Conditions: Nucleophosmin 1-mutated Acute Myeloid Leukemia
Keywords: Acute Myeloid Leukemia Nucleophosmin 1-mutated Acute Myeloid Leukemia Entospletinib ENTO
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 15
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the efficacy of entospletinib (ENTO) compared to placebo when added to chemotherapy in previously untreated nucleophosmin-1 mutated (NPM1-m) acute myeloid leukemia (AML), as defined by the rate of molecularly defined measurable residual disease (MRD).

Detailed description:
This is a multi-center, international, double-blind, placebo-controlled study in previously untreated participants with acute myeloid leukemia (AML) harboring nucleophosmin-1 (NPM1) mutations. Upon fulfillment of all eligibility criteria, participants were randomized 1:1 to receive intensive chemotherapy in combination with either the spleen tyrosine kinase (SYK) inhibitor entospletinib (ENTO), or placebo. The study consisted of Screening, Induction, Consolidation, End-of-Treatment, and Long-term Follow-up phases.

Arms:
arm 1: Participants received intensive chemotherapy (cytarabine and anthracycline \[daunorubicin or idarubicin\]) in combination with entospletinib (ENTO). arm 2: Participants received intensive chemotherapy (cytarabine and anthracycline \[daunorubicin or idarubicin\]) in combination with the matching placebo.

Interventions: intervention 1: Entospletinib intervention 2: Placebo intervention 3: Cytarabine intervention 4: Anthracycline
Intervention descriptions: intervention 1: 400 mg, Orally as tablets intervention 2: Orally as tablets intervention 3: Continuous infusion intervention 4: Either daunorubicin or idarubicin was administered via slow intravenous (IV) push

Protocol document:
Prot_000.pdf: 


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Protocol KB-ENTO-3001 v4.0 Global 
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Title Page 
Protocol Title:  
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety 
of Entospletinib in Combination With Intensive Induction and Consolidation Chemotherapy in 
Adults With Newly Diagnosed Nucleophosmin 1-mutated Acute Myeloid Leukemia 
Protocol Number: KB-ENTO-3001 
Version Number: 4.0 Global (Amendment 3.0 Global) 
Compound: Entospletinib (ENTO, formerly known as GS-9973) 
Brief Title: Entospletinib Plus Intensive Induction/Consolidation Chemotherapy in Newly 
Diagnosed NPM1-mutated AML 
Study Phase: 3 
Sponsor Name: Kronos Bio, Inc. 
Legal Registered Address:  1300 So. El Camino Real 
 
 
 
 
Suite 400 
 
 
 
 
San Mateo, CA 94402 
Regulatory Agency Identifier Number(s): 
IND:   
116416 
EudraCT: 
2021-000761-33 
Approval Date: 10 February 2022 
 
 




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SIGNATURE OF INVESTIGATOR 
 
Protocol title:  
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to 
Assess the Efficacy and Safety of Entospletinib in Combination with 
Intensive Induction and Consolidation Chemotherapy in Adults with 
Newly Diagnosed Nucleophosmin 1-mutated Acute Myeloid Leukemia 
 
 
Protocol identifier:   KB-ENTO-3001 
 
 
This protocol is a confidential communication of Kronos Bio, Inc. (Kronos Bio). I confirm that I 
have read this protocol, understand it, and will execute the trial according to all of its specifications. 
I will also adhere consistently to the ethical principles originating in the Declaration of Helsinki 
and that are consistent with good clinical practices and applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information contained 
herein will be published or disclosed without prior written approval of Kronos Bio. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly. 
 
 
Signature of investigator and Date: ________________________________________________ 
 
Printed name of investigator: 
________________________________________________ 
 
Investigator title: 
________________________________________________ 
 
Name and address of study site: 
________________________________________________ 
 
 
 
________________________________________________ 
 
 
 
________________________________________________ 
 
 
 
________________________________________________ 
 
 


