo-controlled period (Day 365, 
Visit 16):
Immunosuppressive or immunomodulatory therapies (e.g., azathioprine, cyclosporine 
A, cyclophosphamide, D-penicillamine, interferon-gamma, tumor necrosis 
factor-antagonists)
Cytotoxic drugs (e.g., colchicine) if used for IPF indication
Pirfenidone (Exclusion Limited to Cohort A)
N-acetylcysteine
Pulmonary hypertension therapies (e.g., endothelin receptor antagonist, 
phosphodiesterase type-5 inhibitor, riociguat, prostacyclin or prostacyclin analogue)
Tyrosine kinase inhibitors including exclusion of nintedanib for Cohort A and Cohort B
Warfarin or other anticoagulant therapy if given for IPF indication
Any unlicensed therapy given for IPF indication
Any investigational agent

Chronic oral corticosteroid therapy is not permitted within 4 weeks prior to screening 
(Visit 1), during screening and run-in, or throughout the study period.

History of alcohol, drug, or chemical abuse that would impair or risk the patient’s full 
participation in the study, in the opinion of the investigator

Female patients of reproductive potential who are not willing to use a highly effective 
method of contraception (e.g., contraceptive pill or transdermal patch, spermicide and 
barrier [i.e., condoms], intrauterine device, implants for contraception, injections for 
contraception [with prolonged release], hormonal vaginal device, sterilization, surgical tubal 
ligation) for the duration of the study and for at least 18 weeks after the last dose of 
lebrikizumab or placebo study treatment.

Pregnant or lactating

Body weight 40 kg
Additional exclusions that are limited to Cohort B (Pirfenidone Background):

Known achalasia, esophageal stricture, or esophageal dysfunction sufficient to limit the 
ability to swallow oral medication

Tobacco smoking or use of tobacco-related products within 3 months of screening or 
unwillingness to avoid smoking throughout the study (e.g., cigarette, pipe, cigar)

Any condition that, as assessed by the investigator, might be significantly exacerbated by 
the known side effects associated with pirfenidone

Known or suspected peptic ulcer


Appendix 1
Protocol Synopsis (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
30/Statistical Analysis Plan GB28547

Creatinine clearance 40 mL/min, calculated using the Cockcroft-Gault formula

Ongoing use or following therapies within 4 weeks of randomization (Day 1, Visit 2) or 
during the study
Strong inhibitors of CYP1A2 (e.g., fluvoxamine or enoxacin)
Moderate inducers of CYP1A2, limited to tobacco smoking and tobacco-related 
products
Length of Study
The total length of the study will be approximately 4 years from first patient screened to 
completion of the last patient visit.  Individual patients may participate in the study for up to 
2.9 years.
End of Study
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  The 
LPLV is expected to occur a maximum of 118 weeks after the last patient is enrolled and 
randomized into Cohort A.  This timeframe includes a 52-week placebo-controlled period and a 
maximum of an additional 52 week open-label Lebrikizumab treatment period followed by the 
safety follow-up period.  In the case that enrollment in Cohort B is slower than anticipated, LPLV 
is expected occur a maximum of 66 weeks after the last patient is enrolled and randomized into 
Cohort B.  This timeframe includes a 52-weeks placebo-controlled period followed by the safety 
follow-up period.  All patients will be followed for safety for 18 weeks after the last dose of study 
treatment of lebrikizumab or placebo by subcutaneous injection.
Outcome Measures
Efficacy Outcome Measures
The primary efficacy outcome measure for this study is the annualized rate of decrease in 
percentage of predicted FVC over 52 weeks (% FVC/year).
Secondary Outcome Measures
The secondary efficacy outcome measures for this study are as follows:

Annualized rate of decline in 6-minute walk test (6MWT) distance over 52 weeks

Time from randomization to first occurrence of a 10% absolute decline in percentage of 
predicted FVC or death from any cause

Annualized rate of decrease in percentage of predicted DLCO over 52 weeks

PFS, defined as the time from study treatment randomization to the first occurrence of any 
of the following disease progression or death events:
Death from any cause
All cause hospitalization
A decrease from baseline (relative change) of 10% in FVC (mL/year)

Annualized rate of decrease in FVC over a 52-week period (mL/year)

Annualized rate of decrease in ATAQ-IPF total score over a 52-week period

Time from randomization to first occurrence of the SGRQ worsening (total score) as 
defined by reaching MID:  Total Score 7 or death from any cause

Time from randomization to non-elective hospitalization or death from any cause

Time from randomization to first event of acute IPF exacerbation as defined below
IPF exacerbation is defined as an event that meets all of the following criteria as 
determined by the investigator:
Unexplained worsening or development of dyspnea within the previous 30 days


Appendix 1
Protocol Synopsis (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
31/Statistical Analysis Plan GB28547
And radiologic evidence of new bilateral ground-glass abnormality or consolidation 
superimposed on a reticular or honeycomb background pattern that is consistent with 
UIP
And absence of alternative causes, such as left heart failure, pulmonary embolism, 
pulmonary infection (on the basis of endotracheal aspirate or bronchoalveolar lavage, 
if available, or investigator judgment), or other events leading to acute lung injury 
(e.g., sepsis, aspiration, trauma, reperfusion pulmonary edema)
Safety Outcome Measures
All safety outcome measures will be assessed by comparing results from the lebrikizumab 
treatment group with the placebo group.  The safety outcome measures for this study are as 
follows:

Frequency of adverse events during the study

Severity of adverse events during the study

Incidence of anti-therapeutic antibodies (ATAs) against lebrikizumab throughout the study
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Serum lebrikizumab concentration at Week 52 (CWk52)

