Conditions: Follicular Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
The primary objective of this study is to establish a safe and effective dosing regimen of idelalisib in participants with relapsed or refractory follicular lymphoma (FL) who have no other therapeutic options.

Detailed description:

Arms:
arm 1: Participants will receive idelalisib 150 mg twice daily continuously.

For participants enrolled prior to protocol amendment 5: Based on the independent review committee (IRC) response assessment, participants may be discontinued from the study or may receive blinded or open-label idelalisib 150 mg twice daily. arm 2: Participants will receive idelalisib 100 mg twice daily continuously. Based on the IRC response assessment, participants may either be dose escalated to open-label 150 mg twice daily or maintain blind and continue on idelalisib 100 mg twice daily.

As of protocol amendment 5, enrollment to this arm has been closed. arm 3: Participants will receive idelalisib 150 mg twice daily in 28-day cycles with 21 days on-treatment and 7 days off-treatment.

Interventions: intervention 1: Idelalisib
Intervention descriptions: intervention 1: Idelalisib tablet administered orally

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
Dose Optimization Study of Idelalisib in 
Follicular Lymphoma 
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov
Identifier:
101254
2015-000366-66 
NCT02536300
Indication:
Follicular Lymphoma 
Protocol ID:
GS-US-313-1580
Gilead Medical Monitor:
Name:
Office Telephone:
Mobile Telephone:
E-mail:
Protocol Version/Date:
Version 1.0 (Original)
12 June 2015
Version 2.0 (Amendment 1)
28 March 2016
Version 3.0 (Amendment 2)
07 June 2016
Version 4.0 (Amendment 3)
08 September 2016
Version 5.0 (Amendment 4)
25 September 2017
Version 6.0 (Amendment 5)
13 March 2019
Version 7.0 (Amendment 6)       18 March 2021
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in 
the protocol. You will not disclose any of the information to others without written 
authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered.
GILEAU 
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................5
LIST OF IN-TEXT FIGURES........................................................................................................................................5
PROTOCOL SYNOPSIS................................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................................17
1.
INTRODUCTION................................................................................................................................................20
1.1.
Background..............................................................................................................................................20
1.2.
Idelalisib ..................................................................................................................................................20
1.3.
Rationale for This Study..........................................................................................................................21
1.4.
Risk/Benefit Assessment for the Study ...................................................................................................22
1.5.
Compliance..............................................................................................................................................23
2.
OBJECTIVES.......................................................................................................................................................24
3.
STUDY DESIGN.................................................................................................................................................25
3.1.
Endpoints.................................................................................................................................................25
3.2.
Study Design ...........................................................................................................................................25
3.2.1.
Study Schema ........................................................................................................................26
3.2.2.
Subjects Enrolled Prior to Protocol Amendment 5 ...............................................................27
3.3.
Study Treatments.....................................................................................................................................28
3.4.
Duration of Treatment .............................................................................................................................28
3.5.
Discontinuation Criteria ..........................................................................................................................28
3.5.1.
Discontinuation of Study Drug..............................................................................................28
3.5.2.
Discontinuation from Study ..................................................................................................29
3.6.
Biomarker Assessments...........................................................................................................................30
3.6.1.
Biomarker Samples for Optional Future Research................................................................30
3.6.2.
Biomarker Samples for Optional Genomic Research ...........................................................30
4.
SUBJECT POPULATION...................................................................................................................................31
4.1.
Number of Subjects and Subject Selection .............................................................................................31
4.2.
Inclusion Criteria.....................................................................................................................................31
4.3.
Exclusion Criteria....................................................................................................................................33
5.
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................................35
5.1.
Randomization, Blinding and Treatment Codes .....................................................................................35
5.1.1.
Procedures for Breaking Treatment Codes............................................................................35
5.2.
Description and Handling of Idelalisib....................................................................................................36
5.2.1.
Formulation ...........................................................................................................................36
5.2.2.
Packaging and Labeling ........................................................................................................36
5.2.3.
Storage and Handling ............................................................................................................37
5.3.
Dosage and Administration .....................................................................................................................37
5.3.1.
Idelalisib Dose Levels ...........................................................................................................38
5.3.2.
Idelalisib Dose Adjustments..................................................................................................39
5.4.
Prior and Concomitant Medications........................................................................................................42
5.4.1.
Idelalisib ................................................................................................................................42
5.4.2.
Anti-Cancer or Experimental Therapies Other than Idelalisib..............................................42
5.4.3.
Granulocyte Colony-Stimulating Factors and Erythropoietin...............................................42
5.4.4.
Corticosteroids.......................................................................................................................42
5.4.5.
Drugs that Alter CYP3A-Dependent Metabolism.................................................................43


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5.4.6.
Drugs that Undergo CYP3A-Dependent Metabolism...........................................................43
5.4.7.
COVID-19 Vaccination Guidelines ......................................................................................43
5.5.
Accountability for Idelalisib....................................................................................................................43
5.5.1.
Investigational Medicinal Product Return or Disposal .........................................................44
6.
STUDY PROCEDURES......................................................................................................................................45
6.1.
Study Procedure Descriptions .................................................................................................................45
6.1.1.
Informed Consent ..................................................................................................................45
6.1.2.
Medical and Medication History...........................................................................................45
6.1.3.
Physical Examination ............................................................................................................46
6.1.4.
Vital Signs .............................................................................................................................46
6.1.5.
Laboratory Assessments........................................................................................................46
6.1.6.
Electrocardiogram Assessment .............................................................................................49
6.1.7.
Radiology Assessment...........................................................................................................49
6.1.8.
Bone Marrow Biopsy ............................................................................................................50
6.1.9.
Performance Status................................................................................................................50
6.1.10.
Baseline Prognostic Factors, Ann Arbor Stage and FLIPI....................................................50
6.1.11.
Study Drug Dispensing and Dosing ......................................................................................50
6.1.12.
Adverse Events......................................................................................................................51
6.2.
Posttreatment Assessments......................................................................................................................51
6.3.
Assessments for Premature Discontinuation from Study........................................................................52
6.4.
End of Treatment.....................................................................................................................................52
6.5.
30-Day Follow-Up...................................................................................................................................52
6.6.
End of Study............................................................................................................................................52
6.7.
Survival Follow-Up.................................................................................................................................52
6.8.
Unscheduled Visits..................................................................................................................................52
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT................................................................................53
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events .................................53
7.1.1.
Adverse Events......................................................................................................................53
7.1.2.
Serious Adverse Events.........................................................................................................53
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ..........................................................................54
7.2.
Assessment of Adverse Events and Serious Adverse Events..................................................................54
7.2.1.
Assessment of Causality for Study Drugs and Procedures ...................................................55
7.2.2.
Assessment of Severity..........................................................................................................55
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead ........................................................................................................................56
7.3.1.
Electronic Serious Adverse Event (eSAE) Reporting Process..............................................56
7.4.
Gilead Reporting Requirements ..............................................................................................................57
7.4.1.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population............................................................58
7.5.
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
Adverse Events or Conditions.................................................................................................................58
7.5.1.
Dermatological Events ..........................................................................................................58
7.5.2.
Progressive Multifocal Leukoencephalopathy ......................................................................59
7.5.3.
Gastrointestinal Events..........................................................................................................59
7.5.4.
Hepatic Events.......................................................................................................................60
7.5.5.
Hematological and Immunological Events ...........................................................................60
7.5.6.
Infectious Events ...................................................................................................................61
7.5.7.
Pulmonary Events..................................................................................................................61
7.5.8.
Secondary Malignancies........................................................................................................62
7.5.9.
Tumor Lysis Syndrome .........................................................................................................63
7.5.10.
Pregnancy, Lactation, and Reproduction...............................................................................63


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7.5.11.
Ultraviolet Exposure..............................................................................................................64
7.5.12.
Investigation for Idelalisib Late Onset or Severe Diarrhea/Colitis .......................................64
7.5.13.
Further Safety Information....................................................................................................65
7.6.
Special Situations Reports.......................................................................................................................65
7.6.1.
Definitions of Special Situations...........................................................................................65
7.6.2.
Instructions for Reporting Special Situations........................................................................66
8.
STATISTICAL CONSIDERATIONS.................................................................................................................68
8.1.
Analysis Objectives and Endpoints.........................................................................................................68
8.1.1.
Analysis Objectives...............................................................................................................68
8.1.2.
Primary Endpoints.................................................................................................................68
8.1.3.
Secondary Endpoints.............................................................................................................68
8.1.4.
Other Endpoints of Interest ...................................................................................................69
8.2.
Analysis Conventions..............................................................................................................................69
8.2.1.
Analysis Sets .........................................................................................................................69
8.3.
Data Handling Conventions ....................................................................................................................70
8.4.
Demographic Data and Baseline Characteristics ....................................................................................70
8.5.
Efficacy Analysis.....................................................................................................................................70
8.5.1.
Primary and Supportive Analysis for Primary Endpoint.......................................................70
8.5.2.
Analysis for Secondary Endpoints ........................................................................................70
8.6.
Safety Analysis........................................................................................................................................71
8.6.1.
Extent of Exposure ................................................................................................................71
8.6.2.
Adverse Events......................................................................................................................71
8.6.3.
Laboratory Evaluations .........................................................................................................72
8.7.
Pharmacokinetic Analysis .......................................................................................................................72
8.8.
Sample Size .............................................................................................................................................73
8.9.
Data Monitoring Committee....................................................................................................................73
9.
RESPONSIBILITIES...........................................................................................................................................74
9.1.
Investigator Responsibilities ...................................................................................................................74
9.1.1.
Good Clinical Practice...........................................................................................................74
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval............................................................................................................74
9.1.3.
Informed Consent ..................................................................................................................75
9.1.4.
Confidentiality.......................................................................................................................75
9.1.5.
Study Files and Retention of Records and Samples..............................................................75
9.1.6.
Case Report Forms ................................................................................................................77
9.1.7.
Idelalisib Accountability and Return.....................................................................................77
9.1.8.
Inspections.............................................................................................................................78
9.1.9.
Protocol Compliance .............................................................................................................78
9.2.
Sponsor Responsibilities .........................................................................................................................78
9.2.1.
Protocol Modifications ..........................................................................................................78
9.2.2.
Study Report and Publications ..............................................................................................78
9.3.
Joint Investigator/Sponsor Responsibilities ............................................................................................79
9.3.1.
Payment Reporting ................................................................................................................79
9.3.2.
Access to Information for Monitoring...................................................................................79
9.3.3.
Access to Information for Auditing or Inspections ...............................................................79
9.3.4.
Study Discontinuation ...........................................................................................................79
9.4.
Independent Review Committee .............................................................................................................79
10.
REFERENCES.....................................................................................................................................................80
11.
APPENDICES......................................................................................................................................................82


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LIST OF IN-TEXT TABLES
Table 5-1.
Idelalisib Dose Levels .............................................................................................................38
Table 5-2.
Modification of Study Treatment in Response to Adverse Events..........................................39
Table 6-1.
Analytes...................................................................................................................................47
Table 7-1.
Grading of Adverse Event Severity.........................................................................................55
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema ..........................................................................................................................26
Figure 7-1.
Kaplan-Meier Time to Diarrhea or Colitis ..............................................................................65


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title:
Dose Optimization Study of Idelalisib in Follicular Lymphoma
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
101254
2015-000366-66
NCT02536300
Study Centers 
Planned:
Approximately 90 centers globally
Objectives:
The primary objective of this study is as follows:

Establish a safe and effective dosing regimen of idelalisib in 
subjects with relapsed or refractory follicular lymphoma (FL) who 
have no other therapeutic options
The secondary objectives of this study are as follows:

Evaluate the overall response rate (ORR)

Evaluate the progression-free survival (PFS), duration of response 
(DOR), and overall survival (OS)

Evaluate the overall safety profile of idelalisib

Determine the pharmacokinetics (PK) of idelalisib and its major 
metabolite (GS-563117)
The exploratory objective of this study is as follows:

 
Study Design:
This randomized, open-label study will evaluate the safety and efficacy 
of idelalisib in subjects randomized to the following treatment arms: 

Arm A: 150 mg idelalisib administered twice daily continuously. 

Arm C: 150 mg idelalisib administered twice daily in 28-day cycles 
with 21 days on-treatment and 7 days off-treatment.
CCI


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The original protocol for this study included an Arm B, which was 
closed to enrollment as of Protocol Amendment 5.

Arm B (closed to enrollment as of Protocol Amendment 5): 100 mg 
idelalisib administered twice daily continuously.
Study Design as of Protocol Amendment 5:
Study Design prior to Protocol Amendment 5:
Screening 
Screening 
Baseline 
Randomization 
Baseline Randomization 
ldelallslb 
150mg BID 
ldela llslb 
150 mg BID (21 days on-treatment, 7 days off-treatment) 
ldelalisib 
lSOmgBID 
SD/PR/CR 
(PD discontinues) 
Continue ldelallsib 
150 mg BID 
ldelalisib 
150mg BID 
ldelallslb 
lOOffllBID 
8 Week IRC Response Assessment "' 
100 mg BID dose escalation to 150 mg BID based on 
response (SD/PD) 
Endpoints: 
Safety and 
Efficacy 
Endpoints: 
Safety and 
Efficacy 
"'Unblinding and dose modifications may occur al any time during study participation if the IRC Assessment confirms progressive disease. 


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In accordance with Protocol Amendment 6, subjects enrolled prior to 
implementation of Protocol Amendment 5 and still blinded will be 
unblinded at the time of Protocol Amendment 6 implementation; these 
subjects will continue at the randomized dose level if they are still on 
treatment. These subjects were previously randomized in a blinded 
manner to either 150 mg twice daily or 100 mg twice daily idelalisib. 
Based on the 8-week blinded independent review committee (IRC) 
response assessment, subjects with stable disease (SD) or progressive 
disease (PD) were unblinded in both arms. Subjects with a partial 
response (PR) or complete response (CR) maintained the blind and 
continued at the randomized dose level. Subjects randomized to 100 mg 
twice daily with SD or PD had the option to be dose escalated to 
150 mg twice daily. Subjects randomized to 150 mg twice daily with 
SD will continue open-label idelalisib at 150 mg twice daily. Subjects 
randomized to 150 mg twice daily with PD will be discontinued from 
study treatment. These same unblinding and dose modification 
principles were applied at any time throughout study participation when 
disease progression was suspected and confirmed by IRC assessment. 
Number of 
Subjects 
Planned:
Approximately 266 subjects: approximately 120 subjects in Arm A, 
approximately 26 subjects in Arm B, and approximately 120 subjects in 
Arm C. As of Protocol Amendment 5, Arm B enrollment was closed 
after enrollment of approximately 26 subjects into Arm B and 
approximately 26 subjects into Arm A.
As of Protocol Amendment 5, subjects were randomized to 2 arms 
(Arm A and C) with a 1:1 ratio until the enrollment target of 
120 subjects in each arm was met. 
The sample size was originally planned to include 240 subjects 
randomized to Arm A and Arm B with a 1:1 ratio (approximately 
120 subjects receiving 150 mg twice daily in Arm A; approximately 
120 subjects receiving 100 mg twice daily in Arm B). 
Target 
Population:
The target population comprises adults with relapsed or refractory FL 
who have received at least 2 lines of prior therapy for FL with no other 
therapeutic options, have measurable lymphadenopathy, and require 
therapy according to standard response criteria. 
Duration of 
Treatment:
Idelalisib will be administered continuously until the earliest of: disease 
progression, unacceptable toxicity, substantial noncompliance with 
study procedures or study drug, initiation of another systemic 
anti-cancer or experimental therapy, or withdrawal from the study.
Duration of 
Study:
The overall duration of the study is expected to be approximately 
10 years.


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Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible 
for participation in this study:
1) Male or female  18 years of age
2) Histologically confirmed diagnosis of B-cell FL, and grade limited 
to 1, 2, or 3a based on criteria established by the World Health 
Organization (WHO) 2008 classification of tumors of 
hematopoietic and lymphoid tissues
3) Relapsed or refractory FL and have received at least 2 lines of prior 
therapy for FL and have no other available therapeutic options. 
Note: Rituximab maintenance is not routinely considered a 
separate line of therapy when it is given as part of the prior 
rituximab-containing regimen given over a number of cycles 
followed by maintenance. Rituximab monotherapy may be 
considered a separate line of therapy when disease relapse occurs 
between the initiation of rituximab monotherapy and the 
preceding line of therapy. If there are any ambiguities about 
eligibility, the site should consult with the medical monitor. 
4) Ann Arbor Stage 2 (noncontiguous), 3, or 4 disease 
per Lugano Classification
5) Radiographically measurable lymphadenopathy or extranodal 
lymphoid malignancy as determined by IRC, defined as the 
presence of at least 1 lesion that measures  1.5 cm in the longest 
dimension [LD] and  1.0 cm in the longest perpendicular 
dimension as assessed by positron emission tomography-computed 
tomography [PET-CT], computed tomography [CT], or magnetic 
resonance imaging [MRI])
6) Have adequate performance status (such as 
Eastern Cooperative Oncology Group Performance Status of  2 or 
Karnofsky Performance Status of ≥ 60)
7) Required baseline laboratory data (within 4 weeks prior to start of 
study therapy) as shown in the table. Note: Confirmation should be 
considered for out-of-range values to determine if the abnormality 
is real or artifactual. Values should be obtained within the 
screening period and should generally be the most recent 
measurement obtained.
Organ System
Parameter
Required Value
ANC
≥ 1,000/μL
Platelet
≥ 50,000/μL
Hematopoietica
Hemoglobin
≥ 8 g/dL


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Serum total bilirubin
≤ 1.5 x ULN (unless elevated due to 
Gilbert syndrome)
Serum ALT
Hepatic
Serum AST
≤ 2.5 x ULN
Renal
Serum Creatinine
 1.5 x ULN
Calculated or Estimated CrCL 
> 30 mL/min
Pregnancy
-hCGb
Negative
HIV
Negative HIV antibodyc
HBV
Negative HBsAg and 
negative HBcd antibody
HCV
Negative viral RNA
(if HCV antibody is positive)
Infection
CMV
No CMV DNA detected or CMV DNA 
is below the lower limit of 
quantification by PCR
AND
No clinical signs or symptoms 
suggestive of active CMV infection
ANC=absolute neutrophil count, -hCG=beta human chorionic gonadotropin, ALT=alanine 
aminotransferase, AST=aspartate aminotransferase, CMV=cytomegalovirus, CrCL=creatinine 
clearance, HBc antibody=anti-hepatitis B core antibody, HBsAg=hepatitis B surface antigen, 
HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, 
PCR=polymerase chain reaction, RNA=ribonucleic acid, ULN=upper limit of normal
a
Grade ≥ 3 neutropenia, thrombocytopenia, or anemia is permitted if abnormality is related 
to bone marrow involvement with FL (as documented by bone marrow biopsy/aspirate obtained 
since the last prior therapy)
b
For women of childbearing potential only; serum -hCG must be negative during 
screening and urine dipstick pregnancy test must be negative at baseline, prior to randomization
c
If screening test is positive, a negative confirmatory test will be required for eligibility.
d
Subjects who have positive HBc antibody may be enrolled if HBV DNA is undetectable 
by quantitative PCR
8) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception during 
heterosexual intercourse from the signing of informed consent 
throughout the study treatment period and up to 30 days from the 
last dose of idelalisib (see Appendix 4)
9) For male subjects of reproductive potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception during 
heterosexual intercourse and to refrain from sperm donation 
throughout the study treatment period and for 90 days following 
discontinuation of idelalisib (see Appendix 4)


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10) Lactating females must agree to discontinue nursing before study 
drug administration and until at least 30 days following the last 
dose of idelalisib
11) Indicate willingness to comply with scheduled visits, 
drug administration plan, imaging studies, laboratory tests, other 
study procedures, and study restrictions, including mandatory 
prophylaxis for Pneumocystis jirovecii pneumonia 
12) Evidence of a signed informed consent indicating that the subject is 
aware of the neoplastic nature of their disease and has been 
informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) History of lymphoid malignancy other than FL (eg, diffuse large 
B-cell lymphoma). Note: Biopsy documentation of the absence or 
presence of high grade lymphoma is not required
2) Known history of, or clinically apparent, central nervous system 
(CNS) lymphoma or leptomeningeal lymphoma. 
Note: Imaging documentation of the absence or presence of CNS 
disease is not required
3) Known presence of intermediate or high-grade myelodysplastic 
syndrome. Note: intermediate or high-grade myelodysplasia is 
defined as the presence of  5% bone marrow blasts; 
karotypic abnormalities other than normal, Y deletion, 5q deletion, 
or 20q deletion; or  2 lineages of cytopenias due to myelodysplasia 
4) Known history of serious allergic reaction including anaphylaxis or 
Stevens-Johnson syndrome/toxic epidermal necrolysis
5) History of a non-lymphoid malignancy except for the following: 
adequately treated local basal cell or squamous cell carcinoma of 
the skin, cervical carcinoma in situ, superficial bladder cancer, 
asymptomatic prostate cancer without known metastatic disease and 
with no requirement for therapy or requiring only hormonal therapy 
and with normal prostate-specific antigen for  1 year prior to 
enrollment, or any other cancer or malignancy that has been in 
complete remission for ≥ 5 years
6) Evidence of ongoing systemic infection (eg, bacterial, fungal, viral) 
at the time of enrollment


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7) Known history of drug-induced liver injury, chronic active 
hepatitis B virus, chronic active hepatitis C virus, alcoholic liver 
disease, non-alcoholic steatohepatitis, cirrhosis of the liver, 
portal hypertension, primary biliary cirrhosis, or ongoing 
extrahepatic obstruction caused by cholelithiasis
8) History of or ongoing drug-induced pneumonitis
9) History of or ongoing inflammatory bowel disease
10) Known human immunodeficiency virus (HIV) infection
11) Cytomegalovirus (CMV): Ongoing infection, treatment, or 
specifically CMV antiviral prophylaxis within 28 days prior to the 
Screening Visit CMV test
12) Presence of any condition that could, in the opinion of the 
investigator, compromise the subject’s ability to participate in the 
study, such as history of substance abuse, alcoholism, or a 
psychiatric condition
13) History of prior allogeneic bone marrow progenitor cell or solid 
organ transplantation
14) Ongoing immunosuppressive therapy, including systemic 
corticosteroids (> 10 mg prednisone or equivalent/day) with the 
exception of the use of topical, enteric, or inhaled corticosteroids as 
therapy for comorbid conditions or systemic corticosteroids for 
autoimmune anemia and/or thrombocytopenia
15) Concurrent participation in another therapeutic clinical study
16) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, electrocardiogram (ECG) finding, 
or laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of 
study results
17) Prior treatment with PI3K inhibitors
Study Visits:
Clinic visits will occur at Screening, Day 1, every 2 weeks through 
Week 12, every 4 weeks through Week 24, at Weeks 32, 36, 40, 48, 
and every 12 weeks thereafter through the end of study. Subjects will 
be assessed for safety at each visit. Additional visits will be required 
between protocol-specified visits for laboratory testing only.


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Subjects enrolled as of Protocol Amendments 5 and 6: 
Subjects will be assessed for FL disease status by continuous use of a 
single radiographic imaging method including PET-CT, CT, or MRI at 
screening and at Weeks 12, 24, 36, 48, 60, and 84 until IRC 
documented disease progression, and at the End of Treatment (EOT) 
visit (unless radiographic assessments were performed within the 
4 weeks prior to the EOT visit). After Week 84, radiographic 
assessments are performed at the discretion of the investigator. 
Screening CT/PET-CT/MRI may be performed within 6 weeks prior to 
the first dose. Subsequent scans may be done within 1 week prior to the 
clinic visit.
Subjects enrolled prior to Protocol Amendment 5: 
Subjects will be assessed for FL disease status by continuous use of a 
single radiographic imaging method including PET-CT, CT, or MRI at 
screening and at Weeks 8, 16, 24, 36, 48, 60, and 84 until IRC 
documented disease progression, and at the EOT visit (unless 
radiographic assessments were performed within the 4 weeks prior to 
the EOT visit). After Week 84, radiographic assessments are performed 
at the discretion of the investigator. Screening CT/PET-CT/MRI may 
be performed within 6 weeks prior to the first dose. Subsequent scans 
may be done within 1 week prior to the clinic visit.
Study Drug, Dose, 
and Mode of 
Administration:

Arm A: Idelalisib 150 mg will be taken twice daily orally starting 
on Day 1 and administered continuously. Dose reduction to 100 mg 
twice daily is available, if required.

Arm C: Idelalisib 150 mg will be taken twice daily orally starting 
on Day 1 and administered continuously for 21 days, followed by 
7 days of no study drug, within each 28-day cycle. Dose reduction 
to 100 mg twice daily (21 days on-treatment, 7 days off-treatment) 
is available, if required.
The original protocol for this study included an Arm B, which was 
closed to enrollment as of Protocol Amendment 5.

Arm B (closed to enrollment as of Protocol Amendment 5): 
Idelalisib 100 mg will be taken twice daily orally starting on Day 1 
and administered continuously. Dose reductions are not available.


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Criteria for 
Evaluation:
Safety/Efficacy 
Primary 
Endpoints:

ORR, defined as the proportion of subjects who achieve a PR or CR

Incidence of Grade ≥ 4 treatment-emergent adverse events (TEAEs)
Secondary 
Endpoints:

DOR, defined as the interval from the first documentation of CR or 
PR to the earlier of the first documentation of disease progression 
by IRC or death from any cause 

ORR by Week 24, defined as the proportion of subjects who 
achieve a PR or CR by Week 24

Overall safety profile of idelalisib, including the incidence of 
adverse events (AEs) and clinically significant laboratory 
abnormalities, severity, timing, and relationship to idelalisib of any 
AEs; serious adverse events (SAEs); or AEs leading to interruption, 
reduction, or discontinuation of idelalisib

Time to onset of AEs of interest (AEI), defined as the interval from 
the start of idelalisib treatment to the first documentation of start of 
AEI

PFS, defined as the interval from randomization to the earlier of the 
first documentation of disease progression by IRC or death from 
any cause

OS, defined as the interval from randomization to death from any 
cause

Idelalisib trough (predose) and peak (1.5-hour samples) plasma 
concentrations assessed by a validated bioanalytical method
Exploratory 
Endpoint:

 
Statistical 
Methods:
The primary study analysis will be conducted when all enrolled 
subjects have discontinued the study or been on treatment for at least 
48 weeks and completed response assessment of Week 48.
Analysis Data Set
The Intent-to-Treat (ITT) Analysis Set will include all subjects who are 
randomized regardless of whether subjects receive any study drug. 
Treatment assignment will be designated according to a subject’s initial 
randomization. This analysis set will be used in the analysis of subject 
characteristics and efficacy.
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The Safety Analysis Set will include data from all subjects who receive 
at least 1 dose of study treatment, with treatment assignments 
designated according to the actual treatment received. This analysis set 
will be used in the analyses of safety variables as well as study 
treatment administration.
The PK Analysis Set will include data from subjects in the Safety 
Analysis Set who have received the study drug and have at least 
1 sample with detectable drug concentration. 
An IRC will review radiographic data and pertinent clinical data in 
order to provide expert evaluation of tumor status, without receiving 
treatment assignment. The findings of the IRC will be considered 
primary for analyses of the primary efficacy endpoint and other tumor 
control endpoints. Tumor response status and progression will be 
assessed by the IRC using standard response criteria.
Efficacy Analysis
For the primary efficacy analysis, ORR will be evaluated by treatment 
arm using the IRC assessments in the ITT Analysis Set. Subjects who 
do not have sufficient baseline or on-study tumor assessment to 
characterize response will be counted as non-responders. Estimates and 
the corresponding 95% CIs based on the Clopper-Pearson exact method 
will be provided. The potential impact of subject baseline 
characteristics on treatment response may be explored with logistic 
regression modeling. 
The time-to-event efficacy endpoints including PFS, DOR, and OS will 
be analyzed using the Kaplan-Meier method in the ITT Analysis Set, 
and the analyses of DOR will include subjects who achieve a PR or 
CR.
Safety Analysis
Safety will be assessed via AEs, clinical laboratory tests, and 
concomitant medications. Information regarding study drug 
administration, study drug compliance, and other safety variables will 
be summarized by treatment arm. 
For the primary safety endpoint, the number and percentage of subjects 
who experienced at least 1 ≥ Grade 4 TEAE will be listed and 
summarized by treatment arm. The severity, timing, relationship to 
study drug, and drug interruptions for ≥ Grade 4 TEAEs will be 
summarized. 
The frequency, severity, timing, and drug interruptions for AEIs will be 
summarized by treatment arm using descriptive statistics. Time to onset 
and resolution of AEI will be analyzed using the Kaplan-Meier method.