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Table of Contents 
1.0 
Synopsis ...........................................................................................................................8 
2.0 
Introduction ...................................................................................................................14 
2.1 
Acute Myeloid Leukemia - Diagnosis, Classification, Prognosis, 
and Treatment in the Frontline Setting ...........................................................................14 
2.2 
Preclinical and Clinical Rationale for the Investigation of 
Entospletinib in NPM1-mutated AML ...........................................................................18 
2.3 
Study Rationale ...............................................................................................................21 
2.4 
Benefit/Risk Assessment ................................................................................................21 
2.4.1 
COVID-19 Considerations..............................................................................................24 
3.0 
Objectives and Endpoints ............................................................................................25 
4.0 
Study Design ..................................................................................................................28 
4.1 
Overall Design ................................................................................................................28 
4.2 
Justification for Dose of ENTO ......................................................................................31 
4.3 
End of Study Definition ..................................................................................................32 
5.0 
Study Population ...........................................................................................................33 
5.1 
Inclusion Criteria ............................................................................................................33 
5.2 
Exclusion Criteria ...........................................................................................................34 
5.3 
Lifestyle Considerations .................................................................................................37 
6.0 
Study Treatment and Concomitant Therapy .............................................................38 
6.1 
Study Treatment Administered .......................................................................................38 
6.2 
Preparation/Handling/Storage/Accountability ................................................................38 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................38 
6.4 
Compliance with Study Medication Regimen ................................................................39 
6.5 
Dose Modification ..........................................................................................................39 
6.5.1 
ENTO/Placebo ................................................................................................................39 
6.5.2 
Cytarabine Consolidation Therapy Dose Modifications .................................................42 
6.5.3 
Retreatment Criteria ........................................................................................................42 
6.6 
Continued Access to Study Medication After the End of the 
Study ...............................................................................................................................42 
6.7 
Treatment of Overdose ...................................................................................................42 
6.8 
Concomitant Therapy .....................................................................................................42 
7.0 
Discontinuation of Study Treatment/Participation ...................................................44 
7.1 
Discontinuation of Study Treatment ...............................................................................44 
7.2 
Discontinuation from the Study ......................................................................................44 
7.3 
Lost to Follow up ............................................................................................................44 
8.0 
Study Assessments and Procedures.............................................................................46 
8.1 
Informed Consent ...........................................................................................................52 
8.2 
Confirmation of Eligibility .............................................................................................52 
8.3 
Medical and Leukemia History.......................................................................................52 
8.4 
Study Medication Dispensation ......................................................................................52 


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8.5 
Efficacy Assessments .....................................................................................................53 
8.5.1 
Bone Marrow Examination .............................................................................................53 
8.5.2 
Measurable Residual Disease .........................................................................................53 
8.6 
Safety Assessments .........................................................................................................53 
8.6.1 
Physical Examination and Vital Signs ............................................................................53 
8.6.2 
Electrocardiogram ...........................................................................................................54 
8.6.3 
Echocardiography/Multi-gated Acquisition Scan ...........................................................54 
8.6.4 
Laboratory Assessments .................................................................................................54 
8.6.5 
Pregnancy testing ............................................................................................................55 
8.7 
Pharmacokinetic Assessments ........................................................................................56 
8.8 
Biomarker Assessments ..................................................................................................56 
8.9 
Pharmacogenomic Assessments .....................................................................................57 
8.10 
Patient Reported Outcomes ............................................................................................57 
8.11 
Adverse Events (AEs), Serious Adverse Events (SAEs), and 
Other Safety Reporting ...................................................................................................57 
8.11.1 
Time Period for Reporting AEs and SAEs .....................................................................57 
8.11.2 
Method of Detecting AEs and SAEs ..............................................................................57 
8.11.3 
Follow-up of AEs and SAEs ...........................................................................................58 
8.11.4 
Regulatory Reporting Requirements for SAEs ...............................................................58 
8.11.5 
Reporting Pregnancy .......................................................................................................58 
9.0 
Statistical Considerations .............................................................................................59 
9.1 
Statistical Hypotheses .....................................................................................................59 
9.2 
Sample Size Determination ............................................................................................59 
9.3 
Analysis Sets ...................................................................................................................59 
9.4 
Statistical Analyses .........................................................................................................60 
9.4.1 
General Considerations ...................................................................................................60 
9.4.2 
Primary Endpoint ............................................................................................................60 
9.4.2.1 Statement of Estimand ....................................................................................................60 
9.4.2.2 Primary Endpoint Analysis .............................................................................................61 
9.4.3 
Secondary Endpoint(s) ....................................................................................................61 
9.4.4 
Safety Analysis ...............................................................................................................62 
9.5 
Timing of Analyses .........................................................................................................63 
9.5.1 
Data Monitoring Committee ...........................................................................................63 
9.5.2 
Blinded Review of EFS Events .......................................................................................63 
9.5.3 
Primary Endpoint Analysis .............................................................................................63 
9.5.4 
EFS Analysis ...................................................................................................................63 
10.0 
Supporting Documentation and Operational Considerations ..................................64 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................64 
10.1.1 
Regulatory and Ethical Considerations ...........................................................................64 
10.1.2 
Financial Disclosure ........................................................................................................64 
10.1.3 
Informed Consent Process ..............................................................................................65 
10.1.4 
Data Protection................................................................................................................65 
10.1.5 
Dissemination of Clinical Study Data .............................................................................65 