Predose serum lebrikizumab concentrations (Cmin) at Weeks 4, 12, 24, and 36 (Cmin,Wk4, 
Cmin,Wk12, Cmin,Wk24, and Cmin,Wk36)

Elimination half-life of lebrikizumab
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Change from baseline to Week 52 in radiographic findings on pulmonary HRCT, including 
QLF score

Change from screening (corresponding to timing for randomization strata) in serum and 
plasma biomarkers (e.g., periostin and CCL18) and change from baseline in serum and 
plasma biomarkers (e.g., periostin, chemokine (C-C motif) ligand 18 [CCL18], YKL40, 
COMP, OPN, CCL13)

Serum lebrikizumab concentrations during the extended treatment and the 14-week safety 
follow-up period

Exposure-response relationships (to be evaluated as warranted)

Change from baseline to Week 52 in the Borg CR10 Scale

Change from baseline to Week 52 in the ATAQ-IPF

Time from randomization to first occurrence of SGRQ individual domain worsening as 
defined by reaching MID:  Symptom 8, Activity 5, Impact 7, or death from any 
cause

Change from baseline to Week 52 in the SGRQ
The analysis plan for the exploratory HRCT and biomarkers will be specified in a separate 
document.


Appendix 1
Protocol Synopsis (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
32/Statistical Analysis Plan GB28547
Investigational Medicinal Products
Test Product
Lebrikizumab will be administered by subcutaneous injection of 250 mg every 4 weeks, with the 
first injection occurring at the randomization visit (Day 1, Visit 2).  Patients will continue to 
receive blinded study treatment every 4 weeks during the placebo-controlled treatment period 
for a total of 13 doses/26 injections of blinded treatment.
Comparator
For patients in Cohort A, placebo will be administered.  For patients in Cohort B, placebo plus a 
pirfenidone background dose of 2403 mg/d will be administered in divided doses three times 
per day with food.
Statistical Methods
Primary Analysis
The analysis of data from the placebo-controlled period for each cohort will be performed when 
all patients have either completed the end of the placebo-controlled treatment (Week 52/EOT)
visit or discontinued early from the study.  Treatment assignment will be unblinded to the 
personnel performing the analysis when all data through the EOT visit are in the database and 
the data have been cleaned and verified for each cohort.
The analysis of complete data for the study, including data from the placebo-controlled period, 
open-label extension period for Cohort A, and the 14-week safety follow-up period, will be 
performed when all patients have either completed the placebo-controlled period, open-label 
extension period for Cohort A, and 14-week safety follow-up period or discontinued early from 
the study, all data from the study are in the database, and the database is locked.  An interim 
futility analysis of Cohort B was conducted.
Efficacy Analyses
The analysis of data from the treatment period in Cohort A will be performed when all patients 
enrolled in Cohort A have either completed the end of placebo controlled treatment visit (Week 
52), or discontinued early from the study.  Treatment assignment will be unblinded to the 
personnel performing the analysis when all data through the Week 52 visit are in the database 
and the data have been cleaned and verified.
The analysis of data from the treatment period in Cohort B will performed when all patients 
enrolled in Cohort B have either completed the end of treatment visit (Week 52) or discontinued 
early from the study.  Treatment assignment will be unblinded to the personnel performing the 
analysis when all data through the Week 52 visit are in the database and the data have been 
cleaned and verified.
However, the Sponsor study team directly involved in the study conduct (medical monitoring, 
clinical operations, drug safety, etc.) will not have access to individual treatment assignments 
until study completion, when all patients have completed the safety follow-up or discontinued 
the study.  All non-Sponsor personnel who are involved in the conduct of the study 
(e.g., patients, site monitors, and investigators) will remain blinded to patient-specific treatment 
assignments until all patients complete the safety follow-up period or discontinue from the study.
Complete details of the analysis will be provided in the SAP, which will be finalized prior to 
unblinding the data.
Safety Analyses
Safety analyses will be based on all patients who received at least one dose of randomized 
study drug, with patients grouped according to the actual treatment received.  Safety summaries 
will be presented by treatment arm for all treated patients.  In addition, safety listings will be 
provided for any events reported during pirfenidone exposure prior to randomization.