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Pharmacokinetic Analysis
Using data from the PK Analysis Set, idelalisib/metabolite plasma 
concentrations will be listed and summarized by treatment arm and 
visit using descriptive statistics. Relationship between drug exposure 
and efficacy or safety will be explored.
Sample Size Calculation
The planned sample size is approximately 266 subjects: 
approximately 120 subjects in Arm A, approximately 26 subjects in the 
previously closed Arm B, and approximately 120 subjects in Arm C. 
As of Protocol Amendment 5, Arm B enrollment was closed after 
enrollment of approximately 26 subjects into Arm B and approximately 
26 subjects into Arm A.
As of Protocol Amendments 5 and 6, subjects will be randomized to 
2 arms (Arm A and C) with a 1:1 ratio until the enrollment target of 
120 subjects in each arm is met. The ORR was approximately 56% for 
subjects with FL in Study 101-09. If the underlying true ORR is 56% 
for subjects in this study, the chance to observe 60 or more responders 
out of 120 subjects (observed ORR ≥ 50%) is 92%. With 120 subjects 
in each arm, the half-width of a two-sided 95% CI of ORR is ≤ 10% for 
an observed ORR in the range of 40%-60%, and the half-width of a 
two-sided 95% CI of ≥ Grade 4 TEAEs incidence rate is ≤ 10% for an 
observed AE rate in the range of 20%-40%. 
The sample size was originally planned to include 240 subjects 
randomized to Arm A and Arm B with a 1:1 ratio (approximately 
120 subjects receiving 150 mg twice daily in Arm A; approximately 
120 subjects receiving 100 mg twice daily in Arm B).
This study will be conducted in accordance with the guidelines of good clinical practices (GCPs) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
adverse event
AEI
adverse event of interest
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
-hCG
beta-human chorionic gonadotropin
BID
twice daily
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI
confidence interval 
CLL
chronic lymphocytic leukemia
CMV
cytomegalovirus
COVID-19
coronavirus disease 2019
CNS
central nervous system
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DRESS
drug reaction with eosinophilia and systemic symptoms
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCcr
estimated creatinine clearance
eCRF
electronic case report form
EOS
end of study
EOT
end of treatment
EU
European Union
FD&C
food, drug and cosmetics
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose
FL
follicular lymphoma


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FLIPI
Follicular Lymphoma International Prognostic Index
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GM-CSF
granulocyte-macrophage colony-stimulating factors
HBc antibody
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
investigator’s brochure
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
Ig
immunoglobulin
iNHL
indolent non-Hodgkin lymphoma
IRB/IEC
institutional review board or independent ethics committee
IRC
Independent Review Committee
ITT
intent-to-treat
IUD
intrauterine device
IV
intravenous
IWRS
Interactive Web Response System
LD
longest dimension
LDH
lactic dehydrogenase
LPD
longest perpendicular dimension
MRI
magnetic resonance imaging
ND
no disease
NE
not evaluable 
NHL
non-Hodgkin lymphoma
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PE
physical examination
PET-CT
positron emission tomography–computed tomography
PFS
progression-free survival
PI3K
phosphatidylinositol 3-kinase
PJP
Pneumocystis jirovecii pneumonia
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PPD
product of the perpendicular dimensions
PR
partial response


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PT
preferred term
PVA
polyvinyl alcohol
PVE
Pharmacovigilance & Epidemiology
RNA
ribonucleic acid
SAE
serious adverse event
SD
stable disease
SJS
Stevens-Johnson syndrome
SLL
small lymphocytic lymphoma
SOC
system organ class
SOP
standard operating procedure
SPD
sum of the products of the diameters
StD
standard deviation
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
TEN
toxic epidermal necrolysis
UGT1A4
uridine diphosphate glucuronosyltransferase 1A4
ULN
upper limit of normal
US
United States
WHO
World Health Organization


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1.
INTRODUCTION
1.1.
Background
Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma 
(iNHL) in the United States (US); approximately 22% of all newly diagnosed non-Hodgkin 
lymphoma (NHL) and the second most frequent subtype of lymphoid malignancies in 
Western Europe; 5%-7% annual incidence {Dreyling 2014, National Comprehensive Cancer 
Network (NCCN) 2014}.
Computed tomography (CT) or magnetic resonance imaging (MRI) scans of the neck, chest, 
abdomen, and pelvis, as well as bone marrow aspirate and biopsy, are employed to stage iNHL 
{Zelenetz 2011}. The Lugano Classification for NHL modified the Ann Arbor classification for 
anatomic description of disease extent; single sites of involvement or a group of adjacent nodes 
(Stage 1), ≥ 2 sites of disease on the same side of the diaphragm (Stage 2), sites of disease on 
both sides of the diaphragm or nodes above the diaphragm with spleen involvement (Stage 3), or 
additional noncontiguous extralymphatic involvement (Stage 4) {Cheson 2014}.
For FL, the Follicular Lymphoma International Prognostic Index (FLIPI) has been developed to 
define outcomes {Solal-Celigny 2004}. The FLIPI characterizes patients in terms of 5 adverse 
prognostic factors: age > 60 years, Ann Arbor stage III-IV, hemoglobin < 12 g/dL, number of 
nodal areas > 4, and serum lactic dehydrogenase (LDH) above normal. Patients are scored as low 
risk (≤1 factor), intermediate risk (2 factors), or high risk (≥ 3 factors).
Radiation therapy to involved sites is the most common treatment for the infrequent patients with 
localized iNHL (Stage 1 or non-bulky Stage 2 disease) {Tsang 2005, Wilder 2001}. Systemic 
therapy is considered for the majority of patients with iNHL, in whom extensive lymphoma 
(Stage 2 bulky, Stage 3, or Stage 4 disease) is present {Zelenetz 2011}. Watchful waiting is 
possible but patients are generally treated if they have lymphoma-related symptoms or end-organ 
dysfunction, bulky disease, cytopenias, or persistent disease progression. Because iNHL 
requiring systemic therapy is essentially incurable and patients may be older and have 
comorbidities, the goal of therapy is primarily to alleviate lymphoma-related symptoms and 
prolong progression-free interval.
1.2.
Idelalisib
Idelalisib was first approved under the tradename Zydelig® in the US on July 23, 2014 for the 
treatment of relapsed chronic lymphocytic leukemia (CLL), FL, and small lymphocytic 
lymphoma (SLL), followed by centrally-authorized approval in the European Union (EU) on 
September 18, 2014 for the treatment of relapsed CLL and refractory FL. Zydelig® is currently 
approved in over 35 countries, including the US, EU, Switzerland, Australia, and Canada. Refer 
to local labeling for the approved indication statements.


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Idelalisib is a potent competitive inhibitor of the adenosine triphosphate binding site of the 
phosphatidylinositol 3-kinase (PI3K) p110δ catalytic domain, which has been shown to be 
prominently expressed in cells of hematopoietic origin {Okkenhaug 2003, Vanhaesebroeck 
2005}. The effects of p110δ on lymphocyte activation/function, cellular proliferation, and 
protection from apoptosis provide the rationale for targeting this isoform as a therapy for 
hematologic malignancies. Further details on the preclinical pharmacology, toxicology, 
metabolism and pharmacokinetics (PK) of idelalisib can be found in the idelalisib investigator’s 
brochure (IB).
1.3.
Rationale for This Study
Zydelig® (idelalisib) received accelerated approval in the US for the treatment of patients with 
relapsed FL who have received at least 2 prior systemic therapies based on results from a 
single-arm study (101-09) in 125 subjects with iNHL, including 72 subjects with FL, who had 
relapsed within 6 months following rituximab and an alkylating agent and had received at least 
2 prior treatments. In Study 101-09, all subjects received idelalisib 150 mg twice daily, with dose 
reductions to 100 mg twice daily allowed during the study to manage toxicity, consistent with the 
subsequently approved Zydelig® dosing regimen. The present study, GS-US-313-1580, is being 
conducted as a US postmarketing requirement (PMR 2180-10) under the accelerated approval 
regulations to verify the clinical benefit of Zydelig® monotherapy in patients with relapsed or 
refractory FL.
The subject population to be enrolled under the original version of this protocol comprised 
patients with previous systemic treatment for FL or SLL. In 2016, following identification of a 
safety signal and termination of several ongoing studies evaluating idelalisib in unapproved 
combinations (see Section 1.4, Anticipated Risks), the subject population in this study was 
restricted to align with the Zydelig® EU Summary of Product Characteristics while the European 
Medicines Agency Pharmacovigilance Risk Assessment Committee conducted a review under 
Article 20 of Regulation (EC) No 726/2004. The outcome of the Article 20 procedure confirmed 
a positive risk-benefit profile in the approved Zydelig® indications. Following discussions with 
the Food and Drug Administration (FDA) regarding this postmarketing study requirement, and a 
careful benefit-risk evaluation, the eligible subject population in Protocol Amendment 5 is being 
modified to include patients with relapsed or refractory FL who have received at least 2 lines of 
prior therapy for FL, have no other therapeutic options, and require therapy according to standard 
response criteria.
Prior to Protocol Amendment 5, this study was originally designed to evaluate the safety and 
efficacy of administration of idelalisib in subjects with FL at either 150 mg twice daily (Arm A) 
or 100 mg twice daily (Arm B). Based on the 8-week response assessment, subjects randomized 
to 100 mg twice daily idelalisib with stable disease (SD) or progressive disease (PD) would dose 
escalate to 150 mg twice daily. Subjects randomized to 150 mg twice daily with SD would 
continue 150 mg twice daily idelalisib. Subjects randomized to 150 mg twice daily with PD were 
discontinued. The rationale for selecting an 8-week independent review committee (IRC) 
confirmed response assessment was based on data from Study 101-09 in which: 56% (40/71) of 
responses occurred at the first assessment by 2 months, 83% (59/71) occurred by 4 months, and 
96% (67/71) occurred by 6 months.


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The idelalisib safety profile in relapsed iNHL has observed Grade ≥ 3 transaminase elevations 
with a median time to onset of 1.6 months and minimal occurrence beyond 4 months. 
Pneumonitis may develop at any time during treatment (median time to onset of 4.8 months, 
range from 3.7 to 14.1 months). Grade ≥ 3 diarrhea/colitis has a median time to onset of 
5 months and continues to occur throughout treatment at a rate of 0.041 per person years. 
Grade ≥ 3 rash has occurred at a median time to onset of 2 months, range from 0.4-7.9 months. 
These events are managed by dose interruptions, reductions, and re-escalation or discontinuation 
as medically appropriate.
As of Protocol Amendment 5, enrollment to Arm B was closed. This decision was based on 
preliminary data suggesting that Arm B appeared unlikely to meet Gilead’s FDA PMR 
2180-10 objective of achieving an overall response rate (ORR) ≥ 50% and there would have 
been insufficient exposure to the 100 mg twice daily dosing regimen to evaluate intermediate and 
long-term safety.
As of Protocol Amendments 5 and 6, this open-label study will evaluate the approved dosing 
regimen of 150 mg twice daily (Arm A) and an alternative dosing regimen (Arm C), with the 
goal of assessing whether the efficacy of the approved dosing regimen could be confirmed and 
alternative dosing regimen can achieve similar efficacy as the approved dosing regimen with 
reduced toxicity. Arm A will utilize the standard dosing schedule of continuous idelalisib 
administered twice daily. Subjects in Arm C will receive idelalisib at the approved dose of 
150 mg twice daily for the first 21 days of each 28-day cycle, followed by 7 days off treatment.
As of Protocol Amendment 6, there will be a planned global unblinding of all blinded subjects.
In addition to the aforementioned efficacy assessments, this study will assess the incidence of 
Grade ≥ 4 treatment-emergent adverse events (TEAEs) in each treatment arm. Of the 72 subjects 
with FL in Study 101-09, 23 subjects (32%) reported at least 1 Grade ≥ 4 TEAE, most frequently 
neutropenia (5 subjects [7%]), hypokalaemia (3 subjects [4%]), infections (2 subjects [3%]), 
increased aspartate aminotransferase (AST) (2 subjects [3%]), and thrombocytopenia (2 subjects 
[3%]).
1.4.
Risk/Benefit Assessment for the Study
Anticipated Benefits
This study randomizes patients with FL to one of 2 idelalisib regimens, the approved regimen or 
the alternative regimen. The alternative regimen with an intermittent dosing schedule (Arm C), 
results in lower idelalisib exposure, and thus has the potential for decreased frequency and 
severity of TEAEs. Subjects on the alternate regimen may thus benefit from reduced toxicity and 
fewer dose interruptions. Since the study requires response assessments on a 12-week schedule 
during the first 15 months of study treatment, a lack of response or progression of disease will be 
identified in a subject’s treatment course. Consequently, while there is the possibility of 
decreased efficacy in Arm C, the risk to the individual subject is minimized by the response 
assessment schedule, with the option for subjects on Arm C to discontinue treatment.


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Anticipated Risks
In 2016, an increased risk of death and a higher incidence of serious adverse events (SAEs), 
predominantly infectious events, were observed among subjects receiving idelalisib in 
combination with standard therapies compared to the control groups in a pooled analysis 
conducted by the independent data monitoring committee (DMC) of 3 Phase 3 clinical studies in 
patients with first-line CLL and early-line iNHL. Global regulatory agencies were notified of these 
findings and independently reviewed the data. These reviews confirmed a positive benefit-risk 
profile of Zydelig® (idelalisib) in the approved indications. Zydelig® country product labels were 
subsequently updated to include measures to minimize the risk of serious infections, including 
Pneumocystis jirovecii pneumonia (PJP) prophylaxis and cytomegalovirus (CMV) monitoring, in 
line with the risk minimization measures employed in clinical studies.
While CMV and PJP are important risks, these pathogens accounted for a relatively small 
proportion of the serious infections observed; therefore, more general measures are also used to 
minimize the risk of serious infections. In particular, treatment should not be initiated in subjects 
with evidence of ongoing systemic infection and subjects should be monitored for respiratory 
signs and symptoms throughout treatment and advised to report new respiratory symptoms 
promptly. Subjects should be administered PJP prophylaxis as described in Section 7.5.6.
Regular clinical and laboratory screening for CMV infection is mandated in all subjects. Blood 
counts should also be monitored in all subjects as described in Section 7.5.5.
Conclusion
The overall benefit-risk assessment for patients enrolled in this study is favorable. The risk of 
serious toxicity, shared by all patients receiving idelalisib, is mitigated by the protocol-specified 
safety assessments and PJP prophylaxis, as described above. There is a hypothetical risk of 
decreased efficacy in subjects receiving the alternate dosing regimen (Arm C), which is 
mitigated by the frequent scheduled response assessments as well as the possibility that subjects 
in Arm C may experience less drug-related toxicity than those in Arm A.
During a pandemic, additional potential risks to subjects may include adequate study drug 
availability, interruptions to the study visit schedule, and adherence to protocol-specified safety 
monitoring or laboratory assessments. Refer to Appendix 8 for further details on the risks and 
risk mitigation strategy.
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objective of this study is as follows:

Establish a safe and effective dosing regimen of idelalisib in subjects with relapsed or 
refractory FL who have no other therapeutic options
The secondary objectives of this study are as follows:

Evaluate the ORR

Evaluate the progression-free survival (PFS), duration of response (DOR), and overall 
survival (OS) 

Evaluate the overall safety profile of idelalisib

Determine the PK of idelalisib and its major metabolite (GS-563117)
The exploratory objective of this study is as follows:

 
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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoints of this study are as follows:

ORR, defined as the proportion of subjects who achieve a partial response (PR) or complete 
response (CR)

Incidence of Grade ≥ 4 treatment-emergent adverse events (TEAEs)
The secondary endpoints of this study are as follows:

DOR, defined as the interval from the first documentation of CR or PR to the earlier of the 
first documentation of disease progression by IRC or death from any cause 

ORR by Week 24, defined as the proportion of subjects who achieve a PR or CR by Week 24

Overall safety profile of idelalisib, including the incidence of adverse events (AEs) and 
clinically significant laboratory abnormalities, severity, timing, and relationship to idelalisib 
of any AEs; SAEs; or AEs leading to interruption, reduction, or discontinuation of idelalisib

Time to onset of AEs of interest (AEIs) defined as the interval from the start of idelalisib 
treatment to the first documentation of start of AEI

PFS, defined as the interval from randomization to the earlier of the first documentation of 
disease progression by IRC or death from any cause

OS, defined as the interval from randomization to death from any cause

Idelalisib trough (predose) and peak (1.5-hour samples) plasma concentrations assessed by 
validated bioanalytical method
The exploratory endpoint is as follows:

3.2.
Study Design
This is a randomized, open-label, multi-center study that will be conducted globally.
Subjects will be randomized in a 1:1 ratio, until the enrollment target per arm is met, to the 
following treatment arms:

Arm A: 150 mg twice daily idelalisib administered continuously
CCI


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
Arm C: 150 mg twice daily idelalisib administered in 28-day cycles (21 days on-treatment, 
7 days off-treatment) 
The original protocol for this study included an Arm B, which was closed to enrollment as of 
Protocol Amendment 5.

Arm B (closed to enrollment as of Protocol Amendment 5): 100 mg twice daily idelalisib 
administered continuously 
Clinic visits will occur at Screening, Day 1, every 2 weeks through Week 12, every 4 weeks 
through Week 24, at Weeks 32, 36, 40, 48, and every 12 weeks thereafter through end of study 
(EOS). Subjects will be assessed for safety at each visit. Additional visits will be required 
between clinic visits for laboratory testing only.
Subjects will be assessed for FL disease status by continuous utilization of a single modality 
including positron emission tomography–computed tomography (PET-CT), CT, or MRI. If 
permanent discontinuation of idelalisib occurs prior to IRC documented progression of FL, 
subjects shall remain on study until progression of FL or withdrawal from the study for reasons 
specified in Section 3.5.2.
3.2.1.
Study Schema
Figure 3-1.
Study Schema 
Screening 
Arm A 
Baseline 
Randomization 
ldelallslb 
150mg BID 
ldelalisib 
150 mg BID (21 days on-treatment, 7 days off-treatment) 
Endpoints : 
Safety and 
Efficacy 


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3.2.2.
Subjects Enrolled Prior to Protocol Amendment 5
Subjects enrolled prior to implementation of Protocol Amendment 5 followed the previous study 
design as shown here. 
In accordance with Protocol Amendment 6, subjects enrolled prior to implementation of Protocol 
Amendment 5 and still blinded will be unblinded at the time of Protocol Amendment 6 
implementation; these subjects will continue at the randomized dose level if they are still on 
treatment. These subjects were previously randomized in a blinded manner to either 150 mg 
twice daily or 100 mg twice daily idelalisib. Based on the 8-week blinded IRC response 
assessment, subjects with SD or PD were unblinded in both arms. Subjects with a PR or CR 
maintained the blind and continued at the randomized dose level. Subjects randomized to 100 mg 
twice daily with SD or PD had the option to be dose escalated to 150 mg twice daily. Subjects 
randomized to 150 mg twice daily with SD will continue open-label idelalisib at 150 mg twice 
daily. Subjects randomized to 150 mg twice daily with PD will be discontinued from study 
treatment. These same unblinding and dose modification principles were applied at any time 
throughout study participation when disease progression was suspected and confirmed by IRC 
assessment.
Subjects should follow study procedures as outlined in Section 6 and Appendix 2 Study 
Procedures Table. Idelalisib will be administered until meeting criteria for discontinuation of 
study drug as described in Section 3.5.1.
Screening 
Baseline Randomization 
ldelalisib 
150mg BID 
klelallslb 
lOOmgBID 
SD/PR/CR 
(PD discontinues) 
Continue ldelalisib 
150 mg BID 
ldelalisib 
150mg BID 
ldelallslb 
lOOmgBID 
8 Week IRC Response Assessment * 
100 mg Bl D dose escalation to 150 mg BID based on 
response (SD/PD) 
Endpoints: 
Safety and 
Efficacy 
• Un blinding and dose modificat ions may occur at any t ime during study participation if t he IRC Assessment confirms progressive disease. 


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3.3.
Study Treatments
Subjects will be randomized to the following treatment arms:

Arm A: Idelalisib 150 mg will be taken twice daily orally starting on Day 1 and administered 
continuously 

Arm C: Idelalisib 150 mg will be taken twice daily orally starting on Day 1 and administered 
continuously for 21 days, followed by 7 days of no study drug, within each 28-day cycle. 
Study drug should not be taken on scheduled “off-treatment” days, regardless of prior missed 
doses, study drug interruptions for toxicity, or PK samples. 
The original protocol for this study included an Arm B, which was closed to enrollment as of 
Protocol Amendment 5.

Arm B (closed to enrollment as of Protocol Amendment 5): 100 mg idelalisib will be taken 
twice daily orally starting on Day 1 and administered continuously. Subjects randomized to 
100 mg twice daily with SD or PD may be dose escalated to 150 mg twice daily.
In case of administrative delays, every attempt should be made to initiate study drug as soon as 
possible, but no more than 7 days from randomization. If needed for toxicity management, a dose 
reduction is available as described in Section 5. The study drug, idelalisib, will be supplied by 
Gilead. The formulation, packaging, and dosing regimen are further described in Section 5.
3.4.
Duration of Treatment
Idelalisib will be administered until a subject meets the criteria for discontinuation of study drug 
as described in Section 3.5.1.
3.5.
Discontinuation Criteria
3.5.1.
Discontinuation of Study Drug
Study drug should be discontinued under the following conditions, in consultation with the 
Gilead Medical Monitor:

Disease progression based on IRC response assessment 
For Arm B subjects only: Subjects randomized to 100 mg twice daily with IRC 
confirmed SD or PD may be dose escalated to 150 mg twice daily. Thereafter, Arm B 
subjects who are assigned to open-label 150 mg twice daily and have IRC documented 
PD after escalation must discontinue study drug. 

Initiation of non-study specific systemic anticancer therapy or concurrent participation in any 
other therapeutic clinical study


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
Any subject for whom the blind is intentionally broken by the subject or the study site 
outside of the planned protocol unblinding

If, in the investigator’s opinion, it is not in the subject’s best interest to continue

Pregnancy or breastfeeding begins during the study

Subject noncompliance

Subject request to discontinue study drug, for any reason

Unacceptable toxicity, either as assessed by the investigator or as specified in Section 5.3.2 
and Table 5-2, including inability of the subject to tolerate a rechallenge of study drug
Subjects who permanently discontinue study drug for a reason other than disease progression 
(as confirmed by the IRC) should continue with disease assessments per the study procedures 
table (Appendix 2) until disease progression, study participation has ended, or another 
anti-cancer or experimental therapy is initiated (see Section 5.4.2).
3.5.2.
Discontinuation from Study
Discontinuation from the study may occur in the following instances:

Disease progression based on IRC response assessment
For Arm B subjects only: Subjects randomized to 100 mg twice daily with IRC 
confirmed SD or PD may be dose escalated to 150 mg twice daily. Thereafter, Arm B 
subjects who are assigned to open-label 150 mg twice daily and have IRC documented 
PD after escalation must discontinue the study treatment. 

Initiation of non-study specific systemic anti-cancer therapy (see Section 5.4.2) or concurrent 
participation in any other therapeutic clinical study

In subjects for whom the blind is intentionally broken by the study site or the subject outside 
of the planned protocol unblinding

If, in the investigator’s opinion and in consultation with Gilead, it is determined not to be in 
the subject’s best interest to continue

Pregnancy or breastfeeding begins during the study

Death

Discontinuation of the study at the request of Gilead, a regulatory agency, or an 
institutional review board or independent ethics committee (IRB/IEC) occurs


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
Withdrawal of consent

Subject is lost to follow-up
3.6.
Biomarker Assessments
3.6.1.
 
 
 
 
 
3.6.2.
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
The planned sample size is approximately 266 subjects: approximately 120 subjects in Arm A, 
approximately 26 subjects in Arm B, and approximately 120 subjects in Arm C. As of Protocol 
Amendment 5, Arm B enrollment was closed after enrollment of approximately 26 subjects into 
Arm B and approximately 26 subjects into Arm A.
This clinical trial can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select subjects for whom study participation is 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject. Eligibility 
criteria may not be waived by the investigator and conformance to the eligibility criteria is 
subject to review in the case of a GCP or a regulatory authority audit. Any questions regarding a 
subject’s eligibility should be discussed with the Medical Monitor prior to enrollment. Entry into 
screening does not guarantee enrollment into the study. In order to manage the total study 
enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any site or 
study-wide at any time.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Male or female  18 years of age
2) Histologically confirmed diagnosis of B-cell FL, and grade limited to 1, 2, or 3a based on 
criteria established by the World Health Organization (WHO) 2008 classification of tumors 
of hematopoietic and lymphoid tissues
3) Relapsed or refractory FL and have received at least 2 lines of prior therapy for FL and have 
no other available therapeutic options. Note: Rituximab maintenance is not routinely 
considered a separate line of therapy when it is given as part of the prior 
rituximab-containing regimen given over a number of cycles followed by maintenance. 
Rituximab monotherapy may be considered a separate line of therapy when disease relapse 
occurs between the initiation of rituximab monotherapy and the preceding line of therapy. 
If there are any ambiguities about eligibility, the site should consult with the medical 
monitor.
4) Ann Arbor Stage 2 (noncontiguous), 3, or 4 disease per Lugano Classification
5) Radiographically measurable lymphadenopathy or extranodal lymphoid malignancy as 
determined by the IRC (defined as the presence of ≥ 1 lesion that measures ≥ 1.5 cm in the 
LD and  1.0 cm in the longest perpendicular dimension [LPD] as assessed by PET-CT, 
CT, or MRI)


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6) Have adequate performance status (such as Eastern Cooperative Oncology Group [ECOG] 
Performance Status of  2 or Karnofsky Performance Status of ≥ 60)
7) Required baseline laboratory data (within 4-weeks prior to start of study therapy) as shown in 
the table. Note: Confirmation should be considered for out-of-range values to determine if 
the abnormality is real or artifactual. Values should be obtained within the screening 
period and should generally be the most recent measurement obtained.
Organ System
Parameter
Required Value
ANC
≥ 1,000/μL
Platelet
≥ 50,000/μL
Hematopoietica
Hemoglobin
≥ 8g/dL
Serum total bilirubin
≤ 1.5 x ULN (unless elevated due to Gilbert syndrome)
Serum ALT
Hepatic
Serum AST
≤ 2.5 x ULN
Renal
Serum Creatinine
 1.5 x ULN Calculated or Estimated CrCL > 30 mL/min
Pregnancy
-hCGb
Negative
HIV
Negative HIV antibodyc
HBV
Negative HBsAg and negative HBcd antibody
HCV
Negative viral RNA (if HCV antibody is positive)
Infection
CMV
No CMV DNA detected or CMV DNA is below the lower 
limit of quantification by PCR
AND
No clinical signs or symptoms suggestive of active CMV 
infection
ANC=absolute neutrophil count, -hCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, CMV=cytomegalovirus, CrCL=creatinine clearance, HBc antibody=anti-hepatitis B core antibody, 
HBsAg=hepatitis B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, 
PCR=polymerase chain reaction, RNA=ribonucleic acid, ULN=upper limit of normal
a
Grade ≥ 3 neutropenia, thrombocytopenia, or anemia is permitted if abnormality is related to bone marrow involvement with 
FL (as documented by bone marrow biopsy/aspirate obtained since the last prior therapy)
b
For women of childbearing potential only; serum -hCG must be negative during screening and urine dipstick pregnancy 
test must be negative at baseline prior to randomization
c
If screening test is positive, a negative confirmatory test will be required for eligibility
d
Subjects who have positive HBc antibody may be enrolled if HBV DNA is undetectable by quantitative PCR
8) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception during heterosexual intercourse from the signing of informed 
consent throughout the study treatment period and up to 30 days from the last dose of 
idelalisib (see Appendix 4)


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9) For male subjects of reproductive potential having intercourse with females of childbearing 
potential, willingness to use a protocol-recommended method of contraception during 
heterosexual intercourse and to refrain from sperm donation throughout the study treatment 
period and for 90 days following discontinuation of idelalisib (see Appendix 4)
10) Lactating females must agree to discontinue nursing before study drug administration and 
until at least 30 days following last dose of idelalisib
11) Indicate willingness to comply with scheduled visits, drug administration plan, 
imaging studies, laboratory tests, other study procedures, and study restrictions, including 
mandatory prophylaxis for PJP
12) Evidence of a signed informed consent indicating that the subject is aware of the neoplastic 
nature of their disease and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study participation
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) History of lymphoid malignancy other than FL (eg, diffuse large B-cell lymphoma). Note: 
Biopsy documentation of the absence or presence of high grade lymphoma is not required
2) Known history of, or clinically apparent, central nervous system (CNS) lymphoma or 
leptomeningeal lymphoma. Note: Imaging documentation of the absence or presence of 
CNS disease is not required
3) Known presence of intermediate- or high-grade myelodysplastic syndrome. 
Note: intermediate- or high-grade myelodysplasia is defined as the presence of 
 5% bone marrow blasts; karotypic abnormalities other than normal, Y deletion, 
5q deletion, or 20q deletion; or  2 lineages of cytopenias due to myelodysplasia 
4) Known history of serious allergic reaction including anaphylaxis or Stevens-Johnson 
syndrome/toxic epidermal necrolysis
5) History of a non-lymphoid malignancy except for the following: adequately treated local 
basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, 
superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease 
and with no requirement for therapy or requiring only hormonal therapy and with normal 
prostate-specific antigen for ≥ 1 year prior to enrollment, or any other cancer or malignancy 
that has been in complete remission for ≥ 5 years
6) Evidence of ongoing systemic infection (eg, bacterial, fungal, viral) at the time of enrollment


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7) Known history of drug-induced liver injury, chronic active hepatitis B virus (HBV), 
chronic active hepatitis C virus (HCV), alcoholic liver disease, non-alcoholic steatohepatitis, 
cirrhosis of the liver, portal hypertension, primary biliary cirrhosis, or ongoing 
extrahepatic obstruction caused by cholelithiasis
8) History of or ongoing drug-induced pneumonitis
9) History of or ongoing inflammatory bowel disease
10) Known human immunodeficiency virus (HIV) infection
11) CMV: Ongoing infection, treatment, or specifically CMV antiviral prophylaxis within 
28 days prior to the Screening Visit CMV test
12) Presence of any condition that could, in the opinion of the investigator, compromise the 
subject’s ability to participate in the study, such as history of substance abuse, alcoholism, or 
a psychiatric condition
13) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation
14) Ongoing immunosuppressive therapy, including systemic corticosteroids (> 10 mg 
prednisone or equivalent/day) with the exception of the use of topical, enteric, or inhaled 
corticosteroids as therapy for comorbid conditions or systemic corticosteroids for 
autoimmune anemia and/or thrombocytopenia
15) Concurrent participation in another therapeutic clinical study
16) Prior or ongoing clinically significant illness, medical condition, surgical history, 
physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results
17) Prior treatment with PI3K inhibitors


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
As of Protocol Amendments 5 and 6, this is an open-label, randomized study. Randomization to 
the treatment assignment (Arm A or C) will occur via the Interactive Web Response System 
(IWRS).
Subjects enrolled prior to Protocol Amendment 5:
The identity of the treatments was concealed by central blinding of study drug assignments. 
Blinding was accomplished through use of a placebo that was well-matched to the active drug in 
appearance. Subjects, caregivers, investigational site personnel, Gilead study team members, and 
all other study personnel remained blinded to the identity of the treatment assignments; these 
assignments were available only to the IWRS, the independent DMC for the study, an 
independent bioanalytical group that supported the DMC, and drug safety personnel who were 
not part of the study team. 
Once Protocol Amendment 6 has been implemented, subjects who are blinded to study treatment 
will be unblinded and will continue on the assigned randomized dose. 
5.1.1.
Procedures for Breaking Treatment Codes
This section applies only to subjects enrolled prior to Protocol Amendment 5. Subjects with IRC 
confirmed SD or PD will be unblinded. Subjects who died or discontinued from study may be 
unblinded.
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject. Gilead recommends but does not require that the investigator contact the 
Gilead Medical Monitor before breaking the blind. Treatment assignment should remain 
blinded unless that knowledge is necessary to determine subject emergency medical care. 
 
 
 Under these special circumstances the investigator may 
break the blind at their discretion. The rationale for unblinding must be clearly explained in 
source documentation and on the electronic case report form (eCRF), along with the date on 
which the treatment assignment was obtained. The investigator is requested to contact the Gilead 
Medical Monitor promptly in case of any treatment unblinding.
Study treatment will be discontinued if a subject’s treatment assignment is disclosed outside of 
the allowed protocol unblinding. All subjects will be followed until study completion unless 
consent to do so is specifically withdrawn by the subject.
CCI


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Gilead Pharmacovigilance & Epidemiology (PVE) may independently unblind cases for 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling of Idelalisib
5.2.1.
Formulation
Idelalisib will be provided in tablets intended for oral administration. Each active tablet contains 
150 mg or 100 mg of idelalisib. 
The 150 mg tablets are pink, and the 100 mg tablets are orange. All tablets are film-coated, and 
include the following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate, food, drug and cosmetics 
(FD&C) Yellow #6/ Sunset Yellow FCF Aluminum Lake (100 mg tablets only), red iron oxide 
(150 mg only), polyethylene glycol, talc, polyvinyl alcohol (PVA), and titanium dioxide. 
Prior to Protocol Amendment 5, a well-matched placebo was provided as the study was still 
blinded. Until global unblinding takes place, placebo will continue to be supplied to the blinded 
subjects. The placebo tablets match the active idelalisib tablets in appearance. The placebo 
tablets include the following inactive ingredients: silicified microcrystalline cellulose, sodium 
starch glycolate, magnesium stearate, red iron oxide (150 mg placebo tablets only), 
FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake (100 mg placebo tablets only), 
polyethylene glycol, talc, PVA, and titanium dioxide.
5.2.2.
Packaging and Labeling
Study drug(s) to be distributed to centers in participating countries shall be labeled to meet 
applicable requirements of the United States Food and Drug Administration (FDA), EU 
Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.
Subjects enrolled as of Protocol Amendments 5 and 6:
Idelalisib will be provided in bottles. Idelalisib tablets are packaged in white, high density 
polyethylene bottles. Each bottle contains 60 tablets and polyester coil packing material. Each 
bottle is enclosed with a white, continuous-thread, child-resistant polypropylene screw cap with 
an induction-sealed and aluminum-faced liner.
Subjects enrolled prior to Protocol Amendment 5:
Study drug (idelalisib/placebo) will be provided in blister cards. The blister cards are made of 
polyvinyl chloride/polychlorotrifluoroethylene film and have aluminum foil lidding materials.
Once Protocol Amendment 6 is implemented, study drug (idelalisib/placebo) will not be 
provided to subjects who are currently blinded once they have been unblinded. These subjects 
will continue on the assigned open-label treatment dose.