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10.1.6 
Data Quality Assurance ..................................................................................................66 
10.1.7 
Source Documents ..........................................................................................................67 
10.1.8 
Study/Site Termination ...................................................................................................67 
10.1.9 
Publication Policy ...........................................................................................................68 
10.2 
Appendix 2: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................69 
10.2.1 
Definition of AE .............................................................................................................69 
10.2.2 
Definition of SAE ...........................................................................................................70 
10.2.3 
Recording and Follow-Up of AE and/or SAE ................................................................71 
10.2.4 
Reporting of SAEs ..........................................................................................................73 
10.3 
Appendix 3: Contraceptive and Barrier Guidance ..........................................................75 
10.3.1 
Definitions.......................................................................................................................75 
10.3.2 
Contraception Guidance ..................................................................................................75 
10.3.3 
Pregnancy Testing ...........................................................................................................76 
10.4 
Appendix 4: Response Criteria .......................................................................................78 
10.5 
Appendix 5: New York Heart Association Classification ..............................................80 
10.6 
Appendix 6: ECOG Performance Status Scale ...............................................................81 
10.7 
Appendix 7: Potential for Drug-Drug Interactions .........................................................82 
10.8 
Appendix 8: Recommended Adjustments to Anti-Platelet and 
Anti-Coagulant Therapy in AML ...................................................................................83 
10.9 
Appendix 9: Guidance on the Management of Clinical Trials 
During COVID-19 Pandemic .........................................................................................84 
10.10 
Appendix 10: List of Abbreviations and Terms .............................................................85 
11.0 
References ......................................................................................................................89 
 


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List of Tables 
Table 1: 
ELN Classification of Genetic Abnormalities and Mutations by Risk Categories 
 
and Corresponding Five-year Survival Estimates ............................................. 15 
Table 2: 
Common Treatment-emergent Adverse Events Reported in Study GS-US-339-
 
1559 Regardless of Causality ............................................................................ 22 
Table 3: 
Grade ≥3 TEAEs Reported in > 1 Subject from Study BAML-16-001-S6A ... 23 
Table 4: 
Induction Chemotherapy ................................................................................... 29 
Table 5: 
Treatment Phase –Consolidation ....................................................................... 31 
Table 6:   
Study Treatment Modifications for Non-hematologic Toxicities ..................... 40 
Table 7: 
Schedule of Assessments and Procedures ......................................................... 47 
  
List of Figures 
Figure 1: 
Expression of HOXA9 and MEIS1 mRNA in Bone Marrow Blasts From AML 
 
Patients With NPM1 Mutations vs Wild-Type NPM1 ...................................... 17 
Figure 2: 
Sensitivity of Primary Patient-derived AML Blasts to Ex Vivo Treatment With 
 
ENTO is Associated With NPM1 Mutation ...................................................... 18 
Figure 3: 
Overall Survival in Newly Diagnosed AML Patients Treated With 7+3 and 
 
ENTO Induction. ............................................................................................... 20 
Figure 4  
Treatment Phase: Cycle 1, Day 1 through Completion of Chemotherapy 
 
Cycle 2: ............................................................................................................. 30 
 






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sequencing) for correlation with morphologic 
relapse. 
• 
To further assess the pharmacokinetics (PK) of 
ENTO in combination with intensive induction 
therapy for population PK modeling. 
• 
To explore the relationship between CYP2C9 
genetic polymorphisms and ENTO exposure. 
• 
To assess the relationship (if any) between 
cytidine deaminase polymorphisms and safety 
and efficacy outcomes. 
• 
Population-based PK parameter assessment. 
• 
Identification of CYP2C9 polymorphisms and 
population-based PK analysis. 
• 
Correlation between cytidine deaminase 
polymorphisms and selected safety metrics 
and efficacy outcomes, described above. 
• 
To 
compare 
changes 
in 
quality-of-life 
measures over time among subjects treated 
with ENTO compared to placebo when added 
to intensive induction therapy in previously 
untreated NPM1-m AML. 
• 
EQ-5D-5L and EORTC-QLQ 30 over time. 
 