Appendix 1
Protocol Synopsis (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
33/Statistical Analysis Plan GB28547
Safety will be assessed through the summary of adverse events, laboratory test results, 
(including antibodies to lebrikizumab), ECG, and vital signs.  These summaries will be produced 
separately for each cohort for the treatment period (placebo-controlled study treatment period, 
the Cohort A open-label lebrikizumab period).
Pharmacokinetic Analyses
Individual and mean serum lebrikizumab concentrationversus-time data will be reported.  
During the treatment period, mean concentrations will be reported at Weeks 4, 12, 24, 36, and 
52 (Cmin,Wk4, Cmin,Wk12, Cmin,Wk24, Cmin,Wk36, CWk52, respectively).  Estimates for these parameters 
will be tabulated and summarized (mean, SD, coefficient of variation, median, minimum, and 
maximum).  Additional PK analyses during the treatment period or the safety follow-up period 
may be conducted as appropriate.  Population PK modeling may be performed to characterize 
inter-individual variability, which may be reported separately from the clinical study report.
Exploratory Analyses
Analysis of exploratory efficacy endpoints will be described in the Statistical Analysis Plan.
Several pharmacodynamic biomarkers have been identified (e.g., periostin, CCL18, YKL40, 
COMP, OPN, CCL13) and will be measured in serum or plasma samples to assess the effect of 
lebrikizumab on these biomarkers.  Exploratory exposure-response analysis will be performed 
as appropriate.
Determination of Sample Size
In Cohort A, a sample size of 75 patients in each treatment group will provide approximately 80% 
power to detect a change in the annualized rate of decline in percentage of predicted FVC over 
52 weeks of a 3.7% difference in the means of the absolute change from baseline in percentage 
of predicted FVC at 52 weeks, assuming that the common standard deviation is 8% (as 
reported in the placebo group in the ASCEND trial of pirfenidone) using a two group t-test with a 
0.05 two-sided significance level.
In Cohort B, a sample size of 165 patients in each treatment group will provide approximately 
80% power to detect a 2.5% difference in the annualized rate of decline in percentage of 
predicted FVC over 52 weeks, assuming that the common standard deviation is 8% (as 
reported in the ASCEND trial of pirfenidone) using a two group t-test with a 0.05 two-sided 
significance level.
Optional Interim Analyses
The Sponsor may choose to conduct up to two interim efficacy analyses.  Interim analyses will 
involve unblinding of treatment assignments to the Sponsor for purposes of data analysis and 
interpretation.  Patients and all study site personnel will remain blinded to individual patient-level 
treatment assignments until completion of the trials.  The decision to conduct optional interim 
analyses and the timing of the analyses will be documented in the Sponsor’s trial master file 
prior to the conduct of the interim analyses.  The interim analyses will be performed and 
interpreted by members of the Sponsor study team and appropriate senior management 
personnel, who will be unblinded at the treatment group level.  Access to treatment assignment 
information will follow the Sponsor’s standard procedures.
After the analysis of Cohort A, the Sponsor formed an IMC to perform an unplanned interim 
futility analysis of Cohort B to determine if it should be terminated for lack of sufficient 
efficacy.  Following this analysis, the decision was made to continue the study and not 
perform additional efficacy and/or futility interim analyses.


Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
34/Statistical Analysis Plan GB28547
Appendix 2
Schedule of Assessments:  Screening and Placebo Controlled Treatment Period - Cohort A
Screening Rand.
Placebo Controlled Study Treatment Period a
EOT a, b
ET a
UV
Week

0
1
4
8
12
16
20
24
28
32
36
40
44
48
52


Day (Window)
–28 
1
8 
(2)
29 
(3)
57 
(3)
85 
(3)
113 
(3)
141 
(3)
169 
(3)
197 
(3)
225 
(3)
253 
(3)
281 
(3)
309 
(3)
337 
(3)
365
(3)


Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16


Informed consent c
x
Demographic data
x
Medical history
x
Physical exam d
x
Limited physical 
examination d
x
x
x
x
Weight
x
x
x
x
x
x
x
Height
x
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Resting pulse 
oximetry
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Single ECG f
x
x
x
x
Spirometry 
x g
x
x
x
x
x
x
x
x
x
x
DLCO
(mL CO/min-1/mmHg-1)
x
x
x
x
x
x
x
x
x
x
x
HRCT SLB central 
review for 
eligibility h
x
Quantitative HRCT i
x
x
x


Appendix 2
Schedule of Assessments:  Screening and Placebo Controlled Treatment Period - Cohort A (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
35/Statistical Analysis Plan GB28547
Screening Rand.
Placebo Controlled Study Treatment Period a
EOT a, b
ET a
UV
Week

0
1
4
8
12
16
20
24
28
32
36
40
44
48
52


Day (Window)
–28 
1
8 
(2)
29 
(3)
57 
(3)
85 
(3)
113 
(3)
141 
(3)
169 
(3)
197 
(3)
225 
(3)
253 
(3)
281 
(3)
309 
(3)
337 
(3)
365
(3)


Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16


6MWT/Borg CR10 
Scale j
x
x
x
x
x
ATAQ-IPF k
x
x
x
x
x
x
x
SGRQk
x
x
x
x
x
x
x
EQ-5D k
x
x
x
x
x
x
x
x
Hematology l
x
x
x
x
x
x
x
x
x
x
x
Chemistry m
x
x
x
x
x
x
x
x
x
x
x
B-type natriuretic 
peptide
x
Urinalysis n
x
x
x
x
x
x
x
Serum pregnancy 
test o
x
Urine pregnancy 
test o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PK sample p
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments:  Screening and Placebo Controlled Treatment Period - Cohort A (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
36/Statistical Analysis Plan GB28547
Screening Rand.
Placebo Controlled Study Treatment Period a
EOT a, b
ET a
UV
Week

0
1
4
8
12
16
20
24
28
32
36
40
44
48
52


Day (Window)
–28 
1
8 
(2)
29 
(3)
57 
(3)
85 
(3)
113 
(3)
141 
(3)
169 
(3)
197 
(3)
225 
(3)
253 
(3)
281 
(3)
309 
(3)
337 
(3)
365
(3)


Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16


Plasma PD 
sample p, q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PD 
sample p, q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum antibodies p
x
x
x
x
x
x
x
Serum tryptase r
Optional DNA 
sample s
x
Optional RNA 
sample s
x
x
x
x
Study drug 
administration t
x r
x r
x r
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events d, u
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Notes:  On treatment days, all assessments should be performed prior to dosing unless otherwise specified.
6MWT6-minute walk test; ATAQ-IPFA Tool to Assess Quality of Life in IPF; Borg CR10Borg Category Ratio 10 Scale®; DLCOdiffusion 
capacity of the lung for carbon monoxide; ECG electrocardiogram; EOTend of treatment; EQ-5DEuroQol 5-Dimension Questionnaire;