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Each blister card contains 120 tablets (4-week supply plus a modest overage) of one of the 
relevant dose strengths. 
The 100 mg or 150 mg tablets will be combined with matching placebo tablets in one blister card 
while ensuring the blind is maintained.
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects in 
the 2 treatment arms will appear identical.
Subjects will be unblinded once Protocol Amendment 6 has been approved by the Ministry of 
Health, Central Ethics Committee, and Local Ethics Committee (if applicable). At that time, 
idelalisib will be provided in bottles. Idelalisib tablets are packaged in white, high density 
polyethylene bottles. Each bottle contains 60 tablets and polyester coil packing material. Each 
bottle is enclosed with a white, continuous-thread, child-resistant polypropylene screw cap with 
an induction-sealed and aluminum-faced liner.
5.2.3.
Storage and Handling
Until dispensed to subjects, the study drug product should be stored in a securely locked area, 
accessible only to authorized personnel.
Idelalisib should be stored at controlled room temperature of 25°C (77°F); excursions are 
permitted between 15°C and 30°C (59°F and 86°F). Storage conditions are specified on the label. 
To ensure the stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were supplied.
Measures that minimize drug contact with the body should always be considered during 
handling, preparation, and disposal procedures. Any unused study drug should be disposed of in 
accordance with local requirements.
5.3.
Dosage and Administration 
The prescribed dose of study drug (idelalisib/placebo) should be taken orally. At each dose 
administration, the study drug is to be swallowed whole with 120 to 240 mL 
(approximately 4 to 8 ounces) of water. In the case of tablets breaking in the oral cavity, 
additional water should be taken as a rinse.
Study drug may be taken with or without food. There are no known dietary restrictions related to 
study drug use.
Study drug will be taken twice daily. Study drug should be taken at approximately the same times 
each day. Ideally, doses should be taken at approximately 12 hour intervals as instructed 
(eg, at 7 AM and at 7 PM). While it is realized that variations in dosing schedule may occur in 
the outpatient setting, the prescribed regimen should be followed as closely as possible, 
especially in the clinic.


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At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for idelalisib PK. Clinic staff should record study 
drug administration information, including the date and exact clock time of each dose for doses 
of study drug administered in the clinic or hospital. Prior to these visits, subjects should be 
reminded not to take their morning dose of study drug before coming into the clinic. Subjects 
should also be reminded to bring their study drug with them to clinic for dosing.
Thereafter, subjects will be given an adequate supply of tablets to take at home.
Subjects who have a delay in administration of a dose of study drug of < 6 hours should take the 
planned dose as soon as possible after the intended time of administration. For subjects who have 
a delay in administration of study drug of  6 hours, the dose should not be taken. Study drug 
administration may continue but the missed dose should not be made up and the planned timing 
of subsequent study drug dosing should not be altered.
Vomited doses may be retaken, but only if the tablet is visible in the vomitus. 
5.3.1.
Idelalisib Dose Levels
Idelalisib dose levels are shown in Table 5-1. Subjects will be randomized to Arm A or C. Dose 
modifications may be made in response to toxicity; see Table 5-2 for dose adjustment rules.
Table 5-1.
Idelalisib Dose Levels
Subjects enrolled prior to Protocol Amendment 5:
Dose Level
Dosing Regimen
Dose Level 0
150 mg BID
100 mg BID
Dose Level -1
100 mg BID
100 mg BID
Subjects enrolled as of Protocol Amendment 5:
Treatment Arm
Starting Dose
Reduced Dose
Arm A
150 mg BID
100 mg BID
Arm C*
150 mg BID
100 mg BID
BID=twice daily
*Arm C: administered in 28-day cycles (21 days on-treatment, 7 days off-treatment)
Consistent with the dose adjustment rules presented in Table 5-2, if a subject experiences an AE 
that is suspected to be related to idelalisib during the course of study, idelalisib administration 
should be held, as defined in Table 5-2, until the AE resolves or stabilizes to an acceptable 
degree. Thereafter, idelalisib may be reinitiated, consistent with the instructions in Section 5.3.2. 
For any AE that is not included in Table 5-2, reinitiation of idelalisib should be per investigator’s 
discretion.


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After an idelalisib dose reduction, the dose need not be re-escalated. However, if the subject 
tolerates the reduced dose of idelalisib for  4 weeks, then the dose may be increased back to 
starting dose at the discretion of the investigator. Such a re-escalation may be particularly 
warranted if further evaluation reveals that the AE that led to the dose reduction was not related 
to idelalisib.
5.3.2.
Idelalisib Dose Adjustments 
The dose adjustment recommendations and requirements in Table 5-2 are based on the Common 
Terminology Criteria for Adverse Events (CTCAE) grade of specific toxicities. However, 
exceptions are expected for subjects who initiate study treatment with low blood counts. Clinical 
judgment should apply, and in cases of uncertainty, the medical monitor should be contacted.
The dose modification instructions focus on the types of events most commonly attributed to 
idelalisib. The modifications in Table 5-2 include both recommended as well as required actions. 
When a modification is indicated as a recommendation it only serves as a guideline; variations 
from the recommendation may be warranted based on an investigator’s individual judgment in 
considering potential risks, benefits, and therapeutic alternatives available to each subject. Refer 
to Section 7.5 for specific AE or condition recommendations.
NOTE: For subjects randomized to Arm C, study drug should not be taken on scheduled 
“off-treatment” days, regardless of prior missed doses, study drug interruptions for toxicity, or 
PK samples.
Table 5-2.
Modification of Study Treatment in Response to Adverse Events
Pneumonitis (with new onset or worsening of baseline dyspnea, cough, or hypoxia without obvious infectious cause)
Grade 1 
(asymptomatic)
Required Action: Withhold idelalisib until resolution to baseline. May resume at reduced dose 
level (100 mg BID) or discontinue at investigator discretion.
Grade ≥ 2
Required Action: Discontinue idelalisib permanently in subjects with any severity of 
symptomatic pneumonitis and institute therapy as clinically appropriate.
Pneumocystis jirovecii pneumonia (PJP)
Any Grade
Required Action: Discontinue idelalisib permanently.
Organizing Pneumonia
Any Grade
Required Action: Discontinue idelalisib permanently.
Cytomegalovirus (CMV)
Required Actions:
1.
Interrupt idelalisib upon unequivocal clinical or laboratory evidence of CMV infection.
2.
Institute treatment according to established clinical guidelines.
If the benefits of resuming idelalisib are judged to outweigh the risks, consideration should be given to administering 
pre-emptive CMV therapy.


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Rash Grade ≥ 3
Required Actions: Withhold idelalisib until Grade ≤ 1. May resume at reduced dose level (100 mg BID) or discontinue 
at investigator discretion.
SJS/TEN
Required Actions:
1.
Discontinue idelalisib
2.
Interrupt coadministered medications potentially associated with SJS or TEN
3.
Institute treatment per institutional standards
Bowel perforation
Required Action: Discontinue idelalisib permanently.
Progressive Multifocal Leukoencephalopathy (PML)
Any Grade
Required Action: Withhold idelalisib until PML is excluded. Refer to Section 7.5.2
ALT/AST, Bilirubin
ALT/AST
> 3-5 x ULN
(Grade 2)
> 5-20 x ULN
(Grade 3)
> 20 x ULN
(Grade 4)
Required Action: Monitor 
at least weekly until 
Grade ≤ 1.
Recommended Action: 
Maintain idelalisib dose. 
Required Actions: Withhold 
idelalisib. Monitor at least 
weekly until ALT/AST are 
Grade ≤ 1.
Recommended Action: May 
resume idelalisib at reduced 
dose level (100 mg BID) when 
ALT/AST are Grade ≤ 1.
Required Action: 
Discontinue 
idelalisib 
permanently.
Bilirubin
> 1.5-3 x ULN
(Grade 2)
> 3-10 x ULN
(Grade 3)
> 10 x ULN
(Grade 4)
Required Action: Monitor 
at least weekly until 
Grade ≤ 1.
Recommended Action: 
Maintain idelalisib dose.
Required Actions: Withhold 
idelalisib. Monitor at least 
weekly until bilirubin is 
Grade ≤ 1.
Recommended Actions: May 
resume idelalisib at reduced 
dose level (100 mg BID) when 
bilirubin is Grade ≤ 1.
Required Action: 
Discontinue 
idelalisib 
permanently.
Diarrhea or colitis, any Grade
Required Actions:
1.
Obtain history of onset and duration of diarrhea, including description of number of stools and stool 
composition (eg, watery, bloody, nocturnal), travel history, dietary changes and a medication review to 
identify possible diarrheogenic agents
2.
Perform physical examination including assessment for fever, dizziness, abdominal pain/cramping, and 
weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Recommended Actions:
1.
Provide anti-diarrheal and maintain current idelalisib dose level and schedule
2.
Differentiate between small-bowel and large-bowel diarrhea on a clinical basis. If unclear, consider upper and 
lower tract endoscopy with biopsy.


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
Small bowel diarrhea is characterized by large volume diarrhea (more than one per day), possible 
associated dehydration, weight loss and paraumbilical pain. Consider an endoscopic small-bowel biopsy 
and evaluate other etiologies such as celiac disease.

Large-bowel diarrhea may present with lower pelvic pain, tenesmus, and generally smaller stool volumes 
with gross blood frequently found in the stool. Consider a colonoscopic evaluation and biopsy.
3.
Ensure good hydration status
Grade ≥ 2 diarrhea or colitis (unless clinical diagnosis is established from medical history and physical 
examination) 
Required Actions:
1.
Monitor diarrhea at least weekly until resolved.
2.
Stool culture for routine pathogens (Salmonella, Shigella, Campylobacter species), testing for Clostridium 
difficile toxin, Rotavirus, Cytomegalovirus (CMV), and Adenovirus 
3.
Stool for Ova and Parasites (Cryptosporidium parvum, Isospora belli, Enterocytozoon bieneusi, Septata 
intestinalis, Strongyloides, Microsporidia, Entamoeba histolytica, Cyclospora), Giardia antigen
Grade ≥ 3 diarrhea or colitis or persistent Grade 2 diarrhea or colitis without clear etiology 
Required Actions:
1.
Withhold idelalisib.
2.
Consider anti-diarrheal (eg, loperamide) and/or addition of anti-inflammatory agent (eg, sulfasalazine, 
budesonide).
Recommended Actions:
1.
Endoscopy with biopsy is strongly recommended. All biopsy samples should include immunohistochemistry 
and PCR for CMV, Adenovirus.
2.
3.
At Grade ≤1, may resume idelalisib at reduced dose level (100 mg BID) or discontinue at investigator 
discretion.
Grade 4 diarrhea or colitis 
Required Actions: Discontinue idelalisib permanently.
Neutropenia
Grade 2
(ANC 1.0 to < 1.5 Gi/L)
Recommended Action: Maintain idelalisib dose level and schedule.
Grade 3
(ANC 0.5 to < 1.0 Gi/L)
Required Action: ANC must be monitored at least weekly until ANC Grade ≤ 2.
Recommended Action: Maintain idelalisib dose level and schedule. 
Grade 4
(ANC < 0.5 Gi/L)
(or occurrence of 
neutropenic fever or 
infection)
Dosing:

Required Action: Withhold idelalisib.

Recommended Action: May resume idelalisib at reduced dose level (100 mg BID) 
when ANC Grade ≤ 3.
Required Action: ANC must be monitored at least weekly until ANC Grade ≤ 2.
Recommended Action: Neutropenia should be managed according to established clinical 
guidelines.
Thrombocytopenia
Grade 2
(Platelets 50 to 
< 75 Gi/L)
Recommended Action: Maintain idelalisib dose.
CCI


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Grade 3
(Platelets 25 to 
< 50 Gi/L)
Required Action: Monitor platelet counts at least weekly.
Recommended Action: Maintain idelalisib dose.
Grade 4
(Platelets < 25 Gi/L)
Required Actions: Interrupt idelalisib. Monitor platelet counts at least weekly.
Recommended Action: May resume idelalisib at reduced dose level (100 mg BID) after 
platelets ≥ 25 Gi/L (Grade ≤ 3)
ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate aminotransferase; BID=twice daily; 
ULN=upper limit of normal
a
Refer to Section 6.1.5.6 for recommendations if the differentiation between small-bowel and large-bowel diarrhea is unclear.
5.4.
Prior and Concomitant Medications
5.4.1.
Idelalisib
No specific premedications are required in conjunction with idelalisib. Subjects must begin PJP 
prophylaxis when they begin taking study drug and will remain on prophylaxis until after study 
drug is discontinued. See Section 7.5.6 for additional information.
5.4.2.
Anti-Cancer or Experimental Therapies Other than Idelalisib
No other systemic anti-cancer therapies (including but not limited to chemotherapy, radiation, 
antibody therapy, immunotherapy, or other experimental therapies) of any kind are permitted 
while the subject is receiving study treatment with idelalisib. Discuss the use of topical 
anticancer agents (eg, topical 5-FU) with the medical monitor. Subjects are not allowed to 
participate concurrently in any other therapeutic clinical study.
5.4.3.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factors (GM-CSF) should not be administered 
given the potential for GM-CSF-related inflammatory symptoms. The use of supportive care 
agents such as granulocyte colony-stimulating factor agents or erythropoietic agents are 
permitted in compliance with regional prescribing information.
5.4.4.
Corticosteroids
Subjects may receive topical or inhaled, enteric, or systemic corticosteroids while on study. The 
use of systemic corticosteroids is discouraged because their potential antineoplastic activity in 
subjects with iNHL may confound interpretation of idelalisib-mediated antitumor effects. 
However, subjects who develop severe or life-threatening conditions that may be alleviated by 
systemic corticosteroid therapy are permitted to receive such drugs and are not required to 
discontinue study participation.


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5.4.5.
Drugs that Alter CYP3A-Dependent Metabolism
Idelalisib is metabolized to its major metabolite GS-563117 via aldehyde oxidase and 
cytochrome P450 3A (CYP3A). Idelalisib also undergoes minor metabolism by uridine 
diphosphate glucuronosyltransferase 1A4 (UGT1A4). The AUC of idelalisib was increased 
1.8-fold when idelalisib was coadministered with a strong CYP3A inhibitor. Therefore, if 
subjects are taking concomitant strong CYP3A inhibitors, the subject should be monitored 
closely for signs of idelalisib toxicity and the dose modifications for adverse reactions should be 
followed in the event of toxicity (see Table 5-2).
Additionally, idelalisib exposures are approximately 75% lower when coadministered with 
rifampin, a highly potent inducer of CYP3A. Therefore, avoid coadministration of strong 
inducers of CYP3A (rifampin, carbamazepine, phenytoin, and St. John’s wort) with idelalisib.
5.4.6.
Drugs that Undergo CYP3A-Dependent Metabolism
The major metabolite of idelalisib, GS-563117, is a reversible and time dependent inhibitor of 
CYP3A; accordingly, coadministration of idelalisib with midazolam, a probe CYP3A substrate, 
resulted in an approximately 5-fold increase in midazolam systemic exposure (AUC), indicating 
that idelalisib is a strong inhibitor of CYP3A. Coadministration of CYP3A substrates with 
idelalisib may result in an increase in their systemic exposures (eg, antiarrhythmics, calcium 
channel blockers, benzodiazepines, certain 3-hydroxy-3-methyl-glutaryl-Coenzyme A reductase 
inhibitors, phosphodiesterase-5 inhibitors, warfarin). Avoid coadministration of drugs that are 
narrow therapeutic index CYP3A substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, 
cisapride, pimozide, fentanyl, quinidine, ergotamine, dihydroergotamine, astemizole, 
terfenadine) with idelalisib.
5.4.7.
COVID-19 Vaccination Guidelines
Administration of a coronavirus disease 2019 (COVID-19) vaccine is not considered 
contraindicated with idelalisib. Investigators should use their clinical judgment in determining if 
and when to enroll study participants who have received a COVID-19 vaccine, or whether to 
continue, interrupt, or discontinue study treatment in subjects who are administered a COVID-19 
vaccine during study conduct.
5.5.
Accountability for Idelalisib
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgement of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug dispensed to subjects must be returned to the site.


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Study drug accountability records will be provided to each study site to:

Record the date received and quantity of study drug

Record the date, subject number, subject initials, the study drug blister card number/bottle 
number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information
Institution-specific accountability records may be used if they capture the same information 
listed above. 
5.5.1.
Investigational Medicinal Product Return or Disposal
Gilead recommends that used and unused study drug supplies be destroyed at the site. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead, the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for the electronic trial master file. If study drug is destroyed at the site, the investigator must 
maintain accurate records for all study drugs destroyed. Records must show the identification 
and quantity of each unit destroyed, the method of destruction, and the person who disposed of 
the study drug. Upon study completion, copies of the study drug accountability records must be 
filed at the site. Another copy will be returned to Gilead. 
If the site does not have an appropriate SOP for drug destruction, used and unused study drug 
supplies are to be sent to the designated disposal facility for destruction. The study monitor will 
provide instructions for return.
The study monitor will review study drug supplies and associated records at periodic intervals.
For both disposal options listed above, the study monitor must first perform drug accountability 
during an on-site monitoring visit.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows.
For subjects who discontinue idelalisib prior to IRC documented disease progression, every 
attempt should be made to keep the subject in the study and continue to perform regular 
assessments per the schedule of procedures (with the exception of PK sampling and CMV 
monitoring) until the subject meets criteria for study discontinuation (see Section 3.5.2).
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
Safety and tolerability assessments will include regular monitoring of AEs, changes from 
baseline in laboratory variables, physical examinations (PEs), vital signs, and special safety 
assessment like ECGs.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all SAEs, as well as any non-serious AEs related to protocol-mandated 
procedures on the AEs eCRF. All other untoward medical occurrences observed during the 
screening period, including exacerbation or changes in medical history are to be captured on the 
medical history eCRF. See Section 7 for additional details.
6.1.
Study Procedure Descriptions
During the treatment period, all visits may be performed within the specified visit window as 
noted in the schedule of events (see Appendix 2).
6.1.1.
Informed Consent
All subjects must sign and date the most recent IRB/IEC-approved informed consent form before 
any study procedures are performed.
6.1.2.
Medical and Medication History
A complete medical and surgical history will be obtained during screening including disease 
history and prior therapies.
A history of all medication taken within the 3 months prior to screening and during the screening 
period will be obtained.


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6.1.3.
Physical Examination
A physical exam will be performed at screening and will include assessment of clinical signs and 
symptoms. The exam will be performed by a physician, a physician’s assistant, or nurse 
practitioner qualified to perform assessments. Breast, genital, and rectal examinations are not 
required, unless warranted in the opinion of the healthcare provider.
A limited physical exam (consistent with standard institutional guidelines) should be performed 
at the following visits:
Subjects enrolled as of Protocol Amendment 5:
Weeks 12, 24, 36, 48, 60, and every 24 weeks thereafter.
Subjects enrolled prior to Protocol Amendment 5:
Weeks 8, 16, 24, 36, 48, 60, and every 24 weeks thereafter.
6.1.4.
Vital Signs
At Screening, vital signs including oxygen saturation, systolic and diastolic blood pressure, heart 
rate, respiratory rate, temperature, and anthropometric measurements of height and weight will 
be measured by the investigator or qualified designee as per standard institutional guidelines.
6.1.5.
Laboratory Assessments
Analytes to be tested are listed in Table 6-1. Specific instructions for processing, labeling, and 
shipping samples will be provided in a Central Laboratory Manual.
Blood samples for hematology and chemistry will be collected at each study visit. Additional 
clinic visits may be needed to monitor absolute neutrophil count (ANC) at Weeks 14, 18, and 22.
At screening, blood samples will also be obtained for serum pregnancy (if applicable), HBV, 
HCV, and HIV.
Blood samples for coagulation will be collected at screening, baseline, Weeks 8, 16, 32, 48, 
every 12 weeks thereafter.
Blood samples for Beta-2 microglobulin will be collected at screening, Weeks 24, 48, 
every 12 weeks thereafter, and at the End of Treatment (EOT) visit.
Blood samples for CMV will be collected at screening, Weeks 4, 8, 12, 16, 20, 24, and 
every 4 weeks thereafter throughout the course of study drug treatment, (including during drug 
interruptions due to toxicity or AEs), and at the EOT visit.
Blood sample for CMV serology (immunoglobulin [Ig]G, IgM) will be collected at baseline 
(Day 1) only.


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Blood samples for immune-monitoring will be collected at Screening, Weeks 4, 12, 24, every 
12 weeks thereafter, and at the EOT and EOS visits. Immune-monitoring samples include:

Lymphocyte subset panel using flow cytometry (immunophenotyping) 

Quantitative immunoglobulins: IgG, IgM, IgA, IgE

Serum CH50 level
At any time during the study, abnormal laboratory parameters that are clinically relevant 
(eg, lead to clinical symptoms or signs, require therapeutic intervention), and constitute an AE 
must be recorded in the eCRF.
A urine sample for urinalysis will be collected at screening only.
Table 6-1.
Analytes
Chemistry
Hematology
Urinalysis
Other
ANC
RBC
Hemoglobin
Hematocrit
Platelets
WBC
Differential
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
Bands
pH
Protein
Glucose
Ketones
Bilirubin
Urobilinogen
Blood
Nitrite
Leukocyte esterase
Serum -hCG or urine for 
pregnancy test
HIV antibody
Hepatitis B surface antigen
Hepatitis B core antibody
Hepatitis C antibody
Hepatitis C viral RNA
CMV PCR
Anti-CMV IgG and IgM 
Immunophenotyping 
Serum CH50 level
Albumin
Alkaline phosphatase
ALT/SGPT
AST/SGOT
Bicarbonate
Calcium
Chloride
Cholesterol
Creatinineb
GGT
Glucose
LDH
Phosphorus
Potassium
Sodium
Total bilirubina
Total protein
Triglycerides
Uric acid
BUN
Coagulation
PT/INR
aPTT/PTT
Quantitative Immunoglobulins
IgA
IgE
IgG
IgM
Beta-2 microglobulin
a
Includes direct bilirubin
b
Estimated glomerular filtration rate will be calculated according to the Cockcroft-Gault formula for creatinine clearance. 
Creatinine clearance is only measured at screening.
6.1.5.1.
Pregnancy Test
All females of childbearing potential (see Appendix 4) will have a serum pregnancy test at 
screening. Urine pregnancy tests will be performed at baseline, and every 4 weeks thereafter. 
The pregnancy testing is more frequent than regular clinic visits after Week 24. Urine pregnancy 
tests will also be performed at the EOT and EOS visits.


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6.1.5.2.
Pharmacokinetics
Blood samples will be collected for PK assessments at baseline, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 
24, 32, and 48 predose (within 1 hour prior to dose) and 1.5 hours (± 10 min) post dose in the 
morning. If prior scheduled dose was missed for any reason including due to planned 
“off-treatment” schedule, a predose PK sample is not needed. A single non-timed PK sample will 
also be collected at any unscheduled study visit through Week 48.
For subjects randomized to Arm C, study drug should not be taken on scheduled “off-treatment” 
days, regardless of prior missed doses, study drug interruptions for toxicity, or PK samples.
6.1.5.3.
 
 
 
6.1.5.4.
 
 
6.1.5.5.
Evaluation for Gastrointestinal Events/Colitis
For Grade 2 colitis and diarrhea (unless clinical diagnosis is established from medical history and 
physical examination), the following testing is required:

Stool culture for routine pathogens (Salmonella, Shigella, Campylobacter species, 
Clostridium difficile toxin, Rotavirus, Cytomegalovirus, Adenovirus)

Stool for Ova and Parasites (Cryptosporidium parvum, Isospora belli, Enterocytozoon 
bieneusi, Septata intestinalis, Strongyloides, Microsporidia, Entamoeba histolytica, 
Cyclospora), Giardia antigen
For Grade ≥ 3 or persistent Grade 2 colitis or diarrhea without clear etiology (eg, clostridium 
difficile enterocolitis), endoscopy with biopsy is recommended. All biopsy samples should 
include immunohistochemistry and polymerase chain reaction (PCR) for CMV and adenovirus. 
See Section 6.1.12.1 for additional requirements (ie, collection of information and physical 
exam) when an AE of diarrhea or colitis occurs.
CCI
CCI
CCI
CCI


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6.1.5.6.
Differentiation Between Small-Bowel and Large-Bowel Diarrhea
Differentiation between small-bowel and large-bowel diarrhea: may be possible on a clinical 
basis. If unclear, consider upper and lower tract endoscopy with biopsy.

Small bowel diarrhea is characterized by large volume diarrhea (more than one per day), 
possibly associated dehydration weight loss and paraumbilical pain. Consider an endoscopic 
small-bowel biopsy and evaluate other etiologies such as celiac disease.

Large-bowel diarrhea may present with lower pelvic pain, tenesmus, generally smaller stool 
volume with gross blood frquently found in the stool. Condsider a colonoscopic evaluation 
and biopsy.
6.1.6.
Electrocardiogram Assessment
A standard 12-lead ECG will be performed at screening as per standard institutional practice.
6.1.7.
Radiology Assessment
Subjects will be imaged at neck, chest, abdomen, and pelvis with either PET-CT (diagnostic), 
contrast-enhanced CT, or gadolinium-enhanced MRI. If MRI is chosen, subjects will have an 
MRI of neck, abdomen, and pelvis, but will need a non-contrast enhanced CT of the chest. 
Chest x-ray, ultrasound, endoscopy, laparoscopy, radionuclide scans, or tumor markers will not 
be considered for response assessment. For radiographic evaluations, the same method of 
assessment and the same technique (eg, scan type, scanner, subject position, dose of contrast, 
injection/scan interval) should be used to characterize each identified and reported lesion at 
baseline and during study participation.
All relevant clinical and radiographic information required to make each assessment must be 
made available for source verification and for submission to the IRC.
Investigators will assess the status of each subject’s disease using standard response criteria.
If disease progression is suspected, the IRC will be notified and radiographic images will be 
submitted to the IRC.
The IRC will review radiographic and pertinent clinical data in order to provide a definitive 
interpretation. The findings of the IRC will be considered primary for analyses of efficacy 
endpoints. It is recommended that the investigator consults with the medical monitor if 
considering removing a subject from study prior to a definitive IRC assessment of progression.


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Radiographic assessments will be performed at the following visits:
Subjects enrolled as of Protocol Amendments 5 and 6:
Screening, Weeks 12, 24, 36, 48, 60, and 84 until IRC documented disease progression, and at 
EOT (unless radiographic assessments performed within 4 weeks prior to EOT visit). After 
Week 84, radiographic assessments are performed at the discretion of the investigator. Screening 
CT/PET-CT/MRI may be performed within 6 weeks prior to first dose. Subsequent scans may be 
done within 1 week prior to clinic visit.
Subjects enrolled prior to Protocol Amendment 5:
Screening, Weeks 8, 16, 24, 36, 48, 60, and 84 until IRC documented disease progression, and at 
EOT (unless radiographic assessments performed within 4 weeks prior to EOT visit). After 
Week 84, radiographic assessments are performed at the discretion of the investigator. Screening 
CT/PET-CT/MRI may be performed within 6 weeks prior to first dose. Subsequent scans may be 
done within 1 week prior to clinic visit.
6.1.8.
Bone Marrow Biopsy
For subjects in whom a radiologic CR is determined, a bone marrow biopsy may be required for 
complete assessment. In a subject who has a baseline or on-study bone marrow biopsy showing 
involvement with lymphoma or does not have a baseline bone marrow examination, declaration 
of an on-study CR requires bone marrow biopsy documentation of the absence of lymphoma. In 
a subject who has a baseline or on-study bone marrow biopsy showing no evidence of 
lymphoma, declaration of an on-study CR does not require bone marrow examination as long as 
other criteria for CR are met.
6.1.9.
Performance Status
Performance status may be scored using the ECOG or Karnofsky Performance Status 
Scoring Systems at screening, Weeks 8, 16, 32, 48, every 12 weeks thereafter, and at the EOT 
and EOS visits.
6.1.10.
Baseline Prognostic Factors, Ann Arbor Stage and FLIPI
At Screening, prognostic factors will be assessed. All subjects will have Ann Arbor stage 
assessments recorded (Appendix 3) and FLIPI factors assessed and scores calculated. 
FLIPI scores are a composite of 5 factors: age, number of nodal sites, Ann Arbor stage, 
hemoglobin level, and LDH level (Appendix 5).
6.1.11.
Study Drug Dispensing and Dosing
Study drug will be dispensed at Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48, and 
every 12 weeks thereafter until EOT. Drug may also be dispensed at unscheduled visits if 
necessary. Idelalisib will be administered as per Section 5.3.


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6.1.12.
Adverse Events
Adverse events will be assessed at all study visits. From the time of obtaining informed consent 
through the first administration of study drug, record all SAEs as well as any non-serious AEs 
related to protocol-mandated procedures on the AE eCRF. All other untoward medical 
occurrences observed during the screening period, including exacerbation or changes in medical 
history are to be captured on the medical history eCRF.
From the time of obtaining informed consent through 30 days post the last administration of 
study drug, record any AEs related to protocol-mandated procedures or study drug on the AE 
eCRF. SAEs should be captured on the SAE eCRF.
See Section 7 (Adverse Events and Toxicity Management) for additional details.
6.1.12.1.
Assessment of Diarrhea/Colitis
A history of onset and duration of diarrhea, including description of number of stools and stool 
composition (eg, watery, bloody, nocturnal), travel history, dietary changes, and a medication 
review must be obtained to identify possible diarrheogenic agents.
A physical examination including assessment for fever, dizziness, abdominal pain/cramping, and 
weakness (ie, evaluate for sepsis, bowel obstruction, dehydration) must be performed.
6.1.12.2.
Prior and Concomitant Medications 
Concomitant medications will be collected within the 3 months prior to screening and during the 
screening period. They will also be assessed at all study visits.
6.2.
Posttreatment Assessments
The EOT and EOS visits may be performed on the same day, if the subject will be discontinuing 
study treatment and discontinuing the study at the same time (eg, withdrawal of consent).
For subjects who discontinue idelalisib prior to IRC documented disease progression, every 
attempt should be made to keep the subject in the study and continue to perform regular 
assessments per the schedule of procedures (with the exception of PK sampling and CMV 
monitoring) until the subject meets criteria for study discontinuation (see Section 3.5.2).
During the follow-up period, medical treatment of the subject is left to the investigator 
discretion.


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6.3.
Assessments for Premature Discontinuation from Study
If a subject discontinues idelalisib (for example, as a result of an AE) every attempt should be 
made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures. If this is not possible or acceptable to the subject or investigator, the 
subject may be withdrawn from the study. It is recommended that the investigator consults with 
the medical monitor prior to removing the subject from study for any reason except subject 
withdrawal of consent.
6.4.
End of Treatment
EOT assessments will be performed when a subject permanently discontinues idelalisib. For 
subjects who discontinue idelalisib prior to IRC documented disease progression, every attempt 
should be made to keep the subject in the study and continue to perform regular assessments per 
the schedule of procedures (with the exception of PK sampling and CMV monitoring) until the 
subject meets criteria for study discontinuation (see Section 3.5.2).
6.5.
30-Day Follow-Up
A 30-day follow-up visit will be performed 30 days ( 5 days) following the EOT visit; however, 
this visit may be waived for subjects who have permanently discontinued study drug and have 
had a study visit > 30 days after the last dose of study drug. Information may be gathered during 
a routine clinic visit, via telephone, or via another contact method.
6.6.
End of Study
EOS assessments will be completed once it has been determined that the subject will discontinue 
the study. The EOT and EOS visits may be performed on the same day if the subject will be 
discontinuing study treatment and discontinuing the study at the same time (eg, withdrawal of 
consent). 
6.7.
Survival Follow-Up
Survival follow-up will be conducted at annual intervals ( 4 weeks) for 5 years, starting at the 
EOS visit. Information may be gathered during a routine clinic visit or other contact with the 
subject, or via telephone. Information gathered will include anti-tumor treatment, secondary 
malignancies, survival status, and death details if applicable.
6.8.
Unscheduled Visits
Unscheduled visits may occur at any time while the subject is enrolled on study. Vital signs, 
laboratory assessments, ECG, PE, and radiographic assessments may be conducted at these 
visits. If the unscheduled visit is to manage an AE of interest, PK samples may be included at 
these visits. Data generated during an unscheduled visit will be collected on the eCRF.