Overall Design: 
This will be a multi-center, international, double-blind, placebo-controlled study in previously 
untreated subjects with AML harboring NPM1 mutations. Upon fulfillment of all eligibility 
criteria, subjects will be randomized 1:1 to receive intensive chemotherapy in combination with 
either the SYK inhibitor, ENTO, or placebo. Randomization will be stratified by age (< 60 vs 
≥ 60 years) and anthracycline administered during induction (daunorubicin vs idarubicin). The 
study will consist of Screening, Induction, Consolidation, End-of-Treatment, and Long-term 
Follow-up phases. 
Subjects will undergo a screening bone marrow aspiration within 14 days prior to Cycle 1, Day 1 
(C1D1) of induction for confirmation of diagnosis, morphology assessment (spicule prep), 
detection of cytogenetic abnormalities by cytogenetics/fluorescence in situ hybridization (FISH), 
and biomarker assessments (including NPM1 and FLT3 mutation status). In cases in which an 
adequate bone marrow aspirate cannot be obtained at Screening (eg, due to dry tap, hypocellularity 
or hemodilution), a trephine bone marrow biopsy is mandated. 
ENTO (400 mg) or placebo will be administered continuously BID beginning on C1D1 of 
induction chemotherapy (Synopsis Table 1) through completion of consolidation (Synopsis 
Table 2), including while awaiting blood count recovery. 


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Synopsis Table 1: 
Induction Chemotherapy 
Age < 60 years 
Age ≥ 60 years 
Cycle 1: 
Cytarabinea 
100 mg/m2 by continuous 
infusion, Days 1-7 
100 mg/m2 by continuous 
infusion, Days 1-7 
Anthracycline 
Daunorubicin, 60 mg/m2 slow 
IV push, Days 1-3  
OR 
Idarubicin, 12 mg/m2 slow IV 
push, Days 1-3 
Daunorubicin, 60 mg/m2  
slow IV push, Days 1-3  
OR 
Idarubicin, 12 mg/m2 slow IV 
push, Days 1-3 
Cycle 2 (if administered): 
Cytarabine 
1.0 g/m2, BID Days 1-6 
1.0 g/m2, BID Days 1-6 
Anthracycline 
Daunorubicin, 60 mg/m2 slow 
IV push, Days 1-3  
OR 
Idarubicin, 12 mg/m2 slow IV 
push, Days 1-3 
N/A 
Abbreviations: BID, twice daily; IV, intravenous; N/A, not administered. 
a Subjects who are candidates for continuous infusion of cytarabine in Cycle 1 at doses higher than 100 mg/m2/day 
are ineligible. 
Subjects will undergo bone marrow examination no later than Day 42 of Induction Cycle 1 for 
assessment of response. Subjects with ≥5% residual leukemic blasts in bone marrow will receive 
Induction Cycle 2 as outlined in Synopsis Table 1, which may be administered prior to blood count 
recovery. Subjects with <5% residual blasts will receive Consolidation Cycle 1 as outlined in 
Synopsis Table 2 upon recovery of peripheral blood counts (absolute neutrophil count 
[ANC] > 1.0 x 109/L; platelet count > 100 x 109/L). After completion of Induction Cycle 2 or 
Consolidation Cycle 1 (hereafter referred to collectively as Chemotherapy Cycle 2), subjects will 
undergo bone marrow examination for assessment of remission status at the investigative site 
(bone marrow biopsy is mandated if sufficient or adequate aspirate cannot be obtained, eg, due to 
dry tap, hemodilution or hypocellularity). Bone marrow examination should await recovery of 
ANC to > 1.0 x 109/L and platelet count to > 100 x 109/L later than Day 42 of Chemotherapy Cycle 
2, unless leukemic progression is suspected. Subjects who achieve or remain in morphologic CR 
after Chemotherapy Cycle 2 will undergo MRD assessment in peripheral blood and bone marrow 
aspirate in a central laboratory designated by the Sponsor. Subjects who have not achieved 
morphologic CR after the last cycle of induction (whether it be Induction Cycle 1 or Induction 
Cycle 2) will be deemed treatment failures. Figure 4 provides a schematic representation of the 
study treatment plan from Cycle 1, Day 1 through completion of Chemotherapy Cycle 2. 
Subjects who achieve MRD negative CR status post-induction will undergo retrospective MRD 
assessments in peripheral blood every 3 months until morphologic relapse.  
All subjects who achieve morphologic CR, CRh, or CRi upon completion of Chemotherapy 
Cycle 2 may initiate or continue consolidation therapy in combination with ENTO or placebo (in 


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accordance with their original randomized treatment assignment), as outlined in Synopsis Table 2 
at the investigator’s discretion either instead of or as a bridge to hematopoietic stem cell transplant.  
 