Appendix 2
Schedule of Assessments:  Screening and Placebo Controlled Treatment Period - Cohort A (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
37/Statistical Analysis Plan GB28547
ET early termination; HRCThigh-resolution computed tomography; IPF idiopathic pulmonary fibrosis; Rand. randomization; SGRQSt 
George’s Respiratory Questionnaire; UVunscheduled visit.
a Patients who discontinue study drug are encouraged to remain in the study and complete all scheduled assessments.  If this is not feasible, the 
patient should enter and complete the safety follow-up period or the early termination assessments, unless consent has been withdrawn.  If a 
patient is unable or unwilling to complete the assessment for 6MWT and/or the qtHRCT substudy assessment this will not be considered a 
protocol deviation.
b Patients who enter the open label lebrikizumab treatment period should complete Day1 OL visit 35 on the same day.
c Informed consent may be obtained on the day of Visit 1 or prior to visit 1 at the discretion of the investigator.  The informed consent process 
must be completed before initiating any Visit 1 assessments.
d Record abnormalities observed at baseline on the Medical History and Baseline Conditions eCRF.  New or worsening abnormalities should be 
recorded on the Adverse Event eCRF.
e Respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature.
f
ECGs should be performed prior to any scheduled study procedures (e.g., vital sign measurements, blood draws, and study drug 
administration, if applicable).
g Both pre- and post-bronchodilator testing are required at screening, but only pre-bronchodilator pulmonary function test is required throughout 
other study visits.
h A Multidisciplinary Discussion of Diagnosis (MDD) based on 2011 ATS/ERS/JRS/ALAT guidelines will be utilized to finalize the diagnosis in the 
event the initial central review outcome results for HRCT and SLB are disparate (inconsistent with usual interstitial pneumonitis (UIP)/definite UIP.
i
Optional procedure for patients who have consented to participate in the HRCT substudy limited to the United States and selected countries.  
Baseline qtHRCT scan does not need to be repeated if one was performed as part of the eligibility assessment.  All patients enrolled in the 
substudy will have an additional qtHRCT scan performed at the EoT Visit 16 at Week 52.  Assessment at ET is requested but not considered a 
protocol deviation if the patient is unable or unwilling to perform.
j
The Borg CR10 Scale will be performed immediately before and after the 6MWT.  Assessment of the 6MWT and Borg CR10 Scale at ET is 
requested but not considered a protocol deviation if the patient is unable or unwilling to perform.
k Complete before all other non-PRO assessments and before the patient receives any disease-status information or study treatment during the 
study visit.
l
Includes RBC count, WBC count, hemoglobin, hematocrit, platelet count, and WBC differential count (neutrophils, bands, lymphocytes,
eosinophils, basophils, monocytes, and other cells).


Appendix 2
Schedule of Assessments:  Screening and Placebo Controlled Treatment Period - Cohort A (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
38/Statistical Analysis Plan GB28547
m Includes sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total 
protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatinine phosphokinase, and uric acid.  Any patient who starts rescue therapy 
(including but not limited to pirfenidone) will need monitoring per the prescribing information.  All safety laboratory assessments, 
including those required for the prescribed rescue medication, should be analyzed by the central laboratory utilized for the GB28547 clinical 
study.
n Includes protein, blood, glucose, and microscopic examination (RBC, WBC, casts, and crystals).
o Only for women of childbearing potential see Appendix 9.
p On dosing days.  Samples for serum PK, PD, antibody (including anti-therapeutic antibody), and optional PAXgene mRNA analysis will be taken 
prior to dosing.  An additional sample for serum antibody and PK analysis must be taken in the event of an anaphylactic, anaphylactoid, or 
serious hypersensitivity reaction.  PLB2 antibody testing may be performed as appropriate using serum samples collected at pre-specified 
timepoints.
q Includes IL-13or IPF-related biomarkers (e.g., periostin, CCL18, YKL40, COMP, OPN, CCL13).  Screening serum periostin sample should be 
collected and shipped to the central laboratory within the first 2 weeks of screening.
r
Whenever possible, patients who experience an acute onset of symptoms of an anaphylactic, anaphylactoid, or serious hypersensitivity reaction 
should have a blood sample for total serum tryptase analysis collected 1–6 hours after the event.  The tryptase sample will be collected and 
analyzed per the site’s local laboratory practice.
s The DNA sample and whole blood PAXgene mRNA samples are optional and should be obtained only from patients who sign the separate RCR 
Informed Consent Form.
t
Patients will remain in the clinic for 1 hour after dosing for the first three dosing visits and for 30 minutes after dosing on all other study drug 
administration days for routine safety monitoring.
u All adverse events including serious adverse events and adverse events of special interest.


Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
39/Statistical Analysis Plan GB28547
Appendix 3
Schedule of Assessments:  Open-Label Lebrikizumab Treatment Period - Cohort A
Week
Wk 52 
(Day1
OL
Wk 56 
(Wk4 
OL)
Wk 60 
(Wk8
OL)
Wk 64 
(Wk12 
OL)
Wk 68 
(Wk16 
OL)
Wk 72 
(Wk20 
OL)
Wk 76 
(Wk24 
OL)
Wk 80 
(Wk28 
OL)
Wk84 
(Wk32 
OL)
Wk 88 
(Wk36 
OL)
Wk92 
(Wk40 
OL)
Wk96 
(Wk44 
OL)
Wk100
(Wk48
OL)
Wk104
(Wk52 
OL)
Day (Assessment 
Window)
365
(1OL) 
(± 3)
393
(29OL) 
(± 3)
421
(57OL) 
(± 3)
449
(85OL) 
(± 3)
477
(13OL) 
(± 3)
505 
(141 
OL) 
(± 3)
533
(169 
OL) 
(± 3)
561 
(197 
OL) 
(± 3)
589 
(225 
OL) 
(± 3)
617 
(253 
OL) 
(± 3)
645 
(281 
OL) 
(± 3)
673 
(309 
OL) 
(± 3)
701 
(337 
OL) 
(± 3)
729 
(365 
OL) 
(± 3)
Visit
35
36
37
38
39
40
41
42
43
44
45
46
47
EoT b
/SFU 
Wk4
ETq
UV
Limited physical 
exam a
x
x
x
Weight
x
x
x
x
x
Vital signs c
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Resting Pulse 
Oximetry
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Single ECG d
x
x
Spirometry 
x
x
x
x
x
x
x
x
x
DLco
x
x
x
x
x
x
x
x
x
6MWT/BorgCR10 e
x
x
x
ATAQ-PF f
x
x
x
SGRQ f
x
x
x
EQ-5D f
x
x
x
x