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study subject administered a study drug, 
which does not necessarily have a causal relationship with the treatment. An AE can therefore be 
any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use 
of a study drug, whether or not the AE is considered related to the study drug. Adverse events 
may also include pretreatment or posttreatment complications that occur as a result of 
protocol-specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. 
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an AE and must be reported

Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE, but rather considered to be preexisting and should be documented on the medical history 
case report form (CRF)
Preexisting events that increase in severity or change in nature after study drug initiation or 
during or as a consequence of participation in the clinical study will also be considered AEs.
7.1.2.
Serious Adverse Events
An SAE is defined as an event that, at any dose, results in the following:

Death

A life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe.)


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
In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements
7.1.2.1.
Protocol-Specific Serious Adverse Event Definitions
Hospital admissions for administration of the study drug, procedures required by the study 
protocol, or tumor-related diagnostic procedures are not considered SAEs.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, ECG, x-rays, vital signs) that are associated with 
signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE 
or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the study drug.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol procedures, (eg, venipuncture).
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the CTCAE, Version 5.0. For each episode, all 
increases in severity/grade should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the AE. For purposes of consistency with 
the CTCAE, these intensity grades are defined in Table 7-1.
Table 7-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to 
have a clinically significant effect on the subject’s overall health and 
well-being, does not interfere with the subject’s usual function, and is 
not likely to require medical attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect 
clinical status, and may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical 
status and likely requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.


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The distinction between the seriousness and the severity of an AE should be noted. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met 
one of the criteria for serious events listed in Section 7.1.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required posttreatment follow-up period, must be reported in the 
eCRF database and Gilead PVE as instructed. This also includes any SAEs resulting from 
protocol-associated procedures performed from Screening onwards.
All AEs, regardless of cause or relationship, which occur from initiation of study drug until 
30 days after last administration of study drug must be reported to the eCRF database as 
instructed.
All special situations including pregnancy, regardless of cause or relationship, until 30 days for 
females or 90 days for males after last administration of study drug(s) must be reported to the 
CRF/eCRF database as instructed.
Any SAEs and deaths that occur after the posttreatment follow-up visit but within 30 days of the 
last dose of the study drug, regardless of causality, should also be reported.
All AEs should be followed up until resolution if possible. If by the last day on study (including 
the off-study medication follow-up period) the AE has not resolved, then the AE will be 
followed up until the investigator and/or Gilead determine that the subject's condition is stable. 
However, Gilead may request that certain AEs be followed until resolution.
Investigators are not obligated to actively seek SAEs after the 30-day period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the event 
is deemed relevant to the use of study drug, he/she should promptly document and report the 
event to Gilead PVE.
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guidelines.
7.3.1.
Electronic Serious Adverse Event (eSAE) Reporting Process
Site personnel will record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead PVE within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.
If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper SAE reporting form and submit within 


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24 hours as described above. As soon as it is possible to do so, any SAE reported via paper must 
be transcribed into the eCRF Database according to instructions in the eCRF completion 
guidelines.
If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.
Additional information may be requested to ensure the timely completion of accurate safety 
reports.
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions, or SUSARs. 
In accordance with the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee 
will notify worldwide regulatory agencies and the relevant IEC in concerned Member States of 
applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable.
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.


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7.4.1.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population
Given the endpoints of the study, in order to maintain the integrity of the study, the following 
events that are assessed as unrelated to study drug will not be considered SAEs:

Progression of FL

Death related to progression of FL
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the study drugs caused or contributed to the disease 
progression (ie, by a means other than lack of effect). Unrelated disease progression should be 
captured on the eCRF.
These unrelated events will be reported, as appropriate, in the final clinical study report (CSR) 
and in any relevant aggregate safety reports. The safety information from this study will also be 
reviewed by an independent DMC on an ongoing basis. The DMC can have access to partially 
blinded or unblinded data in order to determine if it is safe to continue the study according to the 
protocol.
7.5.
Recommendations for Evaluation, Intervention, and Drug Discontinuation 
for Specific Adverse Events or Conditions
7.5.1.
Dermatological Events
Subjects receiving idelalisib with ≥ Grade 3 rash have generally presented with a maculopapular 
rash on the trunk and extremities that is occasionally associated with fever and/or pruritus and 
responded to treatment with diphenhydramine and/or topical or oral corticosteroids. 
For subjects who develop a Grade ≥ 3 rash for which an underlying etiology cannot be identified 
(eg, infection, co-suspect drug), study drug must be interrupted until Grade ≤ 1; idelalisib can 
then be resumed at the reduced dose level,100 mg twice daily or discontinued at the 
investigator’s discretion.
Severe cutaneous reactions, including fatal events of Stevens-Johnson syndrome (SJS), 
toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms 
(DRESS) have been reported in subjects receiving idelalisib. Assessment of potential causal 
association between idelalisib and the occurrence of SJS or TEN has been confounded by the 
coadministration of antineoplastic agents (eg, bendamustine, rituximab) and/or other 
concomitant medications known to be associated with SJS or TEN (eg, allopurinol). If SJS, TEN, 
or DRESS is suspected, idelalisib and all coadministered medications associated with SJS, TEN, 
or DRESS should be interrupted and the subject treated accordingly. 
Subjects should be monitored for the development of SJS, TEN, or DRESS and idelalisib 
treatment must be permanently discontinued if such events occur.


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7.5.2.
Progressive Multifocal Leukoencephalopathy 
Cases of progressive multifocal leukoencephalopathy (PML) have been reported following the 
use of idelalisib within the context of prior or concomitant immunosuppressive therapies 
(including fludarabine and select anti-DC20 monoclonal antibodies [eg, rituximab]) that have 
been associated with PML. Investigators should consider PML in the differential diagnosis in 
subjects with new or worsening neurological, cognitive, or behavioral signs or symptoms. If 
PML is suspected, then appropriate diagnostic evaluations (referral to neurologist including MRI 
scan preferably with contrast, cerebrospinal fluid testing for John Cunningham viral DNA) 
should be undertaken and treatment needs to be suspended until PML is excluded.
7.5.3.
Gastrointestinal Events 
Isolated cases of gastrointestinal inflammation (eg, stomatitis, colitis, cecitis) have been noted in 
subjects receiving idelalisib. Rare cases of gastrointestinal perforation have occurred, generally 
in the setting of occult carcinoma, mesenteric embolus or diverticular disease. Study treatment 
must be permanently discontinued in subjects who experience bowel perforation.
Subjects who have developed evidence of enteritis during idelalisib therapy have been 
successfully treated with antidiarrheals (eg, loperamide) and with enteric steroidal (eg, budesonide) 
or non-steroidal (eg sulfasalazine [Azulfidine®]) anti-inflammatory agents and have been able to 
continue or resume idelalisib.
For study subjects who develop severe abdominal pain the possibility of a bowel obstruction or 
perforation should be considered. Appropriate clinical and radiographic examination should be 
performed and supportive care or surgical intervention should be considered. 
For subjects who develop persistent diarrhea, obtain history of onset and duration of diarrhea and 
perform a physical exam per Section 6.1.12.1.
For Grade ≥ 2 diarrhea/colitis causes may relate to concomitant medications or gastrointestinal 
infections. Stool collection is required per Section 6.1.5.5. Differentiate between small-bowel 
and large-bowel diarrhea on a clinical basis. If unclear, consider upper and lower tract endoscopy 
with biopsy. Refer to Section 6.1.5.6 for additional information. In the event that an infectious 
cause is not identified, an antimotility agent (eg, loperamide) may lessen symptoms and 
intervention with enteric steroidal (eg, budesonide) or non-steroidal (eg, sulfasalazine) 
anti-inflammatory agents should be considered. Ensure good hydration status. In such subjects, 
rechallenge with idelalisib at a lower dose level has resulted in recurrence of symptoms in some 
but not all subjects and has not been associated with other SAEs. Withhold idelalisib for subjects 
with Grade 3 diarrhea and monitor at least weekly until Grade ≤ 1, then the subject may resume 
idelalisib at the reduced dose level, 100 mg twice daily. Discontinue idelalisib permanently for 
Grade 4 diarrhea.


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7.5.4.
Hepatic Events
Transaminase Elevations: Consistent with observations in a dog toxicology study, reversible 
asymptomatic alanine aminotransferase (ALT)/AST increases were also observed early in the 
idelalisib program in phase 1 studies (101-02 and 101-07) in subjects with hematologic 
malignancies. Transaminase elevations generally occurred within 4 to 12 weeks of drug 
initiation, and resolved spontaneously over a period of 2 to 4 weeks with drug being continued 
for Grade 1 and 2 elevations and drug withheld for Grade 3 or 4 elevations until resolution. These 
early observations have been consistent with the ongoing experience with idelalisib treatment and 
transaminase elevations are now well characterized as most frequently asymptomatic, transient and 
occurring within the first 3 months of treatment.
Grade 1 or 2 elevations commonly resolve despite continued idelalisib treatment and Grade 
3 elevations must be managed by withholding idelalisib. After resolution to ≤ 1 x upper limit of 
normal, idelalisib may be resumed at the reduced dose level, 100 mg twice daily. Discontinue 
idelalisib permanently for Grade 4 elevation. There has been no evidence of impaired synthetic 
function. Close monitoring of hepatic laboratory tests during therapy is important to allow for 
appropriate idelalisib interruption and reinstitution so that subjects may continue with study drug 
treatment. Monitor ALT, AST, and bilirubin at least weekly until all abnormalities are Grade ≤ 1.
Cholangitis manifest as hyperbilirubinemia out of proportion to serum transaminase elevations 
has been observed. While disease-related factors, neutropenia, toxicity from prior therapies, 
effects of ongoing supportive care, or pre-existing cholelithiasis may have initiated such events, 
it is possible that idelalisib played a contributory role. In such subjects, rechallenge with 
idelalisib has been possible and has not been associated with other SAEs.
7.5.5.
Hematological and Immunological Events 
In the Phase 1 experience with idelalisib in patients with NHL and CLL, subjects with Grade  3 
neutropenia, anemia, and/or thrombocytopenia were enrolled to clinical trials. Decreased levels 
of neutrophil counts, hemoglobin, or platelet counts during idelalisib administration were largely 
due to minor fluctuations in these parameters among subjects with pre-existing hematological 
abnormalities due to disease or prior therapy. Thus, idelalisib did not appear to induce overt 
myelosuppression. Obvious patterns of drug-mediated reductions in circulating CD4+ 
lymphocyte counts or suppression of serum IgG levels were also not observed.
Treatment-emergent Grade 3 or 4 neutropenia events, including febrile neutropenia, have 
occurred in subjects treated with idelalisib. All subjects should have their blood counts 
monitored at least every 2 weeks for the first 6 months of idelalisib treatment. For subjects who 
develop Grade 3 neutropenia, maintain idelalisib dose and blood counts must be monitored at 
least weekly until ANC ≤ Grade 2. For subjects who develop Grade 4 neutropenia, idelalisib 
must be interrupted and blood counts monitored at least weekly until ANC ≤ Grade 2. Idelalisib 
may be resumed at the reduced dose level, 100 mg twice daily, when ANC ≤ Grade 3. 
Neutropenia should be managed according to established clinical guidelines.
No modification of any drug for changes in circulating CD4+ counts or Ig levels is planned.


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7.5.6.
Infectious Events 
Patients with lymphoid cancers receiving idelalisib have developed serious and fatal infections 
during therapy. Opportunistic infections, most notably PJP and CMV infection, have most 
frequently occurred within the first 6 months of treatment with idelalisib and are increased in the 
context of concurrent myelosuppressive therapy such as bendamustine.
Subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP 
throughout the course of idelalisib treatment. Prophylaxis must continue for a minimum period 
of 2 months after idelalisib discontinuation and should last for a period of 2-6 months. 
Prophylaxis may stop within the 2-6 months after idelalisib discontinuation when the CD4+ 
T-cell count is documented to be > 200 cells/mcL. Prophylaxis may continue beyond 6 months at 
the discretion of the investigator. The duration of prophylaxis beyond the minimum requirement 
post idelalisib discontinuation should be based on clinical judgment and may take into account 
risk factors such as concomitant corticosteroid treatment and prolonged neutropenia after 
idelalisib treatment ends. Subjects must permanently discontinue idelalisib upon diagnosis of 
PJP.
CMV surveillance for active disease (quantitative PCR) must be conducted approximately every 
4 weeks throughout the course of idelalisib treatment, including during drug interruptions due to 
toxicity or AEs. CMV viral load testing should be performed from the same specimen type 
whenever possible and caution should be exercised when comparing CMV viral load results 
across different testing centers. If unequivocal clinical or laboratory evidence of CMV infection 
is present, the subject must interrupt idelalisib treatment and undergo effective antiviral 
treatment according to established clinical guidelines. If the benefits of resuming idelalisib are 
judged to outweigh the risks, consideration should be given to administering pre-emptive CMV 
therapy.
In high-risk subjects (history of recurrent infection, allogeneic transplant, treatment with 
alemtuzumab, hypogammaglobulinemia) other infection prophylaxis should be considered per 
consensus guidelines. Administration of intravenous immunoglobulin is permitted per standard 
institutional practice {Raanani 2009}. For subjects who develop an infection, appropriate 
medical therapy should be instituted in a timely manner.
7.5.7.
Pulmonary Events 
Documented bacterial, fungal, viral, and Pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some study subjects receiving 
idelalisib alone or in combination have developed evidence of pneumonitis and organizing 
pneumonia, respectively, without documented pulmonary infection.


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Given the potential for infectious or drug-related pulmonary AEs, clinicians should be 
particularly observant for evidence of respiratory events in subjects participating in this study. 
Subjects who describe pulmonary symptoms (eg, dyspnea on exertion, cough, shortness of breath); 
manifest a decline from baseline of  5% in oxygen saturation, or demonstrate evidence of 
pulmonary inflammation (eg, focal or diffuse interstitial pattern or ground-glass opacities on 
chest CT) should be evaluated. Potential bacterial, fungal, or viral etiologies should be assessed. 
Noninfectious etiologies such as pulmonary edema or thromboembolism should also be 
considered.
As appropriate for the clinical situation and culture results, subjects should be treated empirically 
or given specific antibiotics, antifungals, or antiviral agents for a cultured organism. Supportive 
care, including oxygen or mechanical ventilation, should be provided as necessary.
For subjects with suspected Grade 1 pneumonitis (eg, asymptomatic), withhold idelalisib until 
resolution to baseline. Idelalisib may be resumed at the reduced dose level, 100 mg twice daily or 
discontinued at investigator discretion. For subjects with suspected Grade ≥ 2 pneumonitis 
(eg, onset of cough, dyspnea, hypoxia and/or a diffuse interstitial pattern or ground-glass 
opacities on chest imaging without obvious infectious etiology), idelalisib must be discontinued 
permanently and therapy initiated as clinically appropriate.
Cases of organizing pneumonia, some with fatal outcome, have occurred with idelalisib. In 
subjects presenting with serious lung events, idelalisib should be interrupted and the subject 
assessed for an explanatory etiology. If organizing pneumonia is diagnosed, treatment with 
idelalisib should be permanently discontinued and the subject treated accordingly.
7.5.8.
Secondary Malignancies
Subjects receiving idelalisib for CLL or iNHL have developed pre-malignant and secondary 
malignant diseases, such as basal cell carcinoma, myelodysplastic syndrome, myeloproliferative 
disorders, and more aggressive lymphoid malignancies (eg, have had Richter transformation). 
Generally this has occurred in subjects who have received multiple previous lines of therapy and 
when idelalisib is combined with other therapies such as rituximab or bendamustine. The specific 
association of the therapeutic agents with these types of events has not been determined.
There are reports of pre-malignant and malignant diseases that have developed in subjects who 
have been treated with bendamustine, including myelodysplastic syndrome, myeloproliferative 
disorders, acute myeloid leukemia, and bronchial carcinoma. The specific association of the 
therapeutic agents with these types of events has not been determined.


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7.5.9.
Tumor Lysis Syndrome 
Tumor lysis syndrome is very uncommonly associated with idelalisib monotherapy.
Subjects with tumor lysis syndrome should receive rapid reversal of hyperkalemia, intravenous 
hydration, antihyperuricemic agents, and appropriate cardiac and renal support, including 
dialysis as indicated. Upon recovery to baseline functioning, such subjects should continue study 
treatment including study drug (idelalisib/placebo).
7.5.10.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, definitive reproductive toxicology studies in animals 
have not yet been performed and the specific effects of idelalisib on human embryogenesis or 
fetal development are unknown. Whether idelalisib is excreted in human breast milk is unknown. 
General toxicology studies of idelalisib in rats and dogs indicated dose-dependent reductions in 
testicular weights, with persistent minimal to mild degeneration of the seminiferous tubules and 
decreased spermatozoa in rats and hypospermatogenesis in dogs. The implications of these 
testicular changes for animal or human fertility are unknown. 
Given the potential risks to a fetus or infant as a result of exposure to idelalisib, women of 
reproductive potential entering this study must have a negative serum pregnancy test at baseline 
and must not be breastfeeding. Males and females of childbearing potential should abstain from 
sexual intercourse or use an effective form of contraception (see Appendix 4). If a female study 
participant becomes pregnant or decides to breastfeed during the course of the study, all study 
therapy must be discontinued.
7.5.10.1.
PJP Prophylaxis Precautions in Pregnancy 
Trimethoprim/sulfamethoxazole is rated a Pregnancy category C agent. In rats, oral doses of 
533 mg/kg or 200 mg/kg produced teratologic effects manifested mainly as cleft palates. 
One survey found no congenital abnormalities in 35 children whose mothers had received oral 
sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter. Because 
sulfamethoxazole and trimethoprim may interfere with folic acid metabolism it should be used 
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Dapsone is rated a Pregnancy Category C agent. Extensive, but uncontrolled experience and 
two published surveys on the use of dapsone in pregnant women have not shown that dapsone 
increases the risk of fetal abnormalities if administered during all trimesters of pregnancy or can 
affect reproduction capacity. Because of the lack of animal studies or controlled human 
experience, dapsone should be given to a pregnant woman only if clearly needed. Dapsone is 
excreted in breast milk in substantial amounts. Hemolytic reactions can occur in neonates. 
Because of the potential for tumorgenicity shown for dapsone in animal studies a decision should 
be made whether to discontinue nursing or discontinue the drug taking into account the 
importance of drug to the mother.


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Atovaquone is rated a Pregnancy Category C agent. Atovaquone is teratogenic and did not cause 
reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human 
exposure. Atovaquone can cause maternal toxicity in rabbits at plasma concentrations that were 
approximately one half the estimated human exposure. Mean fetal body lengths and weights 
were decreased and there were higher numbers of early resorption and post-implantation loss per 
dam. It is not clear whether these effects are caused by atovaquone directly or are secondary to 
maternal toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent 
maternal plasma concentrations. There are no adequate and well-controlled studies in pregnant 
women. Atovaquone should be used during pregnancy only if the potential benefit justifies the 
potential risk to the fetus. It is not known whether atovaquone is excreted into human milk. 
Because many drugs are excreted into human milk, caution should be exercised when 
atovaquone is administered to a nursing woman. In a rat study, atovaquone concentrations in the 
milk were 30% of the concurrent atovaquone concentrations in the maternal plasma.
Aerosolized pentamidine (NebuPent) is a Pregnancy Category C agent. There are no adequate 
and well controlled studies of aerosolized pentamidine in pregnant women. One literature report 
indicated that intravenously administered pentamidine in pregnant rats at 4 mg/kg/day was 
embryolethal; teratogenicity was not observed in this study. It is unknown whether pentamidine 
administered via the aerosolized route crosses the placenta at clinically significant 
concentrations. It is not known whether aerosolized pentamidine can cause fetal harm when 
administered to a pregnant woman. Aerosolized pentamidine should be given to a pregnant 
woman only if clearly needed. It is not known whether aerosolized pentamidine is excreted in 
human milk. Aerosolized pentamidine should not be given to a nursing mother unless the 
potential benefits are judged to outweigh the unknown risks.
7.5.11.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated with 
GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to ultraviolet light. 
While nonclinical findings suggest the hypothetical potential for phototoxicity in humans, 
available clinical data do not reveal a photosafety concern. Although specific clinical correlates 
for these nonclinical data are not available, investigators and study subjects should be observant 
for the possibility that study participants may have exaggerated sunburn reactions 
(eg, burning, erythema, exudation, vesicles, blistering, edema) involving areas of skin exposed to 
ultraviolet light.
7.5.12.
Investigation for Idelalisib Late Onset or Severe Diarrhea/Colitis
See CTCAE Version 5.0 for definitions of colitis and diarrhea.
Among idelalisib-treated patients who reported diarrhea or colitis, the median time to onset of 
any grade diarrhea or colitis was 1.9 months (range, 0.0–29.8), of Grade 1 or 2 was 1.5 months 
(range, 0.0–15.2) and of Grade 3 or 4 was 7.1 months (range, 0.5–29.8). Kaplan-Meier curves of 
time to onset of diarrhea or colitis are shown for all idelalisib- treated patients in Figure 7-1 
{Coutre 2015}.


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Figure 7-1.
Kaplan-Meier Time to Diarrhea or Colitis
Idelalisib-associated severe diarrhea responds poorly to antimotility agents however, median 
time to resolution ranged between 1 week and 1 month across trials following interruption of 
idelalisib treatment and, in some instances, initiation of corticosteroid treatment 
{Gilead Sciences Inc 2014}.
7.5.13.
Further Safety Information
Further safety information regarding the study drug may be found in the IB for idelalisib. The 
idelalisib IB contains information related to toxicity management that is not covered in 
Section 5.3.2. The dose modification guidelines in the current idelalisib IB may be slightly 
different than those listed in Section 5.3.2 because different recommended dose modifications 
were used in prior clinical studies.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, and pregnancy reports regardless of an associated 
AE. Reports of adverse reactions in infants following exposure from breastfeeding, and reports 
of adverse reactions associated with product complaints and reports arising from occupational 
exposure are also considered special situation reports.

A pregnancy report is used to report any pregnancy in female subjects or female partners of 
male subjects on study.

Medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product while in the control of the health care provider, subject, or consumer.
100 
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Vertical dot line represents median time to onset calculated based on a11 subjects with an event 


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
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject.

Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.

An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labeling (as it applies to the daily dose 
of the subject in question). In cases of a discrepancy in drug accountability, overdose will be 
established only when it is clear that the subject has taken the excess dose(s). Overdose 
cannot be established when the subject cannot account for the discrepancy except in cases in 
which the investigator has reason to suspect that the subject has taken the additional dose(s).

Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal product.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to Gilead PVE using the pregnancy report form within 
24 hours of becoming aware of the pregnancy. Refer to the eCRF completion guidelines for full 
instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
Furthermore, any SAE occurring as an adverse pregnancy outcome post study must be reported 
to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
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Pregnancies of female partners of male study subjects exposed to Gilead study drug must also be 
reported and relevant information should be submitted to Gilead PVE using the pregnancy 
outcome report form within 24 hours. Monitoring of the subject should continue until the 
conclusion of the pregnancy. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead PVE.
Gilead PVE contact information is as follows: Email: 
 and 
Fax: 
.
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Recommendations.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug, but do not apply to concomitant 
medications. Except for situations that result in AEs, special situations involving concomitant 
medications will not be reported. Any inappropriate use of medications prohibited by this 
protocol should not be reported as “misuse,” but may be more appropriately documented as a 
protocol deviation.
Refer to the eCRF completion guidelines for full instructions on the mechanism of special 
situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
PPD
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is as follows:

Establish a safe and effective dosing regimen of idelalisib in subjects with relapsed or 
refractory FL who have no other therapeutic options
The secondary objectives of this study are as follows:

Evaluate the ORR

Evaluate the PFS, DOR, and OS

Evaluate the overall safety profile of idelalisib

Determine the PK of idelalisib and its major metabolite (GS-563117)
The exploratory objective of this study is as follows:

 
8.1.2.
Primary Endpoints
The primary endpoints are as follows:

ORR, defined as the proportion of subjects who achieve a PR or CR

Incidence of Grade ≥ 4 TEAEs
8.1.3.
Secondary Endpoints
The secondary endpoints are as follows:

DOR, defined as the interval from the first documentation of CR or PR to the earlier of the 
first documentation of disease progression by IRC or death from any cause

ORR by Week 24, defined as the proportion of subjects who achieve a PR or CR by Week 24

Overall safety profile of idelalisib, including the incidence of AEs and clinically significant 
laboratory abnormalities, severity, timing, and relationship to idelalisib of any AEs; SAEs; or 
AEs leading to interruption, reduction, or discontinuation of idelalisib
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
Time to onset of AEIs, defined as the interval from the start of idelalisib treatment to the first 
documentation of start of AEI

PFS, defined as the interval from randomization to the earlier of the first documentation of 
disease progression by IRC or death from any cause

OS, defined as the interval from randomization to death from any cause

Idelalisib trough (predose) and peak (1.5-hour samples) plasma concentrations assessed by 
validated bioanalytical method
8.1.4.
Other Endpoints of Interest
The exploratory endpoint is as follows:

8.2.
Analysis Conventions
The primary study analysis will be conducted when all enrolled subjects have discontinued the 
study or been on treatment for at least 48 weeks and completed response assessment of Week 48.
8.2.1.
Analysis Sets
8.2.1.1.
Intent-to-Treat (ITT) Analysis Set
The ITT Analysis Set will include all subjects who are randomized regardless of whether 
subjects receive any study drug. Treatment assignment will be designated according to a 
subject’s initial randomization. This analysis set will be used in the analysis of subject 
characteristics and efficacy.
8.2.1.2.
Safety Analysis Set
The Safety Analysis Set will include data from subjects who receive at least 1 dose of study 
treatment, with treatment assignments designated according to the actual treatment received. 
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration.
8.2.1.3.
Pharmacokinetics Analysis Set
The PK Analysis Set will include data from all subjects in the Safety Analysis Set who have 
received the study drug and have at least 1 sample with detectable drug concentration.
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8.3.
Data Handling Conventions
The baseline value used in each analysis will be the last (most recent) pretreatment value before 
or on the first dosing date of study drug. Data from all sites will be pooled for all analyses. 
Analyses will be based upon the observed data unless methods for handling missing data are 
specified. Data will be described and summarized by relevant treatment arm, analysis set, and 
time point. As appropriate, changes from baseline to each subsequent time point will be 
described and summarized by treatment arm.
In general, for data summaries involving continuous variables, data tables will typically contain 
the following statistics: N (number in analysis set), n (number with data), mean, standard 
deviation (StD), 95% CIs on the mean, median, minimum, and maximum. For categorical 
variables, the following statistics will typically be presented: N, n, percentage, and 95% CIs on 
the percentage. Unless otherwise indicated, 95% CIs for binary variables will be calculated using 
the binomial distribution (exact method) and will be 2-sided.
Tumor response status and progression will be assessed by the IRC using standard response 
criteria. The findings of the IRC will be considered primary for analyses of the primary efficacy 
endpoint and other tumor control endpoints. 
8.4.
Demographic Data and Baseline Characteristics
Subject characteristics will be listed and summarized by treatment arm in the ITT Analysis Set 
using standard descriptive methods. Demographic summaries will include sex, race/ethnicity, 
and age. Baseline characteristics data will include a summary of body weight, height, ECOG 
performance status score, Ann Arbor stage assessments, and FLIPI factors.
8.5.
Efficacy Analysis
8.5.1.
Primary and Supportive Analysis for Primary Endpoint
For the primary efficacy analysis, ORR will be evaluated by treatment arm using the IRC 
assessments in the ITT Analysis Set. The estimation may also be done for subgroups including 
potential predictors of response. Subjects who do not have sufficient baseline or on-study tumor 
assessment to characterize response status will be counted as non-responders. Estimates and the 
corresponding 95% CIs based on the Clopper-Pearson exact method will be provided.
The potential impact of subject baseline characteristics and treatment response rates may be 
explored with logistic regression modeling.
8.5.2.
Analysis for Secondary Endpoints
The ORR by Week 24 and corresponding 95% CIs will be evaluated by treatment arm using the 
IRC assessments in the ITT Analysis Set.


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The time-to-event efficacy endpoints including PFS, DOR, and OS will be analyzed using the 
Kaplan-Meier method in the ITT Analysis Set, and the analysis of DOR will include subjects 
who achieve a PR or CR. Analyses may also be performed for subgroups defined by potential 
predictors of response.
8.6.
Safety Analysis
Safety will be assessed via AEs, clinical laboratory tests, and concomitant medications. Safety 
data collected on or after the date that idelalisib was first administered up to the date of last dose 
of study drug plus 30 days will be summarized by treatment arm.
8.6.1.
Extent of Exposure
Descriptive information will be provided by treatment arm regarding the duration of exposure to 
study drug, and the number and timing of dose interruptions and reductions.
8.6.2.
Adverse Events
All AEs will be listed. The focus of AE summarization will be on treatment-emergent AEs. A 
treatment-emergent AE is defined as any AE with onset date on or after the date of first dose of 
study drug up to 30 days after permanent study drug discontinuation or any AEs leading to 
premature study drug discontinuation.
AEs will be classified using Medical Dictionary for Regulatory Activities with descriptions by 
system organ class (SOC), high-level group term, high-level term, preferred term (PT), and 
lower-level term. The severity of AEs will be graded by the investigator according to the 
CTCAE, Version 5.0, whenever possible. If a CTCAE criterion does not exist for a specific type 
of AE, the grade corresponding to the appropriate adjective will be used by the investigator to 
describe the intensity of the AE: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 
(life threatening), or Grade 5 (fatal). The relationship of the AE to the study drug will be 
categorized as related or unrelated.
For the primary safety endpoint, the number and percentage of subjects who experienced at least 
one Grade ≥ 4 TEAE will be listed and summarized by SOC and PT, and by treatment arm in the 
Safety Analysis Set. The severity, timing, relationship to study drug, drug interruptions, 
reductions, and discontinuations for Grade ≥ 4 TEAEs will be summarized.
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided. A 
subject who reports multiple TEAEs within the same PT (or SOC) is counted only once for that 
PT (or SOC) using the worst severity grade. AE descriptions will be presented by decreasing 
frequency for a given SOC and PT.
Separate summaries will be prepared for the following types of TEAEs:

Idelalisib-related AEs

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
AEs that are Grade ≥ 3 in severity

AEs leading to study drug interruption, reduction, or discontinuation

SAEs
Additional analysis on AEIs will be performed. The AEIs include: Grade ≥ 3 diarrhea/colitis, 
rash, febrile neutropenia, infection and any grade of the following: pneumonitis, bowel 
perforation, progressive multifocal leukoencephalopathy (PML), PJP, CMV infection, and 
organizing pneumonia. The frequency, severity, timing, and drug interruptions for AEIs will be 
summarized by treatment arm using descriptive statistics. Time to first onset of AEIs and time to 
resolution will be summarized using the Kaplan-Meier method.
8.6.3.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 
compared to baseline, worsens by ≥ 1 grade in the period from the first dose of study treatment 
(idelalisib) to 30 days after the last dose of study treatment. If baseline data are missing, then any 
graded abnormality (ie, an abnormality that is Grade ≥ 1 in severity) will be considered treatment 
emergent.
Hematological and serum biochemistry data will be programmatically graded according to 
CTCAE severity grade, when applicable. Hematological and serum biochemistry and their 
changes from baseline will be summarized by treatment and by visit. Summary tables will be 
presented for each relevant assay to show the number of subjects by CTCAE severity grade with 
corresponding percentages. For parameters for which a CTCAE scale does not exist, the 
frequency of subjects with values below, within, and above the normal ranges will be 
summarized. Subjects will be characterized only once for a given assay, based on their worst 
severity grade observed during a period of interest (eg, during the study or from baseline to a 
particular visit). Shift tables for hematology and serum biochemistry will also be presented by 
showing change in CTCAE severity grade from baseline to the worst grade post baseline. 
Separate listings and summaries will be prepared for laboratory abnormalities that are Grade  3 
in severity.
8.7.
Pharmacokinetic Analysis
Plasma concentrations of idelalisib/metabolite will be listed and summarized by treatment arm 
and visit using descriptive statistics (eg, sample size, arithmetic mean, geometric mean, 
% coefficient of variation, StD, median, minimum, and maximum).