Appendix 3
Schedule of Assessments:  Open-Label Lebrikizumab Treatment Period - Cohort A (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
40/Statistical Analysis Plan GB28547
Week
Wk 52 
(Day1
OL
Wk 56 
(Wk4 
OL)
Wk 60 
(Wk8
OL)
Wk 64 
(Wk12 
OL)
Wk 68 
(Wk16 
OL)
Wk 72 
(Wk20 
OL)
Wk 76 
(Wk24 
OL)
Wk 80 
(Wk28 
OL)
Wk84 
(Wk32 
OL)
Wk 88 
(Wk36 
OL)
Wk92 
(Wk40 
OL)
Wk96 
(Wk44 
OL)
Wk100
(Wk48
OL)
Wk104
(Wk52 
OL)
Day (Assessment 
Window)
365
(1OL) 
(± 3)
393
(29OL) 
(± 3)
421
(57OL) 
(± 3)
449
(85OL) 
(± 3)
477
(13OL) 
(± 3)
505 
(141 
OL) 
(± 3)
533
(169 
OL) 
(± 3)
561 
(197 
OL) 
(± 3)
589 
(225 
OL) 
(± 3)
617 
(253 
OL) 
(± 3)
645 
(281 
OL) 
(± 3)
673 
(309 
OL) 
(± 3)
701 
(337 
OL) 
(± 3)
729 
(365 
OL) 
(± 3)
Visit
35
36
37
38
39
40
41
42
43
44
45
46
47
EoT b
/SFU 
Wk4
ETq
UV
Hematology g
x
x
x
x
x
x
x
x
x
x
Chemistry h
x
x
x
x
x
x
x
x
x
x
Urinalysis i
x
x
x
x
x
x
x
x
x
Urine pregnancy j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PK k
x
x
x
x
x
Plasma PD sample k,l
x
x
x
x
x
x
x
x
x
Serum PD k, l
x
x
x
x
x
x
x
x
x
Serum antibodiesk
x
x
x
x
x
Serum Tryptase m
Optional RNA n
x
x
x
Study drug 
administration o,p
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events a,q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 3
Schedule of Assessments:  Open-Label Lebrikizumab Treatment Period - Cohort A (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
41/Statistical Analysis Plan GB28547
6MWTsix minute walk test; ATAQ-IPFA Tool to Assess Quality of Life in IPF; Borg CR10 Scale Borg Category Ratio 10 Scale®; 
CTDconnective-tissue disease; DLCOdiffusion capacity of the lung for carbon monoxide; eCRF electronic Case Report Form; EOMTend 
of minimum treatment; EOTend of treatment; EQ-5DEuroQol 5-Dimension Questionnaire; ET early termination; FEV1forced expiratory 
volume in 1 second; FVCforced vital capacity; HRCT high-resolution computed tomography; IL-13interleukin 13; IPFidiopathic pulmonary 
fibrosis; PDpharmacodynamic; PKpharmacokinetic; Rand.Randomization; SGRQ St. George’s Respiratory Questionnaire; UVunscheduled 
visit.
Notes:  On treatment days, all assessments should be performed prior to dosing unless otherwise specified.
a New or worsening abnormalities should be recorded on the Adverse Event eCRF.
b This visit replaces Safety Follow-up Visit 1 on Appendix 4.  The next visit is Safety Follow-up Visit 2 at Week 12 (12 weeks after last dose of 
study drug). 
c Respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature.
d ECGs should be performed prior to any scheduled study procedures (e.g., vital sign measurements, blood draws, and study drug administration, 
if applicable).
e The Borg CR10 Scale will be performed immediately before and after the 6MWT.
f
Complete before all other non-PRO assessments and before the patient receives any disease-status information or study treatment during the 
study visit.
g Includes RBC count, WBC count, hemoglobin, hematocrit, platelet count, and WBC differential count (neutrophils, bands, lymphocytes, 
eosinophils, basophils, monocytes, and other cells).
h Includes sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total 
protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatinine phosphokinase, and uric acid.  Any patient who starts rescue therapy 
(including but not limited to pirfenidone) will need monitoring per the prescribing information.  All safety laboratory assessments, including those 
required for the prescribed rescue medication, should be analyzed by the central laboratory utilized for the GB28547 clinical study.
i
Includes protein, blood, glucose, and microscopic examination (RBC, WBC, casts, and crystals).
j
Only for women of childbearing potential see Appendix 9.
k On dosing days.  Samples for serum PK, PD, antibody (including anti-therapeutic antibody), and optional PAXgene mRNA analysis will be taken 
prior to dosing.  An additional sample for serum antibody and PK analysis must be taken in the event of an anaphylactic, anaphylactoid, or 
serious hypersensitivity reaction.  PLB2 antibody testing may be performed as appropriate using serum samples collected at pre-specified 
timepoints.
l
Includes IL-13 or IPF-related biomarkers (e.g., periostin, CCL18, YKL40, COMP, OPN, CCL13).
m Whenever possible, patients who experience an acute onset of symptoms of an anaphylactic, anaphylactoid, or serious hypersensitivity reaction 
should have a blood sample for total serum tryptase analysis collected 1–6 hours after the event.  The tryptase sample will be collected and 
analyzed per the site’s local laboratory practice.