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Additionally, a population PK model using a nonlinear mixed-effect modeling technique may be 
used to characterize the PK of idelalisib and GS-563117. Idelalisib exposure-response 
relationship between efficacy, safety, and idelalisib and/or GS-563117 exposure may be 
explored.
A logistic regression model may be used to explore the correlation between drug exposure and 
efficacy or safety.
8.8.
Sample Size
The planned sample size is approximately 266 subjects: approximately 120 subjects in Arm A, 
approximately 26 subjects in Arm B, and approximately 120 subjects in Arm C. As of Protocol 
Amendment 5, Arm B enrollment was closed after enrollment of approximately 26 subjects into 
Arm B and approximately 26 subjects into Arm A.
As of Protocol Amendment 5, subjects will be randomized to 2 arms (Arm A and C) with a 
1:1 ratio until the enrollment target of 120 subjects in each arm is met. The ORR was 
approximately 56% for subjects with FL in Study 101-09. If the underlying true ORR is 56% for 
subjects in this study, the chance to observe 60 or more responders out of 120 subjects (observed 
ORR ≥ 50%) is 92%. With 120 subjects in each arm, the half-width of a two-sided 95% CI of 
ORR is ≤ 10% for an observed ORR in the range of 40%-60%, and the half-width of a two-sided 
95% CI of ≥ Grade 4 TEAEs incidence rate is ≤ 10% for an observed AE rate in the range of 
20%-40%.
The sample size was originally planned to include 240 subjects randomized to Arm A and Arm B 
with a 1:1 ratio. The previous sample size calculation is based on the rate of Grade ≥ 3 
diarrhea/colitis approximately 15% in the prior idelalisib studies. A sample size of 120 subjects 
per arm would provide 73% chance to detect a reduction of 10% (ie, 15% incidence in the 
150 mg twice daily arm versus 5% incidence in the 100 mg twice daily arm) using a 2-sided 
Chi-square test with alpha level of 0.05.
8.9.
Data Monitoring Committee
An external multidisciplinary DMC will review the progress of the study and perform interim 
reviews of safety data at regular intervals until all blinded subjects are either unblinded or off the 
study. The DMC will provide recommendations to Gilead as to whether the nature, frequency, 
and severity of adverse effects associated with study treatment warrant the early termination of 
the study in the best interests of the study participants, whether the study should continue as 
planned, or whether the study should continue with modifications.
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct, and meeting schedule.
 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Council for Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the EU Clinical Trials 
Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of GCP, as outlined in 21 Code of 
Federal Regulations (CFR) 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
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9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC-approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 
and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB/IEC local 
requirements. 
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions provided in the 
laboratory manual. The investigator must keep a screening log showing codes, names, and 
addresses for all subjects screened and for all subjects enrolled in the study. Subject data will be 
processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
IB, this protocol, eCRF, the study drug, and any other study information, remain the sole and 
exclusive property of Gilead during the conduct of the study and thereafter. This information is 
not to be disclosed to any third party (except employees or agents directly involved in the 
conduct of the study or as required by law) without prior written consent from Gilead. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain.
9.1.5.
Study Files and Retention of Records and Samples
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file, and (2) subject 
clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/IEC, and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.


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The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled;

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return;

Record of all AEs and other safety parameters (start and end date, and including causality 
and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.


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If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
Biological samples including tissue and blood samples collected as a study procedure or in the 
course of routine medical care during study participation will be stored and maintained by the 
investigator until notification is received from Gilead that the retained samples and records are 
no longer required. The investigator must obtain written permission from Gilead before 
disposing of any retained samples. The investigator should promptly notify Gilead in the event of 
accidental loss or destruction of any study samples. With the permission of Gilead, the retained 
samples may be transferred to an acceptable designee, such as another investigator, another 
institution, a contract storage site, or to Gilead.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed as per site contract, to enable the sponsor to perform central monitoring of safety data. 
The Eligibility Criteria eCRF should be completed only after all data related to eligibility have 
been received. Subsequent to data entry, a study monitor will perform source data verification 
within the electric data capture system. Original entries as well as any changes to data fields will 
be stored in the audit trail of the system. Prior to database lock (or any interim time points as 
described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (eg, data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Idelalisib Accountability and Return
Where possible, study drug should be destroyed at the site. If the site has an appropriate SOP for 
drug destruction as determined by Gilead, the site may destroy used (empty or partially empty) 
and unused study drug supplies in accordance with that site’s approved SOP. A copy of the site’s 
approved SOP will be obtained for central files. If study drug is destroyed on site, the 
investigator must maintain accurate records for all study drug destroyed. Records must show the 
identification and quantity of each unit destroyed, the method of destruction, and the person who 
disposed of the study drug. Upon study completion, copies of the study drug accountability 
records must be filed at the site. Another copy will be returned to Gilead.


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If the site does not have an appropriate SOP for drug destruction, used and unused study drug 
supplies are to be sent to the designated disposal facility for eventual destruction. The study 
monitor will provide instructions for return.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A CSR will be prepared and provided to the regulatory agency. Gilead will ensure that the report 
meets the standards set out in the ICH Guideline for Structure and Content of CSRs (ICH E3). 
Note that an abbreviated report may be prepared in certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at 
all study sites for at least 2 years.

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation.

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.


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9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Medical Monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.
9.4.
Independent Review Committee
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include 1 independent board-certified radiologist and 1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead. The review of 
radiographic and clinical data by the IRC will be performed on an ongoing basis. The specifics 
of the IRC’s processes and reading methods will be described in an independent review charter 
developed by the contracted imaging facility in conjunction with Gilead. The findings of the IRC 
will be considered primary for the primary efficacy endpoint, and other tumor control endpoints.


Idelalisib
Protocol GS-US-313-1580
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 80
18 March 2021
10.
REFERENCES
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol 
2014.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007;25 (5):579-86.
Coutre SE, Barrientos JC, Brown JR, de Vos S, Furman RR, Keating MJ, et al. Management of 
adverse events associated with idelalisib treatment - expert panel opinion. Leuk 
Lymphoma 2015:1-20.
Dreyling M, Geisler C, Hermine O, Kluin-Nelemans HC, Le Gouill S, Rule S, et al. Newly 
diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-updagger. Ann Oncol 2014;25 
Suppl 3:iii83-iii92.
Gilead Sciences Inc. ZYDELIG® (idelalisib) tablets, for oral use. U.S. Prescribing Information. 
Foster City, CA. July 2014:
Mills EJ, Barnighausen T, Negin J. HIV and aging--preparing for the challenges ahead. N Engl J 
Med 2012;366 (14):1270-3.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in 
Oncology: Non-Hodgkin's Lymphomas.  July, 2014.
Okkenhaug K, Vanhaesebroeck B. PI3K-signalling in B- and T-cells: insights from gene-
targeted mice. Biochemical Society transactions 2003;31 (Pt 1):270-4.
Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin 
prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic 
review and meta-analysis. Leuk Lymphoma 2009;50 (5):764-72.
Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, et al. Follicular 
lymphoma international prognostic index. Blood 2004;104 (5):1258-65.
Tsang RW, Gospodarowicz MK. Radiation therapy for localized low-grade non-Hodgkin's 
lymphomas. Hematol Oncol 2005;23 (1):10-7.
Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC. Signalling by PI3K isoforms: 
insights from gene-targeted mice. Trends Biochem Sci 2005;30 (4):194-204.


Idelalisib
Protocol GS-US-313-1580
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 81
18 March 2021
Wilder RB, Jones D, Tucker SL, Fuller LM, Ha CS, McLaughlin P, et al. Long-term results with 
radiotherapy for Stage I-II follicular lymphomas. International journal of radiation 
oncology, biology, physics 2001;51 (5):1219-27.
Zelenetz AD, Abramson JS, Advani RH, Andreadis CB, Bartlett N, Bellam N, et al. Non-
Hodgkin's lymphomas. J Natl Compr Canc Netw 2011;9 (5):484-560.


Idelalisib
Protocol GS-US-313-1580
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 82
18 March 2021
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Ann Arbor Lymphoma Staging System
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 5.
Follicular Lymphoma International Prognostic Index
Appendix 6.
Efficacy Assessments
Appendix 7.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 8.
Pandemic Risk Assessment and Mitigation Plan


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Idelalisib
Protocol GS-US-313-1580
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 84
18 March 2021
Appendix 2.
Study Procedures Table
Period
Screen Baseline
Treatment
Follow up
Visit
1
2
3
4
5
6
7
8
lab
9
lab
10
lab
11
lab
12
13
14
lab
15
lab
16+
EOT EOS
30
days
Survival
Week 
0
2
4
6
8
10
12
14
16
18
20
22
24
28
32
36
40
44
48
52
60+ 
(Q12
wks)
Cycle 
C1
D1
C1
D15
C2
D1
C2
D15
C3
D1
C3
D15
C4
D1
C4
D15
C5
D1
C5
D15
C6
D1
C6
D15
C7
D1
C8
D1
C9
D1
C10
D1
C11
D1
C12
D1
C13
D1
C14
D1
C16D1
+(Q3 
cycles)
Study Day
Within
28
days
1
15
29
43
57
71
85
99 113 127
141
155
169
197
225
253
281
309
337
365
Within
+30 
days a
Annual 
for 
5 years
Visit Window
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
5
3
5
4
weeks
Written Informed 
Consent
X
Medical History
X
Medication 
History
X
Physical 
Examination
X
Xq
Xr
Xq
X
X
X
Xb
Vital Signs c
X
Performance 
Status
X
X
X
X
X
X
X
X
Ann Arbor 
Staging
X
FLIPI
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
Urinalysis
X


Idelalisib
Protocol GS-US-313-1580
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 85
18 March 2021
Period
Screen Baseline
Treatment
Follow up
Visit
1
2
3
4
5
6
7
8
lab
9
lab
10
lab
11
lab
12
13
14
lab
15
lab
16+
EOT EOS
30
days
Survival
Week 
0
2
4
6
8
10
12
14
16
18
20
22
24
28
32
36
40
44
48
52
60+ 
(Q12
wks)
Cycle 
C1
D1
C1
D15
C2
D1
C2
D15
C3
D1
C3
D15
C4
D1
C4
D15
C5
D1
C5
D15
C6
D1
C6
D15
C7
D1
C8
D1
C9
D1
C10
D1
C11
D1
C12
D1
C13
D1
C14
D1
C16D1
+(Q3 
cycles)
Study Day
Within
28
days
1
15
29
43
57
71
85
99 113 127
141
155
169
197
225
253
281
309
337
365
Within
+30 
days a
Annual 
for 
5 years
Visit Window
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
5
3
5
4
weeks
Serum β-hCG 
(women of 
childbearing 
potential)
X
Urine Pregnancy 
Test (women of 
childbearing 
potential) d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis B 
Screening/Testing
X
Hepatitis C 
Screening
X
HIV Screening
X
CMV testing l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Beta-2 
Microglobulin
X
X
X
X
X
Labs for Immune 
monitoring n
X
X
X
X
X
X
X
X
X
CCI


Idelalisib
Protocol GS-US-313-1580
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 86
18 March 2021
Period
Screen Baseline
Treatment
Follow up
Visit
1
2
3
4
5
6
7
8
lab
9
lab
10
lab
11
lab
12
13
14
lab
15
lab
16+
EOT EOS
30
days
Survival
Week 
0
2
4
6
8
10
12
14
16
18
20
22
24
28
32
36
40
44
48
52
60+ 
(Q12
wks)
Cycle 
C1
D1
C1
D15
C2
D1
C2
D15
C3
D1
C3
D15
C4
D1
C4
D15
C5
D1
C5
D15
C6
D1
C6
D15
C7
D1
C8
D1
C9
D1
C10
D1
C11
D1
C12
D1
C13
D1
C14
D1
C16D1
+(Q3 
cycles)
Study Day
Within
28
days
1
15
29
43
57
71
85
99 113 127
141
155
169
197
225
253
281
309
337
365
Within
+30 
days a
Annual 
for 
5 years
Visit Window
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
5
3
5
4
weeks
PK Sample g
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
Radiology 
(PET-CT/CT/MRI) h
X
Xq
Xr
Xq
X
X
X
X
X
Tumor Response i
X
Xq
Xr
Xq
X
X
X
X
X
Bone Marrow 
Biopsy j
X
Xq
Xr
Xq
X
X
X
X
X
X
Randomizations
X
Idelalisib 
Dispensing
X
X
X
X
X
X
X
X
X
X
X
Idelalisib 
Administration k
X
X
X
X
X
X
X
X
X
X
X
X
PJP prophylaxis o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+ T-cell 
count p
X
X
X
Adverse Events m
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival 
Follow-Up
X


Idelalisib
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Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
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a
Occurs 30-days following EOT.
b
To be performed every 24 weeks.
c
At Screening, vital signs including oxygen saturation, systolic and diastolic blood pressure, heart rate, respiratory rate, temperature, and anthropometric measurements of height and 
weight will be measured by the investigator or qualified designees as per standard institutional guidelines.
d
For females of childbearing potential, urine pregnancy tests will be done every 4 weeks on study.
e
f
g
Pre-AM dose (within 1 hour prior to dose) and 1.5 hours post-AM dose (± 10 min) in the morning. Additional PK samples (single, non-timed) will be collected at unscheduled study 
visits (between Week 0 and Week 48).
h
Screening CT/PET-CT/MRI may be performed within 6 weeks prior to first dose and subsequent scans may be done within 1 week prior to clinic visit. Scans to be performed at 
Weeks 60 and 84 until documented IRC progressive disease, and at EOT (unless radiographic assessments performed within 4 weeks prior to EOT visit). After Week 84, radiographic 
assessments are performed at the discretion of the investigator.
i
Both Investigator and IRC to perform response assessments.
j
To be performed at baseline to confirm laboratory eligibility due to lymphoma involvement of the marrow. To be performed on-study to assess for a potential CR in a subject who had 
lymphoma involvement of the marrow at baseline or did not have a baseline bone marrow biopsy. After CR is determined, there is no need for any further bone marrow biopsy assessments.
k
Idelalisib morning dose to be administered in clinic after PK 
. For subjects randomized to Arm C, study drug should not be taken 
on scheduled “off-treatment” days, regardless of prior missed doses, study drug interruptions for toxicity, or PK/biomarker samples. If prior scheduled dose was missed for any reason 
including due to planned “off-treatment” schedule, a predose PK sample is not needed.
l
CMV testing must be done at screening and every 4 weeks throughout the course of study drug treatment, including during drug interruptions due to toxicity or AEs, requiring clinic 
visits after Week 24. CMV serology (anti-CMV IgG and IgM) testing will be done at baseline (Day 1) only.
m
For an AE of Diarrhea/Colitis: (1) Obtain history of onset and duration of diarrhea, including description of number of stools and stool composition, travel history, dietary changes and a 
medication review to identify possible diarrheogenic agents, and (2) Perform physical examination including assessment for fever, dizziness, abdominal pain/cramping, and weakness. 
n
The immune monitoring labs at all indicated timepoints include lymphocyte subset panel using flow cytometry (immunophenotyping), quantitative immunoglobulins IgG, IgM, IgA, 
IgE, and Serum CH50 level.
o
PJP prophylaxis: per Section 7.5.6 (“Infectious Events”) subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP throughout the course of 
idelalisib treatment and must continue for a minimum of 2 months after idelalisib discontinuation and should last for a period of 2-6 months. Prophylaxis may stop within the 2-6 months 
after idelalisib discontinuation when the CD4+ T-cell count is documented to be >200 cells/mcL. Subjects must permanently discontinue idelalisib upon diagnosis of PJP.
p
CD4+ T-cell count is needed to determine when PJP prophylaxis may end as specified in Section 7.5.6 (“Infectious Events”). 
q
Subjects enrolled prior to Protocol Amendment 5 only.
r
Subjects enrolled as of Protocol Amendment 5 only.
s
In case of administrative delays, every attempt should be made to initiate study drug as soon as possible, but no more than 7 days from randomization.
CCI
CCI
CCI


Idelalisib
Protocol GS-US-313-1580
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 88
18 March 2021
Appendix 3.
Ann Arbor Lymphoma Staging System
Area of Involvement
Stage
Single lymph node group or lymph node region
1
Two or more node regions on same side of diaphragm
2
Lymph node regions on both sides of the diaphragm 
3
Multiple extra-nodal sites or lymph nodes and extra-nodal sites
4
Additional Anatomic Factors
Designation
Confined to lymph nodes
N
Site of bulky disease (> 10 cm in diameter)
X
Extra-nodal extension or single isolated site of extra-nodal disease
E
Hepatic
H
Lung
L
Bone marrow
M
Spleen
S
Pleura
P
Bone
O
Skin
D
Additional Symptomatic Factors
Designation
No symptoms
A
Symptoms of weight loss > 10% within 6 months, fever, night 
sweats
B


Idelalisib
Protocol GS-US-313-1580
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 89
18 March 2021
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming postmenopausal unless the 
subject is permanently sterile or has medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are ≥ 54 years of age with 
cessation of previously occurring menses for ≥ 12 months without an alternative cause. In 
addition, women of any age with amenorrhea of ≥ 12 months may also be considered 
postmenopausal if their follicle-stimulating hormone level is in the postmenopausal range and 
they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
a) Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless the subject is permanently sterile by bilateral orchidectomy or medical 
documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Idelalisib is contraindicated in pregnancy as a malformation effect has been 
demonstrated/suspected or is unknown taking into consideration class effects, genotoxic 
potential, or a strong suspicion of human teratogenicity/fetotoxicity in early pregnancy based on 
nonclinical data. Idelalisib has demonstrated/suspected or has insufficient data to exclude the 
possibility of a clinically relevant interaction with hormonal contraception that results in reduced 
contraception efficacy. Therefore, contraceptive steroids are not recommended as a contraceptive 
method either solely or as a part of a contraceptive regimen. Please refer to the latest version of 
the investigator’s brochure for additional information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures with a failure rate of < 1% per year. They must also not rely on hormonal 
contraceptives as a form of birth control during the study. They must have a negative serum 
pregnancy test at screening and a negative pregnancy test on Day 1 prior to randomization. 
Pregnancy tests will be performed at monthly intervals thereafter until the end of contraception 
requirement.


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Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
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Duration of required contraception for female subjects in this clinical trial should start from the 
Screening visit until 30 days post last dose of study drug. 
Female subjects must agree to use 1 of the following contraceptive methods:
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual lifestyle.
Or
Consistent and correct use of 1 of the following methods of birth control listed below:

Non-hormonal intrauterine device (IUD) 

Bilateral tubal occlusion (upon medical assessment of surgical success)

Vasectomy in the male partner (upon medical assessment of surgical success)
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved.
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until the end of contraception requirement. If needed, female subjects should be advised to 
seek advice about egg donation and cryopreservation of germ cells prior to treatment.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration of study drug may be achieved 
in a female partner from exposure to the male subject’s seminal fluid and poses a potential risk to 
an embryo/fetus. Therefore, male subjects with female partners of childbearing potential must 
use condoms during treatment until 90 days after last dose of study drug. If the female partner of 
childbearing potential is not pregnant, use of locally approved contraceptive methods should also 
be considered.
Male subjects must also refrain from sperm donation during treatment and until the end of 
contraception requirement.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. A female condom and male condom should not be used together.


Idelalisib
Protocol GS-US-313-1580
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
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5) Procedures to be Followed in the Event of Pregnancy
Female subjects will be instructed to notify the investigator if they become pregnant or suspect 
they are pregnant at any time from start of the study to 30 days post last study drug dose. Study 
drug must be discontinued immediately.
Male subjects whose partner has become pregnant or suspects she is pregnant from start of study 
to 90 days post last study drug dose must also report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.6.2.1.


Idelalisib
Protocol GS-US-313-1580
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
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Appendix 5.
Follicular Lymphoma International Prognostic Index
Follicular Lymphoma International Prognostic Index (FLIPI) Scoring System
Parameter
Value
Point Score
Age
> 60 years of age
1
Ann Arbor stage
Stage III or IV
1
Hemoglobin level
< 120 g/L
(12.0 g/dL or 6.37 mmol/L)
1
Serum LDH
> ULN
1
Number of Nodal Sites
> 5
1
Risk Group by FLIPI Total Point Score
Risk Group
Total Point Score
Low
≤ 1
Intermediate
2
High
≥ 3
{Mills 2012}


Idelalisib
Protocol GS-US-313-1580
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 93
18 March 2021
Appendix 6.
Efficacy Assessments
Tumor Status Assessments
The determination of lymphoma response and progression will be based on standardized criteria 
{Cheson 2007} as specifically modified for this study to reflect the biology of the diseases under 
study and the pharmacology of idelalisib and the methods to be used in evaluation. During the 
course of the study, investigators will periodically assess the status of each subject’s lymphoma. 
If progression is suspected, the IRC will be notified and will review radiographic and pertinent 
clinical data in order to provide expert interpretation. Treatment decisions by the investigator in 
this study will be based, in part, on these assessments. The findings of the IRC will be considered 
primary for analyses of ORR and other tumor control endpoints.
Method of Assessment
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should also be performed. Contrast-enhanced scanning is preferred, but contrast material 
may be omitted in subjects for whom use of a contrast agent would be medically contraindicated. 
If available, PET scan data will be considered in response and progression assessment; however, 
PET scanning will not be a required component of assessment in this study. As appropriate, 
study treatment dosing delays, bone marrow aspirate/biopsy information (eg, for confirmation of 
CR) and lymph node biopsy information (eg, for documentation of disease transformation to an 
aggressive histology) will also be considered.
For radiographic assessments, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline, while on study drug treatment and 
during the open-label extension. Furthermore, the use of intravenous (IV) contrast should be 
consistent across time points. In the event that the screening/baseline CT scan of the neck, chest, 
abdomen, and pelvis is performed without IV contrast, follow-up time points should also be 
performed without IV contrast.
All relevant radiographic and clinical information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC.
Timing of Assessments
During screening, clinical and imaging-based tumor assessments should be performed within the 
specified screening period. On-study PET-CT/CT/MRI tumor assessments should be performed 
at as indicated in Appendix 2. An end-of-study PET-CT/CT/MRI tumor assessment should be 
performed unless the subject already has radiographic confirmation of disease progression 
4 weeks prior to study discontinuation. If a subject permanently discontinues study drug prior 
to objective documentation of lymphoma progression, investigators should continue further 
follow-up until lymphoma progression is documented by the IRC.


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Timing of Assessments − Subjects enrolled Prior to Protocol Amendment 5 
Subjects randomized to 100 mg twice daily idelalisib with SD or PD will be unblinded and dose 
escalated to 150 mg twice daily. Subjects randomized to 150 mg with SD will be unblinded. The 
subjects should continue PET-CT/CT/MRI tumor assessments as indicated in Appendix 2, until 
lymphoma progression is documented by the IRC. Subjects with PD on the 150 mg twice daily 
arm will be discontinued from study.
Identification and Follow-up of Tumor Lesions and Organomegaly
Index Lesions
Up to 6 lesions (eg, lymph nodes, liver or spleen nodules, and/or other circumscribed extra-nodal 
masses) should be selected as index lesions that will be used to quantitate the status of the 
disease during study. Ideally, the index lesions should be located in disparate regions of the body 
and include mediastinal, abdominal, and retroperitoneal areas of disease whenever these sites are 
involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the longest diameter 
[LD] × the longest perpendicular diameter [LPD]) will be recorded (in cm) for each index lesion. 
Using the LD and LPD, the product of the perpendicular diameters (PPD) for each index lesion 
will be calculated. The sum of the products (SPDs) for all index lesions will be calculated and 
recorded. The baseline SPDs will be used as references by which objective tumor response will 
be characterized during treatment. The nadir LDs of individual lesions and the nadir SPDs will 
be used as references by which objective tumor progression will be characterized during study. 
All PPD and SPD measurements will be reported in centimeters squared.
Nodal Index Lesions
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter >1.5 cm 
regardless of the LPD. If a lymph node lesion has a LD of 1.1 to 1.5 cm it should only be 
considered abnormal if its LPD is more than 1.0 cm. 
Abnormal, measurable nodal lesions will be subcategorized as either large or small.

Large nodal lesions have an LD that is > 1.5 cm and an LPD that is 1.0 cm. 

Small nodal lesions have an LD that is > 1.0 cm and  1.5 cm and an LPD that is > 1.0 cm.
Index lesions measuring > 1.5 cm in the LD, regardless of the measurement of the LPD, will be 
prioritized during baseline index lesion selection.


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At follow-up time points, the SPD of all nodal index lesions will be considered. Because nodal 
index lesions that have one or both diameters > 0 cm and  1.0 cm cannot be reliably measured, 
a default value of 1.0 cm will be assigned for each diameter that meets these criteria and the 
resulting PPD will be used in SPD calculations. Based on this convention, a CR may be achieved 
even if an SPD value is > 0 cm2 (ie, if all lymph nodes measure ≤ 1.0 cm2).
New or enlarging nodal lesions that are still  1.0 cm by  1.0 cm will not be considered to 
represent recurrent disease or PD. A new node that measures > 1.5 cm in any diameter or a new 
node that measures > 1.0 cm to  1.5 cm in the LD and measures > 1.0 cm in the LPD will be 
considered PD.
In cases in which a large lymph node mass has split into multiple components, only those 
elements that are > 1.0 cm in at least 1 diameter will be considered abnormal and used in 
calculating the SPD. Components that are ≤ 1.0 cm in the LD are assumed to be normal lymph 
node structures. PD will not be based on the growth of a lesion sub-component until it meets the 
criteria for abnormal. Lesion sub-components that are abnormal (> 1.0 cm in  1 diameter) will 
have the true PPDs calculated with the result used only for calculating an accurate nadir. Lesion 
sub-components that are normal ( 1.0 cm in the LD) will have the default PPD of 1.0 cm2 
(1.0 cm x 1.0 cm) stored only for the purposes of calculating the nadir value. 
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.
Extra-Nodal Index Lesions
An extra-nodal mass may be selected as an index lesion if it is both abnormal and measurable at 
baseline. An extra-nodal mass of any size is considered abnormal. It is considered measurable at 
baseline if it has 2 perpendicular diameters that can be accurately measured in cross section with 
the LD being  1.0 cm and the LPD also being  1.0 cm.
At follow-up time points, the PPD of each single extra-nodal index lesion and the SPD of all 
extra-nodal index lesions will be considered. Because extra-nodal index lesions that have one or 
both diameters > 0 cm and < 1.0 cm cannot be reliably measured, a default value of 1.0 cm will 
be assigned for each diameter that meets these criteria and the resulting PPD will be used in SPD 
calculations. If an extra-nodal lesion is no longer clearly visible, it will be considered resolved 
and its PPD will be defined as 0 cm2.
If an extra-nodal lesion that had resolved (ie, had a PPD of 0 cm2) subsequently reappears 
unequivocally, the subject will be considered to have PD. A new unequivocal extra-nodal lesion 
of any size that appears at a site that was not previously involved with lymphoma and is 
discernible to the radiologist by CT scan will be considered PD.


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Non-Index Lesions
Any other measurable and abnormal nodal or extra-nodal lesions not selected for quantitation as 
index lesions may be considered non-index lesions. In addition, non-measurable evidence of 
lymphoma such as abnormal, non-measurable nodal lesions, extra-nodal lesions with both 
diameters < 1.0 cm, bone lesions, leptomeningeal disease, ascites, pleural or pericardial 
effusions, lymphangitis of the skin or lung, abdominal masses that are not confirmed and 
followed by imaging techniques, cystic lesions, previously irradiated lesions, or lesions with 
artifacts may be considered as non-index disease.
If present at baseline, up to 6 non-index lesions should be recorded. Measurements are not 
required.
Non-index disease will be used as a general reference to further characterize regression or 
progression of lymphoma during assessments of the objective tumor response during treatment. 
These lesions should be followed as “present”, “absent” or “progressed.”
Spleen and Liver
Qualitative assessments of the sizes of the spleen and liver will be performed. In addition, the 
presence or absence of splenic and/or hepatic nodules will be recorded.
Bone Marrow
Bone marrow assessments will be based on morphologic evaluation of bone marrow biopsies. 
Immunohistochemistry may be used to assess response if the sample is indeterminate by 
morphology.
In a subject who has a baseline bone marrow biopsy showing bone marrow lymphoma or does 
not have a baseline bone marrow examination, declaration of an on-study CR requires bone 
marrow biopsy documentation of the absence of bone marrow lymphoma. In a subject who has a 
baseline bone marrow biopsy showing no evidence of lymphoma, declaration of an on-study CR 
does not require bone marrow examination as long as other criteria for CR are met.
Biopsy and Cytology
During study participation, a subject who has a biopsy or cytology indicating a new site of 
disease or transformation to an aggressive lymphoma will be considered to have PD even in the 
absence of other evidence of PD. If the subject has no earlier objective documentation of PD, the 
date of the biopsy or cytology will be considered the date of lymphoma progression.


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Definitions of Tumor Response and Progression
Responses will be categorized as complete response (CR), very good partial response, 
partial response (PR), stable disease (SD), or progressive disease (PD). In addition, a response 
category of not evaluable (NE) is provided for situations in which there is inadequate 
information to otherwise categorize response status. A response category of no disease (ND) is 
included for situations in which there is no evidence of tumor both at baseline and on-treatment.
The best overall response will be determined. The best overall response is the best response 
recorded from the start of study drug until PD/recurrence (taking as reference for PD the smallest 
measurements recorded since study drug started). Subjects with a best overall response of NE or 
ND will be included in the denominators in calculations of tumor response rate.
Response Categories
Complete Response
To satisfy criteria for CR, all of the following criteria must be met:

No evidence of new disease

Regression of all index nodal lesions to normal size (≤ 1.5 cm in the LD for nodes that were 
considered large at baseline and ≤ 1.0 cm in the LD and ≤ 1.0 cm in the LPD for nodes that 
were considered small at baseline) Regression to normal of all nodal non-index disease

Disappearance of all detectable extra-nodal index and non-index disease

Normal spleen and liver size by imaging studies, no hepatic or splenic lymphoma nodules, 
and no new liver or spleen enlargement

Morphologically negative bone marrow based on an adequate unilateral core biopsy 
(> 20 mm unilateral core); if the sample is indeterminate by morphology, it should be 
negative by immunohistochemistry. After the subject meets radiographic CR, the window for 
bone marrow biopsy is within 30 days from the date that CR was met.