Appendix 3
Schedule of Assessments:  Open-Label Lebrikizumab Treatment Period - Cohort A (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
42/Statistical Analysis Plan GB28547
n The whole blood PAXgene mRNA samples are optional and should be obtained only from patients who sign the separate RCR Informed 
Consent Form.
o Patients will remain in the clinic for 1 hour after dosing for the first three dosing visits and for 30 minutes after dosing on all other study drug 
administration days for routine safety monitoring.
p Patients who discontinue study drug are encouraged to remain in the study and complete all scheduled assessments.  If this is not feasible, the 
patient should enter and complete the safety follow-up period or the early termination assessments, unless consent has been withdrawn.
q
All adverse events including serious adverse events and adverse events of special interest.


Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
43/Statistical Analysis Plan GB28547
Appendix 4
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B
Screening
PFD 
titration
-run-in
Rand.
Placebo controlled Study Treatment Period a
EOTa, b ETa
UV
Week

0
1
4
8
12
16
20
24
28
32
36
40
44
48
52


Day (Window)
–28 (14) 4-6 wks
(28-42 
days)
1
8 
(2)
29 
(3)
57 
(3)
85 
(3)
113 
(3)
141 
(3)
169 
(3)
197 
(3)
225 
(3)
253 
(3)
281 
(3)
309 
(3)
337 
(3)
365 
(3)


Visit
1
1.5
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16


Informed 
consent c
x
Demographic 
data
x
Medical history
x
Physical exam d
x
Limited physical 
examination d
x
x
x
x
Weight
x
x
x
x
x
x
x
x
x
x
x
Height
x
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Resting pulse 
oximetry
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Single ECG f
x
x
x
x
Spirometry
x g
x
x
x
x
x
x
x
x
x
x


Appendix 4
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
44/Statistical Analysis Plan GB28547
Screening
PFD 
titration
-run-in
Rand.
Placebo controlled Study Treatment Period a
EOTa, b ETa
UV
Week

0
1
4
8
12
16
20
24
28
32
36
40
44
48
52


Day (Window)
–28 (14) 4-6 wks
(28-42 
days)
1
8 
(2)
29 
(3)
57 
(3)
85 
(3)
113 
(3)
141 
(3)
169 
(3)
197 
(3)
225 
(3)
253 
(3)
281 
(3)
309 
(3)
337 
(3)
365 
(3)


Visit
1
1.5
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16


DLCO
(mL CO/min-1/m
mHg-1)
x
x
x
x
x
x
x
x
x
x
x
HRCT SLB 
central review 
for eligibility h
x
Quantitative 
HRCT i
x
x
x
6MWT/Borg 
CR10 Scale j
x
x
x 
x
x
ATAQ-IPF k
x
x
x
x
x
x
x
x
x
SGRQ k
x
x
x
x
x
x
x
x
x
EQ-5D k
x
x
x
x
x
x
x
x
Hematology l
x
x
x
x
x
x
x
x
x
x
x
Chemistry m
x
xn
x
x
x
x
x
x
x
x
x
x
x
x
x
B-type 
natriuretic 
peptide
x
Urinalysis o
x
x
x
x
x
x
x


Appendix 4
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
45/Statistical Analysis Plan GB28547
Screening
PFD 
titration
-run-in
Rand.
Placebo controlled Study Treatment Period a
EOTa, b ETa
UV
Week

0
1
4
8
12
16
20
24
28
32
36
40
44
48
52


Day (Window)
–28 (14) 4-6 wks
(28-42 
days)
1
8 
(2)
29 
(3)
57 
(3)
85 
(3)
113 
(3)
141 
(3)
169 
(3)
197 
(3)
225 
(3)
253 
(3)
281 
(3)
309 
(3)
337 
(3)
365 
(3)


Visit
1
1.5
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16


Serum 
pregnancy test p
x
Urine pregnancy 
test p
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PK 
sample q
x
x
x
x
x
x
x
x
Plasma PD 
sample q, r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PD 
sample q, r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum 
antibodies q
x
x
x
x
x
x
x
Serum tryptase s
Optional DNA 
sample t
x
Optional RNA 
sample t
x
x
x
x
Study drug 
administration u
x s
x s
x s
x
x
x
x
x
x
x
x
x
x


Appendix 4
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
46/Statistical Analysis Plan GB28547
Screening
PFD 
titration
-run-in
Rand.
Placebo controlled Study Treatment Period a
EOTa, b ETa
UV
Week

0
1
4
8
12
16
20
24
28
32
36
40
44
48
52


Day (Window)
–28 (14) 4-6 wks
(28-42 
days)
1
8 
(2)
29 
(3)
57 
(3)
85 
(3)
113 
(3)
141 
(3)
169 
(3)
197 
(3)
225 
(3)
253 
(3)
281 
(3)
309 
(3)
337 
(3)
365 
(3)


Visit
1
1.5
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16


PFD dispensing
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse 
events v
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
6MWT6-minute walk test; ATAQ-IPFA Tool to Assess Quality of Life in IPF; Borg CR10Borg Category Ratio 10 Scale®; DLCOdiffusion 
capacity of the lung for carbon monoxide; ECG electrocardiogram; EOTend of treatment; EQ-5DEuroQol 5-Dimension Questionnaire;
ET early termination; HRCT high-resolution computed tomography; IPF idiopathic pulmonary fibrosis; PFD pirfenidone, Rand. randomization; 
SGRQSt. George’s Respiratory Questionnaire; UVunscheduled visit.
Notes:  On treatment days, all assessments should be performed prior to dosing unless otherwise specified.