If PET performed (not required), no evidence of residual disease
Partial Response
To satisfy criteria for PR, all of the following criteria must be met as noted below:

No evidence of new disease

A  50% decrease from baseline in the SPD of the index lesions

No increase in the size of non-index disease


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
No increase in the size of the liver or spleen and no new liver or spleen enlargement

Persistence of bone marrow involvement in a subject who meets other criteria for CR based 
on the disappearance of all nodal and extra-nodal masses

If PET performed (not required):
Typically fluorodeoxyglucose (FDG)-avid lymphoma: if no baseline PET scan or if the 
PET scan was positive before initiating study drug(s), the on-treatment PET is positive in 
1 previously involved site. If baseline PET was performed and was negative, there is no 
new PET evidence of disease
Variably FDG-avid lymphoma/FDG-avidity unknown: if no pretreatment PET scan or if 
the pretreatment PET scan was negative for lymphoma, CT criteria should be used in 
assessing the tumor during study. If the PET scan was positive before initiating study 
drug(s), the on-treatment PET is positive in 1 previously involved site.
Stable Disease
To satisfy criteria for SD, all of the following criteria must be met:

No evidence of new disease

Neither sufficient tumor shrinkage from baseline to qualify for PR nor sufficient evidence of 
tumor growth to qualify for PD
Progressive Disease
The occurrence of any of the following events indicates progressive disease (PD):

Evidence of any new disease that was not present at baseline:
A new node that measures > 1.5 cm in LD and > 1.0 cm in the LPD.
A new node that measures > 1.0 cm to ≤ 1.5 cm in the LD and > 1.0 cm in the LPD
Unequivocal reappearance of an extra-nodal lesion that had resolved (ie, had previously 
been assigned a PPD of 0 cm2)
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities) of any size 
unequivocally attributable to lymphoma (usually requires PET, biopsy, cytology, or other 
non-radiologic confirmation to confirm disease attributable to lymphoma). 
Note: Isolated new effusions, ascites, or bone lesions are not sufficient evidence alone 
of PD unless histologically confirmed. In subjects with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are usually benign. Thus, a declaration 
of PD should not be made if this is the only manifestation of an apparently new lesion.


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New or recurrent bone marrow involvement with lymphoma if the last prior bone marrow 
biopsy performed as part of the study (baseline or on-study) was negative for lymphoma

Evidence of worsening of nodal or extra-nodal index lesions:
Increase from the nadir by  50% in the SPD of index lesions
Increase from the nadir by  50% in the LD of an individual node or extra-nodal mass 
that now has an LD of > 1.5 cm and an LPD of > 1.0 cm

Unequivocal increase in the size of non-index disease

Transformation to a more aggressive NHL histology as established by lymph node biopsy

If PET performed (not required):
The appearance of any new lesion compatible with lymphoma with confirmation by other 
radiographic or histological modalities
The reappearance of any activity in a pre-existent lesion that meets size criteria for a new 
lesion on CT
Note: If there is uncertainty regarding whether there is definitive lymphoma progression, the 
subject should continue study drug(s) and remain under close observation (eg, evaluated at 
scheduled intervals) pending confirmation of progression status by the IRC. In particular, 
worsening of constitutional symptoms in the absence of objective evidence of worsening 
lymphoma will not be considered definitive disease progression; in such subjects, both 
lymphoma-related and non-lymphoma-related causes for the constitutional symptoms should 
be considered. Transient worsening of disease during temporary interruption of study drug(s) 
(eg, for intercurrent illness) may also not indicate definitive disease progression. In these 
instances, PET-CT/CT/MRI should be attempted in order to document whether definitive 
disease progression has occurred. If subsequent evaluations suggest that the subject has 
experienced persistent definitive disease progression, then the date of progression will be the 
time point at which progression was first objectively documented.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE:

There are no images or inadequate or missing images.


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Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or non-index 
lesions. Missing non-index lesions will not impact the ability to assess for response or disease 
progression.
No Disease
In a subject who does not have evidence of PD, the occurrence of all of the following conditions 
indicates a response status of ND:

Index disease absent at both baseline and on-study.

Non-index disease absent at both baseline and on-study.

Enlargement of the liver and spleen absent at both baseline and on-study.


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Appendix 7.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used.
Serum
Creatinine Units
Gender
Formula
(140-subject age [years])  subject weight [kilograms]  1
Males
eCcr 
[mL/min]
=
72  subject serum creatinine [mg/dl]
(140-subject age [years])  subject weight 
[kilograms]  0.85
mg/dL
Females
eCcr 
[mL/min]
=
72  subject serum creatinine [mg/dl]
(140-subject age [years])  subject weight [kilograms] 
Males
eCcr [mL/sec]
=
[(72 x serum creatinine (μmol /L) x 0.6786]
(0.85 x (140-subject age [years])  subject weight 
[kilograms] 
μmol/L
Females
eCcr [mL/sec]
=
[(72 x serum creatinine (μmol /L) x 0.6786]
eCcr=estimated creatinine clearance


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Appendix 8.
Pandemic Risk Assessment and Mitigation Plan
During an ongoing pandemic, potential risks associated with subjects being unable to attend 
study visits have been identified for this study. 
These potential risks and mitigation plans can be summarized as follows:
1) Subject screening and enrollment
a) Prior to screening and enrolling any new subjects, the site monitor will confirm
i)
The site is able to perform protocol-required procedures and data collection by 
delegated/trained staff.
ii) The site is able to adequately manage the subject’s safety in light of COVID-19; and 
they should only proceed with screening if there are no known issues that may impact 
the ability for the subject to attend study visits.
iii) The principal investigator (PI) deems study participation and onsite visits outweigh 
the risk of COVID-19 exposure. 
2) Study drug supplies to subjects and sites
a) Subjects may be unable to return to the site for a number of visits to get the study drug, or 
the site may be unable to accept any subject visits. Without study drugs, the subject 
would not be able to stay on the study drug as planned per protocol.
Mitigation plan: 
i)
Study drug supplies may be provided to the subject from the site without a clinic visit, 
once it is confirmed that the subject may safely continue on study drug as determined 
by the PI. 
ii) A virtual study visit, via phone or video conferencing, must be performed prior to 
remote study drug resupply. At the earliest opportunity, the site will schedule 
in-person subject visits and return to the protocol’s regular schedule of assessments.
iii) A qualified courier may be utilized to ship the study drug from sites to study subject’s 
home if permitted by local ethic committee (EC)/institutional review boards 
(IRB)/Regulatory Authority as applicable and with sponsor's approval.
iv) Obtain subject’s consent verbally (eg, by phone) to ship investigational medicinal 
product (IMP) from site to the subject’s home and to provide the subject’s address to 
the courier service responsible for delivering the IMP. The date and time that the 
consent was obtained must be documented in the subject’s source documents.
v) Ensure IMP documentation is complete for the shipment from site to subject.


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vi) Utilize same day or overnight shipping with tracking information. Provide a clear 
chain of custody. 
b) Shipments of study drug could be delayed because of transportation issues. Without study 
drug subject would not be able to stay on the study drug as planned per protocol.
Mitigation plan The study drug supply lookout window was increased to 90 days for all 
drug shipments to mitigate the risk of insufficient study drug supply or shipment delays 
from the depot to the study site. 
i) All sites with active subjects to confirm capacity to store the extra supply of study 
drug prior to shipment. 
ii) The sites' study drug inventory should be closely monitored. Site staff should notify 
the sponsor or delegate if they foresee shortage in study drug inventory or if there is 
any interruption in local shipping service. 
iii) The sponsor will continue to monitor inventory at the study drug depot and study sites. 
Manual shipments will be triggered as necessary.
3) Subject safety monitoring and follow-up:
a) Subjects may be unable or unwilling to come to the study site for their scheduled study 
visits as required per protocol.
Mitigation plan: For subjects who may be unable or unwilling to visit the study site for 
their scheduled study visits as required per protocol, the PI or qualified delegate will 
conduct a virtual study visit, via phone or video conferencing, to assess the subject within 
target visit window date whenever possible. During the virtual study visit, the following 
information at minimum will be reviewed: 
i) Confirm if subject has experienced any adverse events (AEs)/serious adverse events 
(SAEs)/special situations (including pregnancy) and follow-up on any unresolved 
AE/SAEs.
ii) Review current list of concomitant medications and document any new concomitant 
medications.
iii) Confirm if subject dosing diary questionnaires is completed.
iv) Confirm subject’s study drug supply is sufficient to last until the next planned visit 
date. If study drug resupply is needed it will be provided as described above in (2).
v) Remind subject to maintain current dosing and to keep all dispensed study drug kits 
for return at the next on-site visit.


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vi) If more than one visit will be missed, and other local labs or alternatives are not 
possible, please discuss ongoing subject participation with the medical monitor.
b) Subjects may be unable or unwilling to travel to the site for planned assessments 
(eg, safety blood draws); hence samples may not be sent for central lab analyses.
Mitigation plan: Local labs may be utilized as appropriate to monitor subject safety until 
the subject can return to the site for their regular follow-up per protocol. Any laboratory 
assessments conducted at a local lab due to the pandemic will be documented 
accordingly. Pregnancy testing may be performed using a home urine pregnancy test if 
local lab pregnancy testing is not feasible. A positive urine pregnancy test must be 
immediately confirmed with a serum pregnancy test. If serum pregnancy test is positive, 
please see instructions for reporting pregnancy in Section 7.6.2.1 of this document.
c) Subjects may be unable or unwilling to attend the study visit to sign an updated informed 
consent form version.
Mitigation plan: The site staff will follow their approved consent process and remain in 
compliance with local EC/IRB and national laws and regulations. Remote consent will be 
allowed if it has been approved by the local EC/IRB. The consent process will be 
documented and confirmed by normal consent procedure at the earliest opportunity.
d) The safety of trial participants is important and testing of COVID-19 infection will be 
based on local clinical guidelines for testing based on signs/symptoms and or suspected 
exposure to COVID-19.
Mitigation Plan: If subject becomes infected with COVID-19 while on study, please 
inform the Contract Research Organization and Gilead immediately. If test results are 
positive for COVID-19, consider discontinuing or interrupt idelalisib until patient has 
clinically recovered. Discuss with the medical monitor prior to resuming study drug or if 
subject becomes COVID-19 negative.
COVID-19 infections including asymptomatic infections or positive tests for COVID-19, 
should have this recorded as an AE. Any AEs attributed to COVID treatments should 
also be recorded in the electronic data capture, regardless of causality.
4) Protocol and monitoring compliance:
a) Protocol deviations may occur, in case scheduled visits cannot occur as planned per 
protocol.
Mitigation plan: If it is not possible to complete a required procedure, an unscheduled 
visit should be conducted as soon as possible when conditions allow. The situation should 
be recorded and explained as a protocol deviation. Any missed subject visits or deviation 
to the protocol due to the pandemic must be reported in the eCRF and described in the 


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clinical study report. Any virtual study visits that are conducted in lieu of clinic visits due 
to the pandemic will be documented as a protocol deviation related to the pandemic.
b) Study monitors may be unable to carry out source data review or source data verification 
(SDV), or study drug accountability or assess protocol and Good Clinical Practice 
compliance. This may lead to delays in SDV, an increase in protocol deviations, or under 
reporting of AEs.
Mitigation plan: The study monitor is to remain in close communication with the site to 
ensure data entry and query resolution. Remote SDV may be arranged if allowed. The 
study monitor is to reference the Clinical Management Plan for guidance on how to 
conduct a remote monitoring visit. The study staff is to save and document all relevant 
communication in the study files. The status of sites that cannot accept monitoring visits 
and/or subjects on site, must be tracked centrally and updated on a regular basis.
5) Missing data and data integrity:
a) There may be an increased amount of missing data due to subjects missing 
visits/assessments. This could have an impact on the analysis and the interpretation of 
clinical trial data.
Mitigation plan: Implications of a pandemic on methodological aspects for the study will 
be thoroughly assessed and documented, and relevant actions will be taken as appropriate 
(ie, modification of the statistical analysis plan) and in compliance with Regulatory 
Authorities’ guidance. Overall, the clinical study report will describe the impact of the 
pandemic on the interpretability of study data.
Risks will be assessed continuously, and temporary measures will be implemented to mitigate 
these risks as part of a mitigation plan, as described above. These measures will be 
communicated to the relevant stakeholders as appropriate and are intended to provide alternate 
methods that will ensure the evaluation and assessment of the safety of subjects who are enrolled 
in this study.
Since these potential risks are considered mitigated with the implementation of these measures, 
the expected benefit-risk assessment of idelalisib in study subjects remains unchanged.

SAP_001.pdf: 
  
S T A TI S TI C A L A N A L Y SI S P L A N
St u d y Title:
D ose O pti mizati o n St u d y of I delalisi b i n F ollic ular L y m p h o ma 
N a me of Test Dr u g: 
I delalisi b
St u d y N u m ber:
G S- U S- 3 1 3- 1 5 8 0
Pr ot oc ol Versi o n ( D ate): 
Versi o n 1. 0 ( Ori gi nal) 1 2 J u ne 2 0 1 5
Versi o n 2. 0 ( A me n d me nt 1) 2 8 Marc h 2 0 1 6
Versi o n 3. 0 ( A me n d me nt 2) 0 7 J u ne 2 0 1 6
Versi o n 4. 0 ( A me n d me nt 3) 0 8 Se pte m ber 2 0 1 6
Versi o n 5. 0 ( A me n d me nt 4) 2 5 Se pte m ber 2 0 1 7
Versi o n 6. 0 ( A me n d me nt 5) 1 3 Marc h 2 0 1 9
Versi o n 7. 0 ( A me n d me nt 6) 1 8 Marc h 2 0 2 1
A n al ysis T y pe:
Fi nal A nal ysis 
A n al ysis Pl a n Versi o n: 
Versi o n 1. 0
A n al ysis Pl a n D ate: 
2 1 N o ve m ber 2 0 2 2
A n al ysis Pl a n A ut h or:
C O N FI D E N TI A L A N D P R O P RI E T A R Y I N F O R M A TI O N
 
 
P P D


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2
2 1 N o ve m ber 2 0 2 2
T A B L E O F C O N T E N T S
S T A TI S TI C A L A N A L Y SI S P L A N............................................................................................................................... 1
T A B L E O F C O N T E N T S................................................................................................................................................ 2
LI S T O F I N- T E X T FI G U R E S........................................................................................................................................ 3
LI S T O F A B B R E VI A TI O N S......................................................................................................................................... 4
1.  
I N T R O D U C TI O N.................................................................................................................................................. 5
1. 1.  
St u d y O bjecti ves........................................................................................................................................ 5
1. 1. 1.  
Pri mar y O bjecti ves.................................................................................................................. 5
1. 1. 2.  
Sec o n dar y O bjecti ves.............................................................................................................. 5
1. 2.  
St u d y E n d p oi nts......................................................................................................................................... 5
1. 2. 1.  
Pri mar y E n d p oi nts................................................................................................................... 5
1. 2. 2.  
Sec o n dar y E n d p oi nts............................................................................................................... 6
1. 3.  
St u d y Desi g n ............................................................................................................................................. 6
1. 4.  
Sa m ple Size............................................................................................................................................... 8
2.  
P L A N N E D A N A L Y SI S......................................................................................................................................... 9
2. 1.   
Data M o nit ori n g C o m mittee ( D M C) A nal ysis.......................................................................................... 9
2. 2.  
Pri mar y A nal ysis....................................................................................................................................... 9
2. 3.  
Fi nal A nal ysis............................................................................................................................................ 9
3.   
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S............................................................................. 1 0
3. 1.   
A nal ysis Sets ........................................................................................................................................... 1 0
3. 1. 1.   
All E nr olle d A nal ysis Set...................................................................................................... 1 0
3. 1. 2.  
I nte nt-t o- Treat (I T T) A nal ysis Set......................................................................................... 1 0
3. 1. 3.  
Safet y A nal ysis Set................................................................................................................ 1 0
3. 1. 4.  
P har mac o ki netics ( P K) A nal ysis Set..................................................................................... 1 0
3. 2.  
S u bject Gr o u pi n g..................................................................................................................................... 1 1
3. 3.  
Strata a n d C o variates............................................................................................................................... 1 1
3. 4.  
E xa mi nati o n of S u bject S u b gr o u ps......................................................................................................... 1 1
3. 5.   
M ulti ple C o m paris o n............................................................................................................................... 1 1
3. 6.   
Missi n g Data a n d O utliers....................................................................................................................... 1 1
3. 6. 1.   
Missi n g Data.......................................................................................................................... 1 1
3. 6. 2.   
O utliers.................................................................................................................................. 1 1
3. 7.   
Data Ha n dli n g C o n ve nti o ns a n d Tra nsf or mati o ns.................................................................................. 1 2
3. 8.   
A nal ysis Visit Wi n d o ws.......................................................................................................................... 1 3
3. 8. 1.   
Defi niti o n of St u d y Da y ........................................................................................................ 1 3
3. 8. 2.   
A nal ysis Visit Wi n d o ws........................................................................................................ 1 3
3. 8. 3.  
Selecti o n of Data i n t he E ve nt of M ulti ple Rec or ds i n a n A nal ysis Visit 
Wi n d o w................................................................................................................................. 1 4
4.  
S U BJ E C T DI S P O SI TI O N ................................................................................................................................... 1 5
4. 1.  
S u bject E nr oll me nt a n d Dis p ositi o n........................................................................................................ 1 5
4. 2.  
E xte nt of St u d y Dr u g E x p os ure............................................................................................................... 1 6
4. 3.  
Pr ot oc ol De viati o ns................................................................................................................................. 1 6
4. 4.   
Assess me nt of C O VI D- 1 9 I m pact........................................................................................................... 1 6
4. 4. 1.  
Pr ot oc ol De viati o ns D ue t o C O VI D- 1 9 ................................................................................ 1 7
4. 4. 2.   
Misse d a n d Virt ual Visits D ue t o C O VI D- 1 9 ....................................................................... 1 7
5.  
B A S E LI N E C H A R A C T E RI S TI C S..................................................................................................................... 1 8
5. 1.   
De m o gra p hics.......................................................................................................................................... 1 8
5. 2.   
Ot her Baseli ne C haracteristics ................................................................................................................ 1 8


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5. 3.   
Me dical Hist or y....................................................................................................................................... 1 8
5. 4.  
Pri or A nti- Ca ncer T hera p y...................................................................................................................... 1 8
5. 5.  
Pri or a n d O n St u d y Ra di ot hera p y............................................................................................................ 1 8
5. 6.  
S ur geries a n d Pr oce d ures ........................................................................................................................ 1 9
6.  
E F FI C A C Y A N A L Y SI S...................................................................................................................................... 2 0
6. 1.   
Defi niti o n a n d A nal ysis of Efficac y E n d p oi nts....................................................................................... 2 0
6. 1. 1.  
Pri mar y a n d S u p p orti ve A nal ysis f or Pri mar y E n d p oi nt....................................................... 2 0
6. 1. 2.   
A nal ysis f or Sec o n dar y E n d p oi nts ........................................................................................ 2 0
7.   
A N A L Y SI S O F A D V E R S E E V E N T S A N D L A B O R A T O R Y E V A L U A TI O N S............................................. 2 1
7. 1.   
A d verse E ve nts a n d Deat hs..................................................................................................................... 2 1
7. 1. 1.   
A d verse E ve nt Dicti o nar y ..................................................................................................... 2 1
7. 1. 2.   
A d verse E ve nt Se verit y......................................................................................................... 2 1
7. 1. 3.  
Relati o ns hi p of A d verse E ve nts t o St u d y Dr u g..................................................................... 2 1
7. 1. 4.  
Seri o us A d verse E ve nts......................................................................................................... 2 1
7. 1. 5.  
Treat me nt- E mer ge nt A d verse E ve nts.................................................................................... 2 1
7. 1. 6.  
S u m maries of A d verse E ve nts a n d Deat hs............................................................................ 2 2
7. 2.  
La b orat or y E val uati o ns ........................................................................................................................... 2 4
7. 2. 1.   
Gra de d La b orat or y Val ues .................................................................................................... 2 5
7. 3.  
B o d y Wei g ht a n d Vital Si g ns.................................................................................................................. 2 5
7. 4.  
Pri or a n d C o nc o mita nt Me dicati o ns........................................................................................................ 2 5
7. 4. 1.  
Pri or Me dicati o ns .................................................................................................................. 2 6
7. 4. 2.  
C o nc o mita nt Me dicati o ns...................................................................................................... 2 6
7. 5.   
Ot her Safet y Meas ures ............................................................................................................................ 2 7
7. 6.  
C ha n ges fr o m Pr ot oc ol- S pecifie d Safet y A nal yses................................................................................. 2 7
8.  
P H A R M A C O KI N E TI C A N A L Y S E S.................................................................................................................. 2 8
9.  
R E F E R E N C E S..................................................................................................................................................... 2 9
1 0. 
S O F T W A R E......................................................................................................................................................... 3 1
1 1. 
S A P R E VI SI O N................................................................................................................................................... 3 2
A p pe n di x 1.  
C O VI D- 1 9 S M Q wit h Br oa d Sc o pe........................................................................................ 3 3
A p pe n di x 2.   
Deter mi ni n g Missi n g a n d Virt ual Visits D u e t o C O VI D- 1 9................................................... 3 5
LI S T O F I N- T E X T FI G U R E S
Fi g ure 1- 1.  
St u d y Sc he ma............................................................................................................................ 7


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LI S T O F A B B R E VI A TI O N S
A E
a d verse e ve nt
BI D
t wice dail y
c H L
Classical H o d g ki n l y m p h o ma
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C S R
Cli nical St u d y Re p ort
E C G
electr ocar di o gra m 
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
H L G T
hi g h-le vel gr o u p ter m
H L T
hi g h-le vel ter m
L L T
l o wer-le vel ter m
L O Q
li mit of q ua ntitati o n
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M T D
ma xi m u m t olerate d d ose
O R R
O verall Res p o nse Rate
P K
p har mac o ki netics
P T
preferre d ter m
Q 1
first q uartile
Q 3
t hir d q uartile
Q D
o nce dail y
R P 2 D
rec o m me n de d P hase 2 d ose
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S E
sta n dar d err or
S O C
s yste m or ga n class
S R T
safet y re vie w tea m
St D
sta n dar d de viati o n
T P S
T u m or pr o p orti o n sc ore
P D
Pr o gressi ve Disease
D O R
D urati o n of Res p o nse
P F S
Pr o gressi o n Free S ur vi val
O S
O verall S ur vi val
F L
f ollic ular l y m p h o ma


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1.  
I N T R O D U C TI O N
T his statistical a nal ysis pla n ( S A P) descri bes t he statistical a nal ysis met h o ds a n d defi nes ke y 
ele me nts i ncl u di n g varia ble defi niti o ns f or a nal ysis of data of St u d y G S- U S- 3 1 3- 1 5 8 0  i n s u p p ort 
of t he cli nical st u d y re p ort ( C S R) . T his S A P is base d o n t he st u d y pr ot oc ol a me n d me nt 6 date d 
1 8 M arc h 2 0 2 1 . A n y c ha n ges ma de after t he fi nalizati o n of t he S A P will be d oc u me nte d i n t he 
C S R.
T his st u d y was desi g ne d t o e val uate a safe a n d effecti ve d osi n g re gi me n of i delalisi b i n s u bjects 
wit h rela pse d or refract or y F ollic ular L y m p h o ma ( F L) w h o ha ve n o ot her t hera pe utic o pti o ns. It 
is a ra n d o mize d, o pe n-la bel, m ulti-ce nter gl o bal st u d y wit h t hree treat me nt ar ms i n t otal of 
2 6 6 s u bjects pla n ne d. T he st u d y was ter mi nate d earl y d ue t o sl o w e nr oll me nt, wit h ra pi dl y 
e v ol vi n g treat me nt o pti o ns f or F L as t he pri mar y reas o ns. 
A nal ysis met h o ds s pecifie d i n t his d oc u me nt ta ke prece de nce o ver t h ose descri be d i n pr ot oc ol 
s h o ul d t here be a n y differe nce.
1. 1.  
St u d y O bjecti ves
1. 1. 1.  
Pri m ar y O bjecti ves

Esta blis h a safe a n d effecti ve d osi n g re gi me n of i delalisi b i n s u bjects wit h rela pse d or 
refract or y F L w h o ha ve n o ot her t hera pe utic o pti o ns
1. 1. 2.  
Sec o n d ar y O bjecti ves

E val uate t he o verall res p o nse rate ( O R R)

E val uate t he pr o gressi o n-free s ur vi val ( P F S), d urati o n of res p o nse ( D O R), a n d o verall 
s ur vi val ( O S) 

E val uate t he o verall safet y pr ofile of i delalisi b

Deter mi ne t he P K of i delalisi b a n d its maj or meta b olite ( G S- 5 6 3 1 1 7)
1. 2.  
St u d y E n d p oi nts
1. 2. 1.  
Pri m ar y E n d p oi nts

O R R, defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve a partial res p o nse ( P R) or c o m plete 
res p o nse ( C R) b y i n de pe n de nt re vie w c o m mittee (I R C)

I nci de nce of Gra de ≥ 4 treat me nt-e mer ge nt a d verse e ve nts ( T E A Es)


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1. 2. 2.  
Sec o n d ar y E n d p oi nts

D O R, defi ne d as t he i nter val fr o m t he first d oc u me ntati o n of C R or P R t o t he earlier of t he 
first d oc u me ntati o n of disease pr o gressi o n b y i n de pe n de nt re vie w c o m mittee (I R C or deat h 
fr o m a n y ca use

O R R b y Wee k 2 4, defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve a P R or C R b y Wee k 2 4

O verall safet y pr ofile of i delalisi b, i ncl u di n g t he i nci de nce of A Es a n d cli nicall y si g nifica nt 
la b orat or y a b n or malities, se verit y, ti mi n g, a n d relati o ns hi p t o i delalisi b of a n y A Es; S A Es; or 
A Es lea di n g t o i nterr u pti o n, re d ucti o n, or disc o nti n uati o n of i delalisi b Ti me t o o nset of A Es 
of i nterest ( A EIs) defi ne d as t he i nter val fr o m t he start of i delalisi b treat me nt t o t he first 
d oc u me ntati o n of start of A EI

P F S, defi ne d as t he i nter val fr o m ra n d o mizati o n t o t he earlier of t he first d oc u me ntati o n of 
disease pr o gressi o n b y I R C or deat h fr o m a n y ca use

O S, defi ne d as t he i nter val fr o m ra n d o mizati o n t o deat h fr o m a n y ca use

I delalisi b tr o u g h ( pre d ose) a n d pea k ( 1. 5- h o ur sa m ples) plas ma c o nce ntrati o ns assesse d b y 
vali date d bi oa nal ytical met h o d
1. 3.  
St u d y Desi g n
T his is a ra n d o mize d, o pe n-la bel, m ulti-ce nter st u d y t hat will be c o n d ucte d gl o ball y.
S u bjects will be ra n d o mize d i n a 1: 1 rati o, u ntil t he e nr oll me nt tar get per ar m is met, t o t he 
f oll o wi n g treat me nt ar ms:

Ar m A: 1 5 0 m g t wice dail y i delalisi b a d mi nistere d c o nti n u o usl y

Ar m C: 1 5 0 m g t wice dail y i delalisi b a d mi nistere d i n 2 8- da y c ycles ( 2 1 da ys o n-treat me nt, 
7 da ys off-treat me nt) 
T he ori gi nal pr ot oc ol f or t his st u d y i ncl u de d a n Ar m B, w hic h was cl ose d t o e nr oll me nt as of 
Pr ot oc ol A me n d me nt 5.

Ar m B ( cl ose d t o e nr oll me nt as of Pr ot oc ol A me n d me nt 5 ): 1 0 0 m g t wice dail y i delalisi b 
a d mi nistere d c o nti n u o usl y
 
Cli nic visits will occ ur at Scree ni n g, Da y 1, e ver y 2 wee ks t hr o u g h Wee k 1 2, e ver y 4 wee ks 
t hr o u g h Wee k 2 4, at Wee ks 3 2, 3 6, 4 0, 4 8, a n d e ver y 1 2 wee ks t hereafter t hr o u g h e n d of st u d y 
( E O S). S u bjects will be assesse d f or safet y at eac h visit. A d diti o nal visits will be re q uire d 
bet wee n cli nic visits f or la b orat or y testi n g o nl y.


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S u bjects will be assesse d f or F L disease stat us b y c o nti n u o us utilizati o n of a si n gle m o dalit y 
i ncl u di n g p ositr o n e missi o n t o m o gra p h y –c o m p ute d t o m o gra p h y ( P E T- C T), C T, or M RI. If 
per ma ne nt disc o nti n uati o n of i delalisi b occ urs pri or t o I R C d oc u me nte d pr o gressi o n of F L, 
s u bjects s hall re mai n o n st u d y u ntil pr o gressi o n of F L or wit h dra wal fr o m t he st u d y f or reas o ns 
s pecifie d i n Secti o n 3. 5. 2 of t he Pr ot oc ol A me n d me nt 6.
Fi g ure 1- 1.  
St u d y Sc he m a 
S u bjects e nr olle d pri or t o i m ple me ntati o n of Pr ot oc ol A me n d me nt 5 f oll o we d t he pre vi o us st u d y 
desi g n as s h o w n here. 
 
 
   
 
 
 
 
 
  
  
 
 
  
 
 
  
 
   
 
 
 
  
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
  
 
  
  
    
  
  
  
 
  
 
 
  
 
 
 


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I n acc or da nce wit h Pr ot oc ol A me n d me nt 6, s u bjects e nr olle d pri or t o i m ple me ntati o n of Pr ot oc ol 
A me n d me nt 5 a n d still bli n de d will be u n bli n de d at t he ti me of Pr ot oc ol A me n d me nt 6 
i m ple me ntati o n; t hese s u bjects will c o nti n ue at t he ra n d o mize d d ose le vel if t he y are still o n 
treat me nt. T hese s u bjects were pre vi o usl y ra n d o mize d i n a bli n de d ma n ner t o eit her 1 5 0 m g 
t wice dail y or 1 0 0 m g t wice dail y i delalisi b. Base d o n t he 8- wee k bli n de d I R C res p o nse 
assess me nt, s u bjects wit h S D or P D were u n bli n de d i n b ot h ar ms. S u bjects wit h a P R or C R 
mai ntai ne d t he bli n d a n d c o nti n ue d at t he ra n d o mize d d ose le vel. S u bjects ra n d o mize d t o 1 0 0 m g 
t wice dail y wit h S D or P D ha d t he o pti o n t o be d ose escalate d t o 1 5 0 m g t wice dail y. S u bjects 
ra n d o mize d t o 1 5 0 m g t wice dail y wit h S D will c o nti n ue o pe n-la bel i delalisi b at 1 5 0 m g t wice 
dail y. S u bjects ra n d o mize d t o 1 5 0 m g t wice dail y wit h P D will be disc o nti n ue d fr o m st u d y 
treat me nt. T hese sa me u n bli n di n g a n d d ose m o dificati o n pri nci ples were a p plie d at a n y ti me 
t hr o u g h o ut st u d y partici pati o n w he n disease pr o gressi o n was s us pecte d a n d c o nfir me d b y I R C 
assess me nt.
S u bjects s h o ul d f oll o w st u d y pr oce d ures as o utli ne d i n Secti o n 6 a n d A p pe n di x 2 St u d y 
Pr oce d ures Ta ble of t he Pr ot oc ol A me n d me nt 6. I delalisi b will be a d mi nistere d u ntil meeti n g 
criteria f or disc o nti n uati o n of st u d y dr u g as descri be d i n Secti o n 3. 5. 1 of t he pr ot oc ol 
A me n d me nt 6.
1. 4.  
S a m ple Size 
T he pla n ne d sa m ple size is a p pr o xi matel y 2 6 6 s u bjects: a p pr o xi matel y 1 2 0 s u bjects i n Ar m A, 
a p pr o xi matel y 2 6 s u bjects i n Ar m B, a n d a p pr o xi matel y 1 2 0 s u bjects i n Ar m C. As of Pr ot oc ol 
A me n d me nt 5, Ar m B e nr oll me nt was cl ose d after e nr oll me nt of a p pr o xi matel y 2 6 s u bjects i nt o 
Ar m B a n d a p pr o xi matel y 2 6 s u bjects i nt o Ar m A.
As of Pr ot oc ol A me n d me nt 5, s u bjects will be ra n d o mize d t o 2 ar ms ( Ar ms A a n d C) wit h a 
1: 1 rati o u ntil t he e nr oll me nt tar get of 1 2 0 s u bjects i n eac h ar m is met. T he O R R was 
a p pr o xi matel y 5 6 % f or s u bjects wit h F L i n St u d y 1 0 1- 0 9. If t he u n derl yi n g tr ue O R R is 5 6 % f or 
s u bjects i n t his st u d y, t he c ha nce t o o bser ve 6 0 or m ore res p o n ders o ut of 1 2 0 s u bjects ( o bser ve d 
O R R ≥ 5 0 %) is 9 2 %. Wit h 1 2 0 s u bjects i n eac h ar m, t he half- wi dt h of a t w o-si de d 9 5 % CI of 
O R R is ≤ 1 0 % f or a n o bser ve d O R R i n t he ra n ge of 4 0 %- 6 0 %, a n d t he half- wi dt h of a t w o-si de d 
9 5 % CI of ≥ Gra de 4 T E A Es i nci de nce rate is ≤ 1 0 % f or a n o bser ve d A E rate i n t he ra n ge of 
2 0 %- 4 0 %.
T he sa m ple size was ori gi nall y pla n ne d t o i ncl u de  2 4 0 s u bjects ra n d o mize d t o Ar m A a n d Ar m B 
wit h a 1: 1 rati o. T he pre vi o us sa m ple size calc ulati o n is base d o n t he rate of Gra de ≥ 3 
diarr hea/c olitis at a p pr o xi matel y 1 5 % i n t he pri or i delalisi b st u dies. A sa m ple size of 1 2 0 
s u bjects per ar m w o ul d pr o vi de 7 3 % c ha nce t o detect a re d ucti o n of 1 0 % (ie, 1 5 % i nci de nce i n 
t he 1 5 0 m g t wice dail y ar m vers us 5 % i nci de nce i n t he 1 0 0 m g t wice dail y ar m) usi n g a 2-si de d 
C hi-s q uare test wit h al p ha le vel of 0. 0 5.




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3.   
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S
A nal ysis res ults will be prese nte d usi n g descri pti ve statistics. F or cate g orical varia bles, t he 
n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y will be prese nte d; f or c o nti n u o us varia bles, 
t he n u m ber of s u bjects ( n), mea n, sta n dar d de viati o n ( St D) or sta n dar d err or ( S E), me dia n, first 
q uartile ( Q 1), t hir d q uartile ( Q 3), mi ni m u m, a n d ma xi m u m will be prese nte d.
B y-s u bject listi n gs will be prese nte d f or all s u bjects i n t he All E nr olle d A nal ysis Set a n d s orte d 
b y d ose c o h ort, s u bject I D n u m ber, visit date, a n d ti me (if a p plica ble). Data c ollecte d o n l o g 
f or ms, s uc h as A Es, will be prese nte d i n c hr o n ol o gical or der wit hi n t he s u bject. T he c o h ort t o 
w hic h s u bjects were i nitiall y assi g ne d will be use d i n t he listi n gs. A ge, se x at birt h, race, a n d 
et h nicit y i nf or mati o n f or eac h s u bject will be prese nte d i n t he listi n gs, as s pace per mits.
3. 1.   
A n al ysis Sets
A nal ysis sets defi ne w hic h s u bjects are i ncl u de d i n a n a nal ysis. A nal ysis sets a n d t heir 
defi niti o ns are pr o vi de d i n t his secti o n. T he a nal ysis set will be i de ntifie d a n d i ncl u de d as a 
s u btitle of eac h ta ble, fi g ure, a n d listi n g.
3. 1. 1.   
All E nr olle d A n al ysis Set
T he All E nr olle d A nal ysis Set i ncl u des all s u bjects w h o recei ve d a st u d y s u bject i de ntificati o n 
n u m ber i n t he st u d y after scree ni n g. 
T he All E nr olle d A nal ysis Set will be use d f or s u bject e nr oll me nt s u m mar y a n d f or data listi n gs, 
u nless ot her wise s pecifie d.
3. 1. 2.  
I nte nt-t o- Tre at (I T T) A n al ysis Set
T he I T T A nal ysis Set i ncl u des all s u bjects w h o are ra n d o mize d re gar dless of w het her s u bjects 
recei ve a n y st u d y dr u g. Treat me nt assi g n me nt will be desi g nate d acc or di n g t o a s u bject’s i nitial 
ra n d o mizati o n. T his a nal ysis set will be use d i n t he a nal ysis of efficac y. 
3. 1. 3.  
S afet y A n al ysis Set
T he Safet y A nal ysis Set i ncl u des all s u bjects w h o recei ve d at least 1 d ose of st u d y treat me nt, 
wit h treat me nt assi g n me nts desi g nate d acc or di n g t o t he act ual treat me nt recei ve d. T his is t he 
pri mar y a nal ysis set f or t he safet y a nal yses as well as st u d y treat me nt a d mi nistrati o n. 
3. 1. 4.  
P h ar m ac o ki netics ( P K) A n al ysis Set
T he P K A nal ysis Set i ncl u des s u bjects i n t he Safet y A nal ysis Set w h o ha ve recei ve d t he st u d y 
dr u g a n d ha ve at least 1 sa m ple wit h detecta ble dr u g c o nce ntrati o n.


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3. 2.  
S u bject Gr o u pi n g
F or a nal yses base d o n t he I T T A nal ysis Set, s u bjects will be gr o u pe d acc or di n g t o t he treat me nt 
t o w hic h t he y were ra n d o mize d. F or a nal yses base d o n t he Safet y A nal ysis Set, s u bjects will be 
gr o u pe d acc or di n g t o t he act ual treat me nt recei ve d. T he act ual treat me nt recei ve d will differ 
fr o m t he ra n d o mize d treat me nt o nl y w he n t heir act ual treat me nt differs fr o m ra n d o mize d 
treat me nt f or t he e ntire treat me nt d urati o n.
F or t he P K A nal ysis Set, s u bjects will be gr o u pe d acc or di n g t o t he act ual treat me nt t he y 
recei ve d.
3. 3.  
Str at a a n d C o v ari ates
T his st u d y d oes n ot use a stratifie d ra n d o mizati o n sc he d ule w he n e nr olli n g s u bjects. 
N o c o variates will be i ncl u de d i n efficac y a n d safet y a nal yses.
3. 4.  
E x a mi n ati o n of S u bject S u b gr o u ps
T here are n o pres pecifie d s u bject s u b gr o u pi n gs f or efficac y a n d safet y a nal yses.
3. 5.   
M ulti ple C o m p aris o n
A dj ust me nts f or m ulti plicit y will n ot be ma de, beca use n o f or mal statistical testi n g will be 
perf or me d i n t his st u d y.
3. 6.   
Missi n g D at a a n d O utliers 
3. 6. 1.   
Missi n g D at a
I n ge neral, missi n g data will n ot be i m p ute d u nless met h o ds f or ha n dli n g missi n g data are 
s pecifie d. 
F or missi n g last d osi n g date of st u d y dr u g, i m p utati o n r ules are descri be d i n Secti o n 4. 2 . T he 
ha n dli n g of missi n g or i nc o m plete dates f or A E o nset is descri be d i n Secti o n 7. 1. 5. 2 , a n d f or 
pri or a n d c o nc o mita nt me dicati o ns i n Secti o n 7. 4 .
3. 6. 2.   
O utliers
O utliers will be i de ntifie d d uri n g t he data ma na ge me nt a n d data a nal ysis pr ocess, b ut n o 
se nsiti vit y a nal yses will be c o n d ucte d. All data will be i ncl u de d i n t he data a nal ysis.


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3. 7.   
D at a H a n dli n g C o n ve nti o ns a n d Tr a nsf or m ati o ns
T he f oll o wi n g c o n ve nti o ns will be use d f or t he i m p utati o n of date of birt h w he n it is partiall y 
missi n g or n ot c ollecte d:

If o nl y m o nt h a n d year of birt h is c ollecte d, t he n “ 1 5” will be i m p ute d as t he da y of birt h

If o nl y year of birt h is c ollecte d, t he n “ 0 1 J ul y” will be i m p ute d as t he da y a n d m o nt h of birt h

If year of birt h is missi n g, t he n date of birt h will n ot be i m p ute d
I n ge neral, a ge (i n years) c ollecte d at scree ni n g visit will be use d f or a nal yses a n d prese nte d i n 
listi n gs. If a ge at scree ni n g is n ot a vaila ble f or a s u bject, t he n a ge deri ve d base d o n date of birt h 
a n d t he scree ni n g visit date will be use d i nstea d. If a n e nr olle d s u bject was n ot d ose d wit h a n y 
st u d y dr u g, t he ra n d o mizati o n date will be use d i nstea d of t he screei n g visit date. F or scree n 
fail ures, t he date t he first i nf or me d c o nse nt was si g ne d will be use d f or t he a ge deri vati o n. A ge 
re q uire d f or l o n git u di nal a n d te m p oral calc ulati o ns a n d a nal yses (e g, esti mates of creati ni ne 
cleara nce, a ge at date of A E) will be base d o n a ge deri ve d fr o m date of birt h a n d t he date of t he 
meas ure me nt or e ve nt, u nless ot her wise s pecifie d.
N o n- P K data t hat are c o nti n u o us i n nat ure b ut are less t ha n t he l o wer li mit of q ua ntitati o n ( L O Q) 
or a b o ve t he u p per L O Q will be i m p ute d as f oll o ws:

A val ue t hat is 1 u nit less t ha n t he l o wer L O Q will be use d t o calc ulate descri pti ve statistics if 
t he dat u m is re p orte d i n t he f or m of “ x” ( w here x is c o nsi dere d t he L O Q). F or e xa m ple, if 
t he val ues are re p orte d as < 5 0 a n d < 5. 0, val ues of 4 9 a n d 4. 9, res pecti vel y, will be use d t o 
calc ulate s u m mar y statistics. A n e xce pti o n t o t his r ule is a n y val ue re p orte d as < 1 or < 0. 1, 
etc. F or val ues re p orte d as < 1 or < 0. 1, a val ue of 0. 9 or 0. 0 9, res pecti vel y, will be use d t o 
calc ulate s u m mar y statistics.

A val ue t hat is 1 u nit a b o ve t he u p per L O Q will be use d t o calc ulate descri pti ve statistics if 
t he dat u m is re p orte d i n t he f or m of “ > x” ( w here x is c o nsi dere d t he L O Q). Val ues wit h 
deci mal p oi nts will f oll o w t he sa me l o gic as a b o ve.

T he l o wer or u p per L O Q will be use d t o calc ulate descri pti ve statistics if t he dat u m is 
re p orte d i n t he f or m of “ ≤ x” or “ ≥ x” ( w here x is c o nsi dere d t he L O Q).
Nat ural l o garit h m tra nsf or mati o n will be use d f or a nal yzi n g c o nce ntrati o ns i n i nte nsi ve P K 
sa m ples. C o nce ntrati o n val ues t hat are B L Q will be prese nte d as “ B L Q” i n t he c o nce ntrati o n 
data listi n g. Val ues t hat are B L Q will be treate d as 0 f or s u m mar y p ur p oses.


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T he f oll o wi n g c o n ve nti o ns will be use d f or t he prese ntati o n of s u m mar y a n d or der statistics f or 
i nte nsi ve P K c o nce ntrati o ns: 

If at least 1 s u bject has a c o nce ntrati o n val ue of B L Q f or t he ti me p oi nt, t he mi ni m u m val ue 
will be dis pla ye d as “ B L Q.”

If m ore t ha n 2 5 % of t he s u bjects ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m a n d Q 1 val ues will be dis pla ye d as “ B L Q.”

If m ore t ha n 5 0 % of t he s u bjects ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m, Q 1, a n d me dia n val ues will be dis pla ye d as “ B L Q.”

If m ore t ha n 7 5 % of t he s u bjects ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m, Q 1, me dia n, a n d Q 3 val ues will be dis pla ye d as “ B L Q.”

If all s u bjects ha ve c o nce ntrati o n data val ues of B L Q f or a gi ve n ti me p oi nt, all or der 
statistics ( mi ni m u m, Q 1, me dia n, Q 3, a n d ma xi m u m) will be dis pla ye d as “ B L Q.”
P K c o nce ntrati o ns t hat are B L Q will be e xcl u de d bef ore l o g tra nsf or mati o n or statistical m o del 
fitti n g.
3. 8.   
A n al ysis Visit Wi n d o ws
3. 8. 1.   
Defi niti o n of St u d y D a y
St u d y da y will be calc ulate d fr o m t he first d osi n g date of st u d y dr u g a n d deri ve d as f oll o ws:

F or p ost d ose st u d y da ys: Assess me nt Date – First D osi n g Date + 1

F or da ys pri or t o t he first d ose: Assess me nt Date – First D osi n g Date 
T heref ore, st u d y da y 1 is t he da y of first d ose of st u d y dr u g a d mi nistrati o n. 
3. 8. 2.   
A n al ysis Visit Wi n d o ws
T he n o mi nal visit as rec or de d o n t he C R F will be use d w he n data are s u m marize d b y visit. A n y 
data relati n g t o u nsc he d ule d visits will n ot be assi g ne d t o a partic ular visit or ti me p oi nt. 
H o we ver, t he f oll o wi n g e xce pti o ns will be ma de:

A n u nsc he d ule d visit pri or t o t he first d osi n g of st u d y dr u g ma y be i ncl u de d i n t he calc ulati o n 
of t he baseli ne val ue, if a p plica ble.

U nsc he d ule d visits after t he first d osi n g of st u d y dr u g will be i ncl u de d i n deter mi ni n g t he 
ma xi m u m p ost baseli ne t o xicit y gra de.


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
F or s u bjects w h o disc o nti n ue fr o m t he st u d y treat me nt, t he E O T visit data will be assi g ne d t o 
w hat w o ul d ha ve bee n t he ne xt sc he d ule d visit w here t he res pecti ve data were sc he d ule d t o 
be c ollecte d.
3. 8. 3.  
Selecti o n of D at a i n t he E ve nt of M ulti ple Rec or ds i n a n A n al ysis Visit 
Wi n d o w
De pe n di n g o n t he statistical a nal ysis met h o d, si n gle val ues ma y be re q uire d f or eac h a nal ysis 
wi n d o w. F or e xa m ple, c ha n ge fr o m baseli ne b y visit us uall y re q uires a si n gle val ue, w hereas a 
ti me-t o-e ve nt a nal ysis w o ul d n ot re q uire 1 val ue per a nal ysis wi n d o w. 
If m ulti ple vali d, n o n missi n g meas ure me nts e xist i n a n a nal ysis wi n d o w, rec or ds will be c h ose n 
base d o n t he f oll o wi n g r ules if a si n gle val ue is nee de d:

F or baseli ne, t he last n o n missi n g val ue o n or pri or t o t he first d osi n g date of st u d y dr u g will 
be selecte d, u nless s pecifie d differe ntl y. If t here are m ulti ple rec or ds wit h t he sa me ti me or 
n o ti me rec or de d o n t he sa me da y, t he baseli ne val ue will be t he a vera ge of t he 
meas ure me nts f or c o nti n u o us data, or t he meas ure me nt wit h t he l o west se verit y (e g, n or mal 
will be selecte d o ver a b n or mal f or safet y electr ocar di o gra m [ E C G] fi n di n gs) f or cate g orical 
data.

F or p ost baseli ne val ues:

T he rec or d cl osest t o t he n o mi nal da y f or t hat visit will be selecte d.

If t here are 2 rec or ds t hat are e q ui dista nt fr o m t he n o mi nal da y, t he later rec or d will be 
selecte d.

If t here is m ore t ha n 1 rec or d o n t he selecte d da y, t he a vera ge will be ta ke n f or 
c o nti n u o us data a n d t he w orse se verit y will be ta ke n f or cate g orical data, u nless 
ot her wise s pecifie d.


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4.  
S U B J E C T DI S P O SI TI O N
4. 1.  
S u bject E nr oll me nt a n d Dis p ositi o n
A s u m mar y of s u bject e nr oll me nt will be pr o vi de d b y treat me nt ar ms f or eac h c o u ntr y a n d 
o verall base d o n all e nr olle d s u bjects. T he s u m mar y will prese nt t he n u m ber a n d perce nta ge of 
s u bjects e nr olle d. F or eac h c ol u m n, t he de n o mi nat or f or t he perce nta ge calc ulati o n will be t he 
t otal n u m ber of s u bjects a nal yze d f or t hat c ol u m n.
A s u m mar y of s u bject dis p ositi o n will be pr o vi de d b y treat me nt ar ms base d o n All Scree ne d 
S u bjects. T his s u m mar y will prese nt t he n u m ber a n d perce nta ge of s u bjects i n t he f oll o wi n g 
cate g ories:

Scree ne d S u bjects

All E nr olle d S u bjects

I T T A nal ysis Set

Safet y A nal ysis Set

P K A nal ysis Set

St u d y Dr u g C o m pleti o n Stat us 

Disc o nti n ue d St u d y Dr u g

Reas o ns f or Disc o nti n uati o n of St u d y Dr u g

St u d y C o m pleti o n Stat us

Disc o nti n ue d St u d y

Reas o ns f or Disc o nti n uati o n of St u d y 
F or t he stat us of st u d y c o m pleti o n a n d reas o ns f or st u d y dr u g a n d st u d y disc o nti n uati o n, t he 
n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y will be pr o vi de d. T he de n o mi nat or f or t he 
perce nta ge calc ulati o n will be t he t otal n u m ber of s u bjects i n t he All E nr olle d A nal ysis Set 
c orres p o n di n g t o t hat c ol u m n.
T he f oll o wi n g b y-s u bject listi n gs will be pr o vi de d b y treat me nt ar ms a n d s u bject i de ntificati o n 
(I D) n u m ber i n asce n di n g or der t o s u p p ort t he a b o ve s u m mar y ta ble:

Reas o ns f or st u d y dr u g or st u d y disc o nti n uati o n.


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4. 2.  
E xte nt of St u d y Dr u g E x p os ure
E xte nt of e x p os ure t o st u d y treat me nt will be s u m marize d b y treat me nt ar ms usi n g descri pti ve 
statistics f or t otal d urati o n of e x p os ure t o st u d y dr u g (i delalisi b) i ncl u di n g t he n u m ber (ie, 
c u m ulati ve c o u nts) a n d perce nta ge of s u bjects e x p ose d t hr o u g h t he certai n ti me peri o ds. 
S u m maries will be pr o vi de d b y treat me nt ar ms f or t he Safet y A nal ysis Set.
T otal d urati o n of e x p os ure t o st u d y dr u g (i delalisi b) will be defi ne d as last d osi n g date of st u d y 
dr u g mi n us first d osi n g date pl us 1, re gar dless of a n y te m p orar y i nterr u pti o ns i n st u d y dr u g 
a d mi nistrati o n, a n d will be e x presse d i n m o nt hs usi n g u p t o 1 deci mal place (e g, 4. 5 m o nt hs). If 
t he last st u d y dr u g d osi n g date is missi n g, t he latest date a m o n g t he st u d y dr u g e n d date, cli nical 
visit date, la b orat or y sa m ple c ollecti o n date, a n d vital si g ns assess me nt date t hat occ urre d d uri n g 
t he o n-treat me nt peri o d will be use d f or s u bjects i ncl u de d i n t he fi nal a nal yses.
A b y-s u bject listi n g of st u d y dr u g a d mi nistrati o n will be pr o vi de d b y treat me nt ar ms a n d s u bject 
I D n u m ber (i n asce n di n g or der), i ncl u di n g d osi n g date, t otal d urati o n of e x p os ure t o st u d y dr u g 
a n d reas o n f or d ose i nterr u pti o n.
4. 3.  
Pr ot oc ol De vi ati o ns
S u bjects w h o di d n ot meet t he eli gi bilit y criteria f or st u d y e ntr y b ut e nr olle d i n t he st u d y will be 
i de ntifie d re gar dless of w het her t he y were e xe m pte d b y t he s p o ns or or n ot. A b y-s u bject listi n g 
will be pr o vi de d f or t h ose s u bjects w h o di d n ot meet at least 1 eli gi bilit y (i ncl usi o n or e xcl usi o n) 
criteri o n. T he listi n g will prese nt t he eli gi bilit y criteri o n ( or criteria if m ore t ha n 1 de viati o n) t hat 
s u bjects di d n ot meet a n d relate d c o m me nts, if c ollecte d.
Pr ot oc ol de viati o ns occ urri n g after s u bjects e ntere d t he st u d y are d oc u me nte d d uri n g r o uti ne 
m o nit ori n g. A b y-s u bject listi n g will be pr o vi de d f or t h ose s u bjects wit h i m p orta nt pr ot oc ol 
de viati o ns.
4. 4.   
Assess me nt of C O VI D- 1 9 I m p act
T his st u d y was o n g oi n g d uri n g t he n o vel c or o na vir us ( 2 0 1 9 n C O V [ C O VI D- 1 9]) pa n de mic, a n d 
t he C O VI D- 1 9 pa n de mic has ca use d a disr u pti o n i n t he re g ular visit sc he d ules f or t his st u d y. 
S o me s u bjects were u na ble t o atte n d o nsite visits d ue t o s helter-i n- place g ui deli nes, site cl os ures, 
or ot her reas o ns. T his secti o n pr o vi des g ui da nce o n h o w t o ha n dle s pecial sit uati o ns d ue t o 
C O VI D- 1 9 i n t he a nal ysis.
A d verse e ve nts ( A Es) d ue t o C O VI D- 1 9 will be i ncl u de d i n A E a nal yses if a p plica ble. A b y-
s u bject listi n g of A d verse E ve nts d ue t o C O VI D- 1 9 ma y be pr o vi de d. T he C O VI D- 1 9 
Sta n dar dize d Me d D R A Q ueries ( S M Q) wit h Br oa d Sc o pe i n A p pe n di x 1  will be i m ple me nte d.


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4. 4. 1.  
Pr ot oc ol De vi ati o ns D ue t o C O VI D- 1 9
A b y-s u bject listi n g will be pr o vi de d f or s u bjects wit h i m p orta nt pr ot oc ol de viati o n relate d t o 
C O VI D- 1 9. A se parate listi n g will be pr o vi de d f or s u bjects wit h n o n-i m p orta nt pr ot oc ol 
de viati o n relate d t o C O VI D- 1 9.
4. 4. 2.   
Misse d a n d Virt u al Visits D ue t o C O VI D- 1 9
A b y-s u bject listi n g of s u bjects wit h misse d or virt ual visits d ue t o C O VI D- 1 9 will be pr o vi de d 
b y s u bject I D n u m ber i n asce n di n g or der.
I nf or mati o n re gar di n g virt ual or misse d visits d ue t o C O VI D- 1 9 was c ollecte d as free te xt i n t he 
C R F c o m me nt fiel ds. T he deter mi nati o n of missi n g or virt ual visits d ue t o C O VI D- 1 9 was d o ne 
usi n g Nat ural La n g ua ge Pr ocessi n g ( N L P) t o searc h t he C R F c o m me nt fiel ds. A detaile d 
e x pla nati o n of t he al g orit h m is gi ve n i n A p pe n di x 2 .


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5.  
B A S E LI N E C H A R A C T E RI S TI C S
5. 1.   
De m o gr a p hics 
S u bject de m o gra p hic varia bles (ie, a ge, se x, race, a n d et h nicit y) will be s u m marize d f or Safet y 
A nal ysis Set usi n g descri pti ve statistics f or a ge, a n d usi n g n u m ber a n d perce nta ge of s u bjects f or 
se x, race, a n d et h nicit y.
A b y-s u bject de m o gra p hic listi n g, i ncl u di n g t he i nf or me d c o nse nt date, will be pr o vi de d b y 
s u bject I D n u m ber i n asce n di n g or der f or All E nr olle d A nal ysis Set.
5. 2.   
Ot her B aseli ne C h ar acteristics
Ot her baseli ne c haracteristics i ncl u de b o d y wei g ht (i n k g), hei g ht (i n c m), b o d y mass i n de x 
( B MI; i n k g/ m 2), a n d E C O G stat us. B MI will be calc ulate d b y t he f or m ula:
B MI ( k g/ m 2) = wei g ht / ( hei g ht2) (r o u n d t o 1 deci mal p oi nt).
Ot her baseli ne c haracteristics will be s u m marize d b y treat me nt ar ms a n d o verall usi n g 
descri pti ve statistics f or c o nti n u o us varia bles a n d usi n g n u m ber a n d perce nta ge of s u bjects f or 
cate g orical varia bles. T he s u m mar y of de m o gra p hic a n d baseli ne c haracteristics data will be 
pr o vi de d f or t he Safet y A nal ysis Set.
A b y-s u bject listi n g of ot her baseli ne c haracteristics will be pr o vi de d b y s u bject I D n u m ber i n 
asce n di n g or der f or All E nr olle d A nal ysis Set.
5. 3.   
Me dic al Hist or y
Me dical hist or y will be c ollecte d at scree ni n g f or disease-s pecific c o n diti o ns i ncl u di n g s oli d 
t u m or mali g na nc y stat us, a n d ge neral c o n diti o ns (i.e, c o n diti o ns n ot s pecific t o t he disease bei n g 
st u die d).
A b y-s u bject listi n g of me dical hist or y will be pr o vi de d b y treat me nt ar ms a n d s u bject I D 
n u m ber i n asce n di n g or der f or All E nr olle d A nal ysis Set. 
5. 4.  
Pri or A nti- C a ncer T her a p y 
T he details of pri or a nti-ca ncer t hera p y will be liste d b y treat me nt ar ms a n d s u bject I D n u m ber i n 
asce n di n g or der f or All E nr olle d A nal ysis Set. 
5. 5.  
Pri or a n d O n St u d y R a di ot her a p y
T he details of all ra di ot hera p y will als o be liste d b y treat me nt ar ms a n d s u bject I D n u m ber i n 
asce n di n g or der f or All E nr olle d A nal ysis Set.


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
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Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1 9
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5. 6.  
S ur geries a n d Pr oce d ures
A b y-s u bject listi n g of pri or a n d o n-st u d y s ur geries a n d pr oce d ures will be pr o vi de d b y treat me nt 
ar ms a n d s u bject I D n u m ber i n asce n di n g or der f or All E nr olle d A nal ysis Set.


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 0
2 1 N o ve m ber 2 0 2 2
6.  
E F FI C A C Y A N A L Y SI S
Efficac y para meters will be s u m marize d a n d liste d b y treat me nt ar ms base d o n t he I T T A nal ysis 
Set. T he a nal yses will be c o n d ucte d usi n g t he I R C assess me nts base d o n sta n dar d res p o nse 
criteria a p pl yi n g C hes o n 2 0 0 7.
6. 1.   
Defi niti o n a n d A n al ysis of Effic ac y E n d p oi nts
6. 1. 1.  
Pri m ar y a n d S u p p orti ve A n al ysis f or Pri m ar y E n d p oi nt
F or t he pri mar y efficac y a nal ysis, O R R will be e val uate d b y treat me nt ar ms usi n g t he I R C 
assess me nts i n t he I T T A nal ysis Set. S u bjects w h o d o n ot ha ve s ufficie nt baseli ne or o n-st u d y 
t u m or assess me nt t o c haracterize res p o nse stat us will be c o u nte d as n o n-res p o n ders. Esti mates 
a n d t he c orres p o n di n g 9 5 % CIs base d o n t he Cl o p per- Pears o n e xact met h o d will be pr o vi de d.
A b y-s u bject listi n g of o verall res p o nse will be pr o vi de d b y treat me nt ar ms a n d s u bject I D 
n u m ber i n asce n di n g or der.
6. 1. 2.   
A n al ysis f or Sec o n d ar y E n d p oi nts
T he O R R b y Wee k 2 4 a n d c orres p o n di n g 9 5 % CIs will be e val uate d b y treat me nt ar m usi n g t he 
I R C assess me nts i n t he I T T A nal ysis Set.
T he ti me-t o-e ve nt efficac y e n d p oi nts i ncl u di n g P F S, D O R, a n d O S will be a nal yze d usi n g t he 
Ka pla n- Meier met h o d i n t he I T T Set, a n d t he a nal ysis of D O R will i ncl u de s u bjects w h o ac hie ve 
a P R or C R. A nal yses ma y als o be perf or me d f or s u b gr o u ps defi ne d b y p ote ntial pre dict ors of 
res p o nse. T he Ka pla n- Meier pl ot will be pr o vi de d f or P F S a n d O S.
P F S a n d D O R Ce ns ori n g r ules:
1)
S u bjects w h o disc o nti n ue d st u d y pri or t o P D or deat h will be ce ns ore d o n t he last t u m or 
assess me nt date.
2)
S u bjects w h o misse d > = 2 c o nsec uti ve t u m or assess me nts, a n d di d n ot ha ve a P D pri or t o 
missi n g > = 2 c o nsec uti ve t u m or assess me nts will be ce ns ore d o n t he last t u m or assess me nt 
date pri or t o missi n g > = 2 c o nsec uti ve assess me nts.
3)
S u bjects w h o recei ve d ne w a nti-ca ncer t hera p y will be ce ns ore d o n t he last assess me nt date 
pri or t o recei vi n g ne w a nti-ca ncer t hera p y.
4)
S u bjects w h o are ali ve a n d d o n ot ha ve a n y o n-st u d y t u m or assess me nts will be ce ns ore d o n 
t he ra n d o mizati o n date (a p plica ble o nl y f or P F S)
O S ce ns ori n g r ules:
1)
S u bjects w h o d o n ot ha ve a rec or de d deat h date will be ce ns ore d o n t he last k n o w n ali ve 
date.