Appendix 4
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
47/Statistical Analysis Plan GB28547
a Patients who discontinue study drug are encouraged to remain in the study and complete all scheduled assessments.  If a patient is unable or 
unwilling to complete the assessment for 6MWT and/or the qtHRCT substudy assessment this will not be considered a protocol deviation.  If this 
is not feasible, the patient should enter and complete the safety follow-up period or the early termination assessments, unless consent has been 
withdrawn.
b This visit replaces Safety Follow-up Visit 1 on Appendix 4. The next visit is Safety Follow-up Visit 2 at Week 12.
c Informed consent may be obtained on the day of Visit 1 or prior to visit 1 at the discretion of the investigator.  The informed consent process 
must be completed before initiating any Visit 1 assessments.
d Record abnormalities observed at baseline on the Medical History and Baseline Conditions eCRF.  New or worsening abnormalities should be 
recorded on the Adverse Event eCRF.
e Respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature.
f
ECGs should be performed prior to any scheduled study procedures (e.g., vital sign measurements, blood draws, and study drug administration, 
if applicable).
g Both pre- and post-bronchodilator testing are required at screening, but only pre-bronchodilator pulmonary function test is required throughout 
other study visits.
h A Multidisciplinary Discussion of Diagnosis (MDD) based on 2011 ATS/ERS/JRS/ALAT guidelines will be utilized to finalize the diagnosis in the 
event the initial central review outcome results for HRCT and SLB are disparate (inconsistent with usual interstitial pneumonitis (UIP)/definite UIP.
i
Optional procedure for patients who have consented to participate in the HRCT substudy limited to the United States.  Baseline qtHRCT scan 
does not need to be repeated if one was performed as part of the eligibility assessment.  All patients enrolled in the substudy will have an 
additional qtHRCT scan performed at the EOT Visit16 at Week 52.  Assessment at ET visit is requested but not considered a protocol deviation if 
patient is unable or unwilling to perform. 
j
The Borg CR10 Scale will be performed immediately before and after the 6MWT.  Assessment of the 6MWT and Borg CR10 Scale at ET visit is 
requested but not considered a protocol deviation if patient is unable or unwilling to perform.
k Complete before all other non-PRO assessments and before the patient receives any disease-status information or study treatment during the 
study visit.
l
Includes RBC count, WBC count, hemoglobin, hematocrit, platelet count, and WBC differential count (neutrophils, bands, lymphocytes, 
eosinophils, basophils, monocytes, and other cells).
m Includes sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total 
protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatinine phosphokinase, and uric acid.  Any patient who starts rescue therapy 
(including but not limited to pirfenidone) will need monitoring per the prescribing information.  All safety laboratory assessments, 
including those required for the prescribed rescue medication, should be analyzed by the central laboratory utilized for the GB28547 
clinical study.
n If run-in period exceeds 4 weeks, follow pirfenidone guidance provided in the ESBRIET/PIRESPA package insert for liver function test.


Appendix 4
Schedule of Assessments:  Screening, Pirfenidone Titration Run-In, and Placebo-Controlled 
Treatment Period - Cohort B (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
48/Statistical Analysis Plan GB28547
o Includes protein, blood, glucose, and microscopic examination (RBC, WBC, casts, and crystals).
p Only for women of childbearing potential see Appendix 9.
q On lebrikizumab dosing days.  Samples for serum PK, PD, antibody (including anti-therapeutic antibody), and optional PAXgene mRNA analysis 
will be taken prior to lebrikizumab dosing.  An additional sample for serum antibody and PK analysis must be taken in the event of an 
anaphylactic, anaphylactoid, or serious hypersensitivity reaction.  Anti-PLB2 antibody testing may be performed as appropriate using serum 
samples collected at pre-specified timepoints.
r
Includes IL-13or IPF-related biomarkers (e.g., periostin, CCL18, YKL40, COMP, OPN, CCL13).  Screening serum periostin sample should be 
collected and shipped to the central laboratory within the first 2 weeks of screening.
s Whenever possible, patients who experience an acute onset of symptoms of an anaphylactic, anaphylactoid, or serious hypersensitivity reaction 
should have a blood sample for total serum tryptase analysis collected 1–6 hours after the event.  The tryptase sample will be collected and 
analyzed per the site’s local laboratory practice.
t
The DNA sample and whole blood PAXgene mRNA samples are optional and should be obtained only from patients who sign the separate RCR 
Informed Consent Form.
u Patients will remain in the clinic for 1 hour after dosing for the first three dosing visits and for 30 minutes after dosing on all other study drug 
administration days for routine safety monitoring.
v
All adverse events including serious adverse events and adverse events of special interest.


Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
49/Statistical Analysis Plan GB28547
Appendix 5
Schedule of Assessments: Safety Follow-Up Period
WEEK post last dose
4 a
12
18 (final visit)
Day post last dose (assessment window)
28 (± 3)
84 (± 3)
126 (± 3)
Visit
SFU1
SFU2
SFU3
Limited physical exam b
x
x
Weight
x
x
Vital signs c
x
x
x
Resting pulse oximetry
x
x
x
Single ECG (all patients) d
x
x
Spirometry i
x
x
x
DLco
x
x
x
6MWT/BorgCR10 e
x
ATAQ-IPF f
x
x
SGRQ f
x
x
EQ-5D f
x
x
Hematology g
x
x
x
Chemistry h
x
x
x
Urinalysis i
x
Urine pregnancy test j
x
Serum PK sample k
x
x
x
Plasma PD sample k,l
x
x
x
Serum PD sample k,l
x
x
x
Serum antibodies k
x
x


Appendix 5
Schedule of Assessments: Safety Follow-Up Period (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
50/Statistical Analysis Plan GB28547
WEEK post last dose
4 a
12
18 (final visit)
Day post last dose (assessment window)
28 (± 3)
84 (± 3)
126 (± 3)
Visit
SFU1
SFU2
SFU3
Optional RNA sample m
x
Concomitant medications
x
x
x
Adverse events a,n
x
x
x
PFD dispensing (Cohort B only)
x
x
6MWT6-minute walk test; ATAQ-IPFA Tool to Assess Quality of Life in IPF; Borg CR10Borg Category Ratio 10 
Scale®; DLCOdiffusion capacity of the lung for carbon monoxide; ECG electrocardiogram; EOTend of treatment; 
EQ-5DEuroQol 5-Dimension Questionnaire; ET early termination; HRCT high-resolution computed tomography; 
IPFidiopathic pulmonary fibrosis; SGRQSt. George’s Respiratory Questionnaire; UVunscheduled visit.
a For patients in Cohort A who only complete the placebo controlled study period at Week 52 and choose to 
discontinue, the Week 52 visit will count as this visit.  For patients in Cohort A who complete the open-label 
lebrikizumab study period at week 52OL, the Week 52OL will count as this visit.  For patients in Cohort B who 
complete the placebo controlled study period at Week 52, the Week 52 visit will count as this visit.
b New or worsening abnormalities should be recorded on the Adverse Event eCRF.
c Respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and
temperature.
d ECGs should be performed prior to any scheduled study procedures (e.g., vital sign measurements, blood draws, 
and study drug administration, if applicable).
e The Borg CR10 Scale will be performed immediately before and after the 6MWT.
f
Complete before all other non-PRO assessments and before the patient receives any disease-status information or 
study treatment during the study visit.
g Includes RBC count, WBC count, hemoglobin, hematocrit, platelet count, and WBC differential count (neutrophils, 
bands, lymphocytes, eosinophils, basophils, monocytes, and other cells).


Appendix 5
Schedule of Assessments: Safety Follow-Up Period (cont.)
Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
51/Statistical Analysis Plan GB28547
h Includes sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, 
total and direct bilirubin, total protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatinine phosphokinase,
and uric acid.  Any patient who starts rescue therapy (including but not limited to pirfenidone) will need 
monitoring per the prescribing information.  All safety laboratory assessments, including those required for the 
prescribed rescue medication, should be analyzed by the central laboratory utilized for the GB28547 clinical study.
i
Includes protein, blood, glucose, and microscopic exam ination (RBC, WBC, casts, and crystals).
j
Only for women of childbearing potential see Appendix 9.
k On lebrikizumab dosing days.  Samples for serum PK, PD, antibody (including anti-therapeutic antibody), and 
optional PAXgene mRNA analysis will be taken prior to lebrikizumab dosing.  An additional sample for serum 
antibody and PK analysis must be taken in the event of an anaphylactic, anaphylactoid, or serious hypersensitivity 
reaction.  Anti-PLB2 antibody testing may be performed as appropriate using serum samples collected at pre-
specified timepoints.
l
Includes IL-13or IPF-related biomarkers (e.g., periostin, CCL18, YKL40, COMP, OPN, CCL13).  
m The whole blood PAXgene mRNA samples are optional and should be obtained only from patients who sign the 
separate RCR Informed Consent Form.
n All adverse events including serious adverse events and adverse events of special interest.


Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
52/Statistical Analysis Plan GB28547
Appendix 6
GAP Index and Staging System for IPF
The GAP index is an IPF disease staging system consisting of points ranging from 0 to 8 
that correspond to increasing disease severity as outlined below.
Predictor
Points
G
Gender
Female
0
Male
1
A
Age (years)
60
0
61–65 
1
>65
2
P
Physiology
FVC, % predicted
>75
0
50–75
1
49
2
DLco, % predicted
>55
0
36–55
1
35
2
Cannot perform
3
Total possible points
8
Stage
I
II
III
Points
0–3
4–5
6–8
Mortality
1-year
5.6
16.2
39.2
2-year
10.9
29.9
62.1
3-year
16.3
42.1
76.8
Notes: GAPgender, age, and two lung physiology variables (FVC and DLco). 
Patients should be scored in the “Cannot perform” category for DLco if their 
symptoms or lung function prohibited performance of the DLco maneuver. If 
DLco is unavailable because it was not ordered or not completed because of 
nonrespiratory limitations, then the model cannot be applied. 
Source: Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging 
system for idiopathic pulmonary fibrosis. Annals of Internal Medicine 2012; 156: 684–
691.


Lebrikizumab (RO5490255)—F. Hoffmann-La Roche Ltd
53/Statistical Analysis Plan GB28547
Appendix 7
Clinical Criteria for Diagnosing Anaphylaxis 
These criteria are taken from a summary report from the second symposium on the 
definition and management of anaphylaxis, conducted by the National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network. Anaphylaxis is highly 
likely when any one of the following three criteria is fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING:

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms of end-organ dysfunction 
(e.g., hypotonia, syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):

Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope, 
incontinence)

Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3. Reduced blood pressure after exposure to known allergen for that patient 
(minutes to several hours), defined in adults as systolic blood pressure of less 
than 90 mmHg or greater than 30% decrease from that person’s baseline.