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C O N FI D E N TI A L
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7.   
A N A L Y SI S O F A D V E R S E E V E N T S A N D L A B O R A T O R Y 
E V A L U A TI O N S
All A Es will be liste d. T he f oc us of A E s u m marizati o n will be o n treat me nt-e mer ge nt A Es. 
Safet y a nal yses will be c o n d ucte d usi n g Safet y A nal ysis Set, u nless ot her wise s pecifie d.
7. 1.   
A d verse E ve nts a n d De at hs
7. 1. 1.   
A d verse E ve nt Dicti o n ar y
Cli nical a n d la b orat or y a d verse e ve nts ( A Es) will be c o de d usi n g t he c urre nt versi o n of Me dical 
Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A). S yste m or ga n class ( S O C), hi g h-le vel gr o u p 
ter m ( H L G T), hi g h-le vel ter m ( H L T), preferre d ter m ( P T), a n d l o wer-le vel ter m ( L L T) will be 
pr o vi de d i n t he A E dataset.
7. 1. 2.   
A d verse E ve nt Se verit y
A d verse e ve nts are gra de d b y t he i n vesti gat or as Gra de 1, 2, 3, 4, or 5 acc or di n g t o C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) Versi o n 5. 0. T he se verit y gra de of e ve nts f or 
w hic h t he i n vesti gat or di d n ot rec or d se verit y will be cate g orize d as “ missi n g” f or ta b ular 
s u m maries a n d data listi n gs. T he missi n g cate g or y will be liste d last i n s u m mar y prese ntati o n.
7. 1. 3.   
Rel ati o ns hi p of A d verse E ve nts t o St u d y Dr u g
Relate d A Es are t h ose f or w hic h t he i n vesti gat or selecte d “ Relate d” o n t he A E C R F t o t he 
q uesti o n of “ Relate d t o St u d y Treat me nt.” Relate d ness will al wa ys defa ult t o t he i n vesti gat or’s 
c h oice, n ot t hat of t he me dical m o nit or. E ve nts f or w hic h t he i n vesti gat or di d n ot rec or d 
relati o ns hi p t o st u d y dr u g will be c o nsi dere d relate d t o st u d y dr u g f or s u m mar y p ur p oses. 
H o we ver, b y-s u bject data listi n gs will s h o w t he relati o ns hi p as missi n g.
7. 1. 4.  
Seri o us A d verse E ve nts
Seri o us a d verse e ve nts ( S A Es) will be i de ntifie d a n d ca pt ure d as S A Es if t he A Es met t he 
defi niti o ns of S A Es t hat are s pecifie d i n t he st u d y pr ot oc ol. S A Es ca pt ure d a n d st ore d i n t he 
cli nical data base will be rec o ncile d wit h t he S A E data base fr o m t he n Gilea d Gl o bal Safet y 
De part me nt bef ore data fi nalizati o n.
7. 1. 5.  
Tre at me nt- E mer ge nt A d verse E ve nts 
7. 1. 5. 1.   
Defi niti o n of Treat me nt- E mer ge nt A d verse E ve nts
Treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) are defi ne d as 1 or b ot h of t he f oll o wi n g:

A n y A Es wit h a n o nset date o n or after t he st u d y dr u g start date a n d n o later t ha n 3 0 da ys 
after per ma ne nt disc o nti n uati o n of st u d y dr u g

A n y A Es lea di n g t o per ma ne nt disc o nti n uati o n of st u d y dr u g.


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C O N FI D E N TI A L
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7. 1. 5. 2.  
I nc o m plete Dates
If t he o nset date of t he A E is i nc o m plete a n d t he A E st o p date is n ot pri or t o t he first d osi n g date 
of st u d y dr u g, t he n t he m o nt h a n d year ( or year al o ne if m o nt h is n ot rec or de d) of o nset 
deter mi ne w het her a n A E is treat me nt e mer ge nt. T he e ve nt is c o nsi dere d treat me nt e mer ge nt if 
b ot h of t he f oll o wi n g 2 criteria are met:

T he A E o nset is t he sa me as or after t he m o nt h a n d year ( or year) of t he first d osi n g date of 
st u d y dr u g, a n d

T he A E o nset date is t he sa me as or bef ore t he m o nt h a n d year ( or year) of t he date 
c orres p o n di n g t o 3 0 da ys after t he date of t he last d ose of st u d y dr u g.
A n A E wit h c o m pletel y missi n g o nset a n d st o p dates, or wit h t he o nset date missi n g a n d a st o p 
date later t ha n t he first d osi n g date of st u d y dr u g, will be c o nsi dere d t o be treat me nt e mer ge nt. I n 
a d diti o n, a n A E wit h t he o nset date missi n g a n d i nc o m plete st o p date wit h t he sa me or later 
m o nt h a n d year ( or year al o ne if m o nt h is n ot rec or de d) as t he first d osi n g date of st u d y dr u g will 
be c o nsi dere d treat me nt e mer ge nt.
I n case w he n t he A E o nset date is i nc o m plete a n d nee ds t o be i m p ute d, t he f oll o wi n g al g orit h m 
will be f oll o we d:

 If t he da y is missi n g b ut t he m o nt h a n d year are a vaila ble, t he n t he i m p ute d da y will be t he 
first da y of t he m o nt h or t he first d osi n g date if t he y ha ve t he sa me m o nt h a n d year, 
w hic he ver is later.

If t he da y a n d m o nt h are missi n g b ut year is a vaila ble, t he n t he i m p ute d da y a n d m o nt h will 
be 0 1 Ja n or t he first d osi n g date if t he y ha ve t he sa me year, w hic he ver is later.
7. 1. 6.  
S u m m aries of A d verse E ve nts a n d De at hs
T E A Es will be s u m marize d b y treat me nt ar ms base d o n t he Safet y A nal ysis Set.
7. 1. 6. 1.  
S u m maries of A d verse E ve nts I nci de nce b y Se verit y
T he n u m ber a n d perce nta ge of s u bjects w h o e x perie nce d at least 1 T E A E will be pr o vi de d a n d 
s u m marize d b y S O C a n d P T.
T he n u m ber a n d perce nta ge of s u bjects w h o e x perie nce d at least 1 T E A E will be pr o vi de d a n d 
s u m marize d b y P T a n d se verit y i n desce n di n g or der of t otal fre q ue nc y:

Treat me nt- E mer ge nt A d verse E ve nts b y P T a n d Se verit y


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
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Pa ge 2 3
2 1 N o ve m ber 2 0 2 2
F or t he A E cate g orizes descri be d bel o w, s u m maries will be pr o vi de d b y P T i n desce n di n g or der 
of t otal fre q ue nc y:

All Treat me nt- E mer ge nt A d verse E ve nts

Gra de 4 or Hi g her Treat me nt- E mer ge nt A d verse E ve nts 

Gra de 3 or Hi g her Treat me nt- E mer ge nt A d verse E ve nts 

Treat me nt- E mer ge nt I delalisi b relate d A d verse E ve nts 

Treat me nt- E mer ge nt Seri o us A d verse E ve nts 

Treat me nt- E mer ge nt I delalisi b relate d Seri o us A d verse E ve nts 

Treat me nt- E mer ge nt A d verse E ve nts lea di n g t o disc o nti n uati o n of I delalisi b

Treat me nt- E mer ge nt A d verse E ve nts lea di n g t o te m p orar y i nterr u pti o n of I delalisi b

Treat me nt- E mer ge nt A d verse E ve nts lea di n g t o st u d y disc o nti n uati o n

Treat me nt- E mer ge nt A d verse E ve nts lea di n g t o Deat h
A brief, hi g h-le vel s u m mar y of A Es descri be d a b o ve will be pr o vi de d b y treat me nt ar ms a n d b y 
t he n u m ber a n d perce nta ge of s u bjects w h o e x perie nce d t he a b o ve A Es.
F or s u m maries of T E A Es b y P T, m ulti ple e ve nts will be c o u nte d o nl y o nce per s u bject i n eac h 
s u m mar y. A d verse e ve nts will be s u m marize d a n d liste d b y P T i n desce n di n g or der of t otal 
fre q ue nc y. F or s u m maries b y se verit y, t he m ost se vere se verit y will be use d f or t h ose A Es t hat 
occ urre d m ore t ha n o nce i n a gi ve n s u bject d uri n g t he st u d y.
I n a d diti o n, b y-s u bject data listi n gs will be pr o vi de d b y treat me nt ar ms a n d s u bject I D n u m ber i n 
asce n di n g or der f or t he f oll o wi n g:

All A Es, i n dicati n g w het her t he e ve nt is treat me nt e mer ge nt

All S A Es

All Deat hs

All A d verse E ve nts lea di n g t o Deat h

All A d verse E ve nts wit h Gra de 3 or Hi g her

All A d verse E ve nts wit h Gra de 4 or Hi g her


I delalisi b
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Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 4
2 1 N o ve m ber 2 0 2 2

All A d verse E ve nts lea di n g t o disc o nti n uati o n of I delalisi b

All A d verse E ve nts lea di n g t o te m p orar y i nterr u pti o n of I delalisi b 

All A d verse E ve nts lea di n g t o st u d y disc o nti n uati o n
A fla g will be i ncl u de d i n t he listi n gs t o i n dicate w het her t he e ve nt is treat me nt e mer ge nt.
7. 1. 6. 2.  
S u m mar y of Deat hs
A s u m mar y ( n u m ber a n d perce nta ge of s u bjects) of deat hs will be pr o vi de d b y treat me nt ar ms. 
T he s u m mar y will i ncl u de t he f oll o wi n g cate g ories:

All deat hs

Deat hs wit hi n 3 0 da ys of t he last d osi n g of st u d y dr u g

Deat hs be y o n d 3 0 da ys of t he last d osi n g of st u d y dr u g.
E ver y atte m pt will be ma de t o e ns ure t hat c o m plete deat h dates are rec or de d. I n t h ose rare 
i nsta nces w here c o m plete deat h dates are n ot rec or de d, t he f oll o wi n g al g orit h m will be use d:

If da y is missi n g b ut t he m o nt h a n d year are a vaila ble, t he n t he i m p ute d date will be t he 1st 
da y of t he m o nt h or t he last k n o w n ali ve date + 1, w hic he ver is later.
A b y-s u bject listi n g of all deat hs occ urre d d uri n g t his st u d y will be pr o vi de d b y treat me nt ar ms 
a n d s u bject I D n u m ber i n asce n di n g or der.
7. 2.  
L a b or at or y E v al u ati o ns
La b orat or y data c ollecte d d uri n g t he st u d y will be a nal yze d a n d s u m marize d usi n g b ot h 
q ua ntitati ve a n d q ualitati ve met h o ds. S u m maries of la b orat or y data will be pr o vi de d f or t he 
Safet y A nal ysis Set a n d will i ncl u de data c ollecte d u p t o t he last d ose of st u d y dr u g pl us 3 0 da ys. 
T he a nal ysis will be base d o n val ues re p orte d i n c o n ve nti o nal u nits. W he n val ues are bel o w t he 
L O Q, t he y will be liste d as s uc h, a n d t he cl osest i m p ute d val ue will be use d f or t he p ur p ose of 
calc ulati n g s u m mar y statistics as s pecifie d i n Secti o n 3. 5 .
A b y-s u bject listi n g f or all la b test res ults will be pr o vi de d b y treat me nt ar ms, s u bject I D n u m ber 
a n d ti me p oi nt i n c hr o n ol o gical or der f or he mat ol o g y a n d ser u m c he mistr y, se paratel y. Val ues 
falli n g o utsi de of t he rele va nt refere nce ra n ge a n d/ or ha vi n g a se verit y Gra de of 1 or hi g her o n 
t he C T C A E se verit y gra de will be fla g ge d i n t he data listi n gs, as a p pr o priate. 
N o f or mal statistical testi n g is pla n ne d.


I delalisi b
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Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 5
2 1 N o ve m ber 2 0 2 2
7. 2. 1.   
Gr a de d L a b or at or y V al ues
C T C A E Versi o n 5. 0 will be use d t o assi g n t o xicit y Gra des ( 0 t o 4) t o la b orat or y res ults f or 
a nal ysis. Gra de 0 i ncl u des all val ues t hat d o n ot meet t he criteria f or a n a b n or malit y of at least 
Gra de 1. F or la b orat or y tests wit h criteria f or b ot h i ncrease d a n d decrease d le vels, a nal yses f or 
eac h directi o n (ie, i ncrease d, decrease d) will be prese nte d se paratel y. 
L o cal la bs will be gra de d base d o n ce ntral la b n or mal ra n ges wit h i n- h o use macr o. Baseli ne 
gra de will be base d o n ce ntral la b orat or y res ults, u nless o nl y l ocal la bs are c ollecte d pri or t o t he 
first d osi n g of st u d y dr u g.  F or p ost- baseli ne gra de, t he w orst t o xicit y gra de c o nsi deri n g b ot h 
ce ntral a n d l ocal la b res ults will be use d f or t he s u m mar y of la b t o xicities. All ce ntral a n d l ocal 
la b orat or y val ues will be liste d f or All E nr olle d S u bjects.
7. 2. 1. 1.  
Treat me nt- E mer ge nt La b orat or y A b n or malities
Treat me nt-e mer ge nt la b orat or y a b n or malities are defi ne d as val ues t hat i ncrease at least 
1 t o xicit y gra de fr o m baseli ne at a n y p ost baseli ne ti me p oi nt, u p t o a n d i ncl u di n g t he date of last 
d ose of st u d y dr u g pl us 3 0 da ys f or s u bjects w h o per ma ne ntl y disc o nti n ue d st u d y dr u g, or t he 
last a vaila ble date i n t he data base s na ps h ot f or s u bjects w h o were still o n treat me nt at t he ti me of 
a n a nal ysis. A baseli ne la b orat or y val ue will be defi ne d as t he last meas ure me nt o btai ne d o n or 
pri or t o t he date/ti me of first d ose of st u d y dr u g. If t he rele va nt baseli ne la b orat or y val ue is 
missi n g, a n y a b n or malit y of at least Gra de 1 o bser ve d wit hi n t he ti me fra me s pecifie d a b o ve will 
be c o nsi dere d treat me nt e mer ge nt.
7. 2. 1. 2.  
S u m maries of La b orat or y A b n or malities
T he f oll o wi n g s u m maries ( n u m ber a n d perce nta ge of s u bjects) f or treat me nt-e mer ge nt la b orat or y 
a b n or malities will be pr o vi de d b y la b test a n d treat me nt ar m; s u bjects will be cate g orize d 
acc or di n g t o t he m ost se vere p ost baseli ne a b n or malit y gra de f or a gi ve n la b test:

T E la b orat or y a b n or malities
I n t he s u m mar y of la b orat or y a b n or malities, t he de n o mi nat or is t he n u m ber of s u bjects wit h 
n o n missi n g p ost baseli ne val ues u p t o 3 0 da ys after last d osi n g date.
7. 3.  
B o d y Wei g ht a n d Vit al Si g ns
A b y-s u bject listi n g of b o d y wei g ht a n d vital si g ns will be pr o vi de d f or All E nr olle d S u bjects b y 
treat me nt ar ms s u bject I D n u m ber a n d visit i n c hr o n ol o gical or der.
7. 4.  
Pri or a n d C o nc o mit a nt Me dic ati o ns
Me dicati o ns c ollecte d at scree ni n g a n d d uri n g t he st u d y will be c o de d usi n g t he c urre nt versi o n 
of t he  W orl d Healt h Or ga nizati o n Dr u g dicti o nar y.  Listi n gs will be pr o vi de d f or All E nr olle d 
A nal ysis Set. 


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 6
2 1 N o ve m ber 2 0 2 2
7. 4. 1.  
Pri or Me dic ati o ns
Pri or me dicati o ns are defi ne d as a n y me dicati o ns be g u n bef ore a s u bject t o o k t he first st u d y 
dr u g.
F or t he p ur p oses of a nal ysis, a n y me dicati o n wit h a start date pri or t o t he first d osi n g date of 
st u d y dr u g will be c o nsi dere d as pri or me dicati o n re gar dless of w he n t he st o p date is. If a partial 
start date is e ntere d t he me dicati o n will be c o nsi dere d pri or u nless t he m o nt h a n d year (if da y is 
missi n g) or year (if da y a n d m o nt h are missi n g) of t he start date are after t he first d osi n g date. 
Me dicati o ns wit h a c o m pletel y missi n g start date will be c o nsi dere d as pri or me dicati o n, u nless 
ot her wise s pecifie d.
All pri or me dicati o ns ( ot her t ha n per- pr ot oc ol st u d y dr u gs) will be pr o vi de d i n a b y-s u bject 
listi n g s orte d b y treat me nt ar ms, s u bject I D n u m ber a n d a d mi nistrati o n date i n c hr o n ol o gical 
or der base d o n All E nr olle d A nal ysis Set.
7. 4. 2.   
C o nc o mit a nt Me dic ati o ns
F or t he p ur p oses of a nal ysis, c o nc o mita nt me dicati o ns are defi ne d as a n y me dicati o ns

starte d pri or t o or o n t he first d osi n g date of st u d y dr u g a n d c o nti n ue d t o be ta ke n after t he 
first d osi n g date, or 

starte d after t he first d osi n g date b ut pri or t o or o n t he last d osi n g date of st u d y dr u g.
Me dicati o ns starte d a n d st o p pe d o n t he sa me da y as t he first d osi n g date or t he last d osi n g date of 
st u d y dr u g will als o be c o nsi dere d c o nc o mita nt. Me dicati o ns wit h a st o p date t hat is pri or t o t he 
date of first d osi n g date of st u d y dr u g or a start date t hat is after t he last d osi n g date of st u d y dr u g 
will n ot be c o nsi dere d as c o nc o mita nt me dicati o n. 
If a partial st o p date is e ntere d, a n y me dicati o n wit h t he m o nt h a n d year (if da y is missi n g) or 
year (if da y a n d m o nt h are missi n g) pri or t o t he date of first st u d y dr u g a d mi nistrati o n will n ot be 
c o nsi dere d as c o nc o mita nt me dicati o n. If a partial start date is e ntere d, a n y me dicati o n wit h t he 
m o nt h a n d year (if da y is missi n g) or year (if da y a n d m o nt h are missi n g) after t he st u d y dr u g 
st o p date will n ot be c o nsi dere d as c o nc o mita nt me dicati o n. Me dicati o ns wit h c o m pletel y 
missi n g start a n d st o p dates will be c o nsi dere d as t he c o nc o mita nt me dicati o n, u nless ot her wise 
s pecifie d.
All c o nc o mita nt me dicati o ns ( ot her t ha n per- pr ot oc ol st u d y dr u gs) will be pr o vi de d i n a b y-
s u bject listi n g s orte d b y treat me nt ar ms, s u bject I D n u m ber a n d a d mi nistrati o n date i n 
c hr o n ol o gical or der base d o n All E nr olle d A nal ysis Set.


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 7
2 1 N o ve m ber 2 0 2 2
7. 5.   
Ot her S afet y Me as ures
Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us is a n i n vesti gat or assess me nt 
of t he i m pact of t he disease o n t he s u bject’s acti vities of dail y li vi n g. E C O G assess me nts will be 
perf or me d at t he ti me p oi nts liste d i n t he St u d y Pr oce d ures Ta ble ( A p pe n di x 2 of t he pr ot oc ol).
B y-s u bject listi n gs will be ge nerate d f or t he All E nr olle d A nal ysis Set b y treat me nt ar ms a n d 
s u bject I D n u m ber i n asce n di n g or der f or t he f oll o wi n g safet y para meters a n d c o m me nts:

E C O G perf or ma nce sc ores

Ge neral C o m me nts
7. 6.   
C h a n ges fr o m Pr ot oc ol- S pecifie d S afet y A n al yses
Pr ot oc ol defi ne d a sec o n dar y e n d p oi nt of Ti me t o o nset of A Es of i nterest ( A EIs).  T his a nal ysis 
was n ot perf or me d.


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 8
2 1 N o ve m ber 2 0 2 2
8.  
P H A R M A C O KI N E TI C A N A L Y S E S
Plas ma c o nce ntrati o ns of i delalisi b/ G S- 5 6 3 1 1 7 will be liste d a n d s u m marize d b y treat me nt ar m 
a n d visit usi n g descri pti ve statistics (e g, sa m ple size, arit h metic mea n, ge o metric mea n, 
% c oefficie nt of variati o n, St D, me dia n, mi ni m u m, a n d ma xi m u m).


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 9
2 1 N o ve m ber 2 0 2 2
9.   
R E F E R E N C E S
C hes o n B D, Fis her RI, Barri n gt o n S F, Ca valli F, Sc h wartz L H, Z ucca E, et al. 
Rec o m me n dati o ns f or I nitial E val uati o n, Sta gi n g, a n d Res p o nse Assess me nt of 
H o d g ki n a n d N o n- H o d g ki n L y m p h o ma: T he L u ga n o Classificati o n. J Cli n O nc ol 
2 0 1 4.
C hes o n B D, Pfist ner B, J u wei d M E, Gasc o y ne R D, S pec ht L, H or ni n g SJ, et al. Re vise d 
res p o nse criteria f or mali g na nt l y m p h o ma. J Cli n O nc ol 2 0 0 7; 2 5 ( 5): 5 7 9- 8 6.
C o utre S E, Barrie nt os J C, Br o w n J R, de V os S, F ur ma n R R, Keati n g MJ, et al. Ma na ge me nt of 
a d verse e ve nts ass ociate d wit h i delalisi b treat me nt - e x pert pa nel o pi ni o n. Le u k 
L y m p h o ma 2 0 1 5: 1- 2 0.
Dre yli n g M, Geisler C, Her mi ne O, Kl ui n- Nele ma ns H C, Le G o uill S, R ule S, et al. Ne wl y 
dia g n ose d a n d rela pse d ma ntle cell l y m p h o ma: E S M O Cli nical Practice 
G ui deli nes f or dia g n osis, treat me nt a n d f oll o w- u p da g ger. A n n O nc ol 2 0 1 4; 2 5 
S u p pl 3:iii 8 3-iii 9 2.
Gilea d Scie nces I nc. Z Y D E LI G ® (i delalisi b) ta blets, f or oral use. U. S. Prescri bi n g I nf or mati o n. 
F oster Cit y, C A. J ul y 2 0 1 4:
Mills EJ, Bar ni g ha use n T, Ne gi n J. HI V a n d a gi n g-- pre pari n g f or t he c halle n ges a hea d. N E n gl J 
Me d 2 0 1 2; 3 6 6 ( 1 4): 1 2 7 0- 3.
Nati o nal C o m pre he nsi ve Ca ncer Net w or k ( N C C N). N C C N Cli nical Practice G ui deli nes i n 
O nc ol o g y: N o n- H o d g ki n's L y m p h o mas.  J ul y, 2 0 1 4.
O k ke n ha u g K, Va n haese br oec k B. PI 3 K-si g nalli n g i n B- a n d T-cells: i nsi g hts fr o m ge ne-
tar gete d mice. Bi oc he mical S ociet y tra nsacti o ns 2 0 0 3; 3 1 ( Pt 1): 2 7 0- 4.
Raa na ni P, Gafter- G vili A, Pa ul M, Be n- Bassat I, Lei b o vici L, S h pil ber g O. I m m u n o gl o b uli n 
pr o p h yla xis i n c hr o nic l y m p h oc ytic le u ke mia a n d m ulti ple m yel o ma: s yste matic 
re vie w a n d meta-a nal ysis. Le u k L y m p h o ma 2 0 0 9; 5 0 ( 5): 7 6 4- 7 2.
S olal- Celi g n y P, R o y P, C ol o m bat P, W hite J, Ar mita ge J O, Arra nz- Saez R, et al. F ollic ular 
l y m p h o ma i nter nati o nal pr o g n ostic i n de x. Bl o o d 2 0 0 4; 1 0 4 ( 5): 1 2 5 8- 6 5.
Tsa n g R W, G os p o dar o wicz M K. Ra diati o n t hera p y f or l ocalize d l o w- gra de n o n- H o d g ki n's 
l y m p h o mas. He mat ol O nc ol 2 0 0 5; 2 3 ( 1): 1 0- 7.
Va n haese br oec k B, Ali K, Bila nci o A, Geeri n g B, F o u kas L C. Si g nalli n g b y PI 3 K is of or ms: 
i nsi g hts fr o m ge ne-tar gete d mice. Tre n ds Bi oc he m Sci 2 0 0 5; 3 0 ( 4): 1 9 4- 2 0 4.


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 0
2 1 N o ve m ber 2 0 2 2
Wil der R B, J o nes D, T uc ker S L, F uller L M, Ha C S, Mc La u g hli n P, et al. L o n g-ter m res ults wit h 
ra di ot hera p y f or Sta ge I-II f ollic ular l y m p h o mas. I nter nati o nal j o ur nal of ra diati o n 
o nc ol o g y, bi ol o g y, p h ysics 2 0 0 1; 5 1 ( 5): 1 2 1 9- 2 7.
Zele netz A D, A bra ms o n J S, A d va ni R H, A n drea dis C B, Bartlett N, Bella m N, et al. N o n-
H o d g ki n's l y m p h o mas. J Natl C o m pr Ca nc Net w 2 0 1 1; 9 ( 5): 4 8 4- 5 6 0.


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 1
2 1 N o ve m ber 2 0 2 2
1 0.  
S O F T W A R E
S A S  ( S A S I nstit ute I nc. Versi o n 9. 4, Car y, N C) is t o be use d f or all pr o gra m mi n g of ta bles, 
fi g ures, a n d listi n gs ( T F Ls).


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 2
2 1 N o ve m ber 2 0 2 2
1 1.  
S A P R E VI SI O N
Re visi o n D ate
( D D M M M Y Y Y Y) 
Secti o n 
S u m m ar y of Re visi o n
Re as o n f or Re visi o n
2 7 O C T 2 0 2 2
1. 2. 1, 
1. 2. 2,
6. 1. 2
A d de d pri mar y e n d p oi nts,  
A d de d sec o n dar y e n d p oi nts
A d de d ce ns ori n g r ules
A d de d t hese secti o ns f or 
c o m plete ness
2 7 O C T 2 0 2 2
T hr o u g h o ut 
t he 
d oc u me nt
Mi n or e dits 
F or clarificati o n


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 3
2 1 N o ve m ber 2 0 2 2
A p pe n di x 1.   
C O VI D- 1 9 S M Q wit h Br o a d Sc o pe
N ote: T he list prese nte d bel o w is base d o n Me d D R A Versi o n 2 3. 1. T he act ual list will be u p-
versi o ne d t o t he Me d D R A versi o n use d at t he ti me of data base fi nalizati o n.
Me d D R A Preferre d Ter m
P T C o de
As y m pt o matic C O VI D- 1 9
1 0 0 8 4 4 5 9
C or o na vir us i nfecti o n
1 0 0 5 1 9 0 5
C or o na vir us test p ositi ve
1 0 0 7 0 2 5 5
C O VI D- 1 9
1 0 0 8 4 2 6 8
C O VI D- 1 9 i m m u nisati o n
1 0 0 8 4 4 5 7
C O VI D- 1 9 p ne u m o nia
1 0 0 8 4 3 8 0
C O VI D- 1 9 pr o p h yla xis
1 0 0 8 4 4 5 8
C O VI D- 1 9 treat me nt
1 0 0 8 4 4 6 0
E x p os ure t o S A R S- C o V- 2
1 0 0 8 4 4 5 6
M ultis yste m i nfla m mat or y s y n dr o me i n c hil dre n
1 0 0 8 4 7 6 7
Occ u pati o nal e x p os ure t o S A R S- C o V- 2
1 0 0 8 4 3 9 4
S A R S- C o V- 2 a nti b o d y test p ositi ve
1 0 0 8 4 4 9 1
S A R S- C o V- 2 carrier
1 0 0 8 4 4 6 1
S A R S- C o V- 2 se psis
1 0 0 8 4 6 3 9
S A R S- C o V- 2 test false ne gati ve
1 0 0 8 4 4 8 0
S A R S- C o V- 2 test p ositi ve
1 0 0 8 4 2 7 1
S A R S- C o V- 2 virae mia
1 0 0 8 4 6 4 0
S us pecte d C O VI D- 1 9
1 0 0 8 4 4 5 1
A nti viral pr o p h yla xis
1 0 0 4 9 0 8 7
A nti viral treat me nt
1 0 0 6 8 7 2 4
C or o na vir us test
1 0 0 8 4 3 5 3
C or o na vir us test ne gati ve
1 0 0 8 4 2 6 9
E x p os ure t o c o m m u nica ble disease
1 0 0 4 9 7 1 1
P ne u m o nia viral
1 0 0 3 5 7 3 7
S A R S- C o V- 2 a nti b o d y test
1 0 0 8 4 5 0 1
S A R S- C o V- 2 a nti b o d y test ne gati ve
1 0 0 8 4 5 0 9
S A R S- C o V- 2 test
1 0 0 8 4 3 5 4
S A R S- C o V- 2 test false p ositi ve
1 0 0 8 4 6 0 2
S A R S- C o V- 2 test ne gati ve
1 0 0 8 4 2 7 3


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 4
2 1 N o ve m ber 2 0 2 2


I delalisi b
St u d y G S- U S- 3 1 3- 1 5 8 0 
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 5
2 1 N o ve m ber 2 0 2 2
A p pe n di x 2.   
Deter mi ni n g Missi n g a n d Virt u al Visits D u e t o C O VI D- 1 9
T his a p pe n di x descri bes t he cli nical trial site c ollecti o n of C O VI D- 1 9 data pertai ni n g t o 
misse d/ virt ual visits a n d t he data pr ocessi n g al g orit h m use d t o deter mi ne w hic h visits were 
missi n g a n d w hic h visits were virt ual.
Data c ollecti o n
A C O VI D- 1 9 s u p ple me nt t o t he e C R F C o m pleti o n G ui deli nes ( C C G) was pr o vi de d b y data 
ma na ge me nt t o i nstr uct cli nical trial sites wit h res pect t o data e ntr y e x pectati o ns pertai ni n g t o 
sce nari os relate d t o t he C O VI D- 1 9 pa n de mic. If a visit was misse d, sites s h o ul d e nter 
“ Visit misse d d ue t o C O VI D- 1 9.” If a n i n- pers o n visit was c o n d ucte d virt uall y, sites s h o ul d e nter
“ Virt ual visit d ue t o C O VI D- 1 9.”
Deter mi nati o n of Misse d a n d Virt ual visits
N L P was use d t o searc h t he C R F c o m me nt fiel ds t o i de ntif y i nsta nces of “ C O VI D- 1 9” ( or 
s y n o n y ms, see t he ta ble bel o w) a n d “ Virt ual” ( or s y n o n y ms, see t he ta ble bel o w). T he searc h 
ter ms are mai ntai ne d i n a gl o bal l o o k u p ta ble a n d ca n be m o difie d t o t u ne t he N L P m o del. F or 
a n y c o m me nts wit h C O VI D- 1 9 searc h ter ms, assi g n “ Misse d visit” or “ Virt ual visit as f oll o ws:
i.  
If C O VI D- 1 9 ter ms are i de ntifie d t hr o u g h N L P a n d t he visit date is missi n g, t he n res ult 
is “ Misse d Visit”
ii.  
If C O VI D- 1 9 a n d Virt ual ter ms are i de ntifie d t hr o u g h N L P f or a visit, t he n res ult is 
“ Virt ual Visit”. W he n t here are m ulti ple rec or ds f or t he sa me s u bject a n d t he sa me 
visit, N L P will be base d o n m ulti ple rec or ds t o e ns ure 1 u ni q ue cate g or y per s u bject per 
visit
iii. 
Ot her wise res ult is missi n g
E x a m ples of Se arc h Ter ms f or “ C O VI D- 1 9 ” a n d “ Virt u al ” Use d t o I de ntif y Misse d a n d 
Virt u al Visits
Se arc h Ter ms f or “ C O VI D- 1 9 ”
Se arc h Ter ms f or “ Virt u al ”
C O VI D 1 9
VI R T U A L
C O R O N A
T E L E M E D
C O R O N A VI R U S
T E L E H E A L T H
P A N D E MI C
T E L E P H O N E
O U T B R E A K
R E M O T E
C RI SI S
T E L E M E DI CI N E
L O C K D O W N
T E L E C O N S U L T A TI O N
Q U A R A N TI N E
T E L E P H O NI C A L L Y
S H E L T E R
P H O N E
H O M E VI SI T
Z O O M
S K Y P E


G S- U S- 3 1 3- 1 5 8 0 S A P v 1. 0
E L E C T R O NI C SI G N A T U R E S
Si g n e d b y
M e a ni n g of Si g n at ur e 
S er v er D at e
( d d- M M M-
y y y y h h: m m: s s)
Bi o st ati sti c s e Si g n e d 
2 2- N o v- 2 0 2 2
1 8: 4 7: 3 0
Cli ni c al R e s e ar c h e Si g n e d
3 0- N o v- 2 0 2 2
0 6: 1 7: 5 1
P P D
P P D