Synopsis Table 2: 
Treatment Phase –Consolidation 
 
Age < 60 years 
Age ≥ 60 years 
Cytarabine 
3.0 g/m2, BID over 3 hours  
on Days 1, 3 and 5 every 
28-35 days for up to 
3 cycles* 
1.5 g/m2, BID over 3 hours 
on Days 1, 3 and 5 every 
28-35 days for up to 
3 cycles* 
For subjects with < 5% residual blasts post-Induction Cycle 1, Consolidation Cycle 1 will consist of Chemotherapy 
Cycle 2. For patients with ≥5% residual blasts post-Induction Cycle 1, Induction Cycle 2 will consist of 
Chemotherapy Cycle 2 (Synopsis Table 1) with consolidation beginning thereafter. All subjects are eligible to 
receive up to 3 cycles of high dose cytarabine after Chemotherapy Cycle 2.   
All subjects will undergo an End-of-Study Treatment Visit 30 ± 7 days after the last study 
treatment (either ENTO/placebo or chemotherapy, whichever is later) or prior to initiation of 
follow-on therapy (eg, maintenance therapy, HSCT), if sooner than 30 ± 7 days after last study 
treatment. 
All subjects regardless of their post-remission status will be followed monthly for 3 months after 
the End-of-Study Treatment Visit and thereafter at least once every 3 months for 
progression/relapse, first salvage therapy, and survival until study termination. Unscheduled study 
visits at other time points are permitted in the setting of suspected leukemic recurrence or for 
evaluation and management of post-treatment sequelae. 
Number of Participants: 
Approximately 180 subjects will be randomized. A sample size of 90 subjects per group will 
provide > 97% power to detect a difference in the MRD negative CR rate of 28% (87% CR 
rate x 80% MRD negativity among patients who achieve CR) = 70% for ENTO vs 70% x 60%, 
respectively = 42% for placebo) with a 2-sided alpha level of 0.05 (PASS 2008: Two sample test 
of Proportion Module). Up to 10% over enrollment is allowed in order to account for technical or 
logistical barriers (eg. inadequate bone marrow aspirate or poor sample quality) related to the 
ascertainment of MRD status in patients who achieve CR post-Chemotherapy Cycle 2. 
Study Duration: 
The study will be completed when all enrolled subjects either relapse, die, or after the last subject 
enrolled completes 5 years of follow-up, whichever is earliest.  
Statistical Analysis:  
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP).  


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Summary statistics will be used to analyze the study data. Continuous variables will be 
summarized by means, standard deviations, medians, quartiles, minimum and maximum values. 
Categorical variables will be summarized by number and percentage. Any statistical testing will 
be conducted at the alpha = 0.05 level (2-sided). 
Unless otherwise specified, data summaries and analyses described below will be reported by 
treatment group.  
The primary efficacy endpoint is the proportion of subjects who achieve CR without MRD (MRD 
negative [<0.01%] CR rate) as defined by the absence of NPM1-m alleles in bone marrow aspirate 
based on a molecular assay (eg, next generation sequencing) in a central reference laboratory 
designated by the Sponsor. The primary efficacy endpoint will be analyzed using the estimand as 
described in Section 9.4.2.1. Additional information on the handling of missing data and planned 
sensitivity measures will be detailed in the SAP. Risk difference will be estimated using stratum-
adjusted Mantel-Haenszel proportions, and 95% confidence intervals around the treatment 
differences will be calculated. The differences are weighted by the harmonic mean of the sample 
size in each treatment group per stratum (age < 60 vs ≥ 60 years; daunorubicin vs idarubicin 
anthracycline).  
Event-free survival (EFS) is defined as time from randomization to the earliest occurring date of 
induction treatment failure (ITF), relapse for those who achieve CR, or death from any cause. For 
this definition, ITF is failure to achieve morphological CR after completion of the last cycle of 
induction chemotherapy (no later than Day 42 of the last cycle of induction). 
Subjects who do not experience an event (ITF, relapse from CR, or death) will be censored at 
their last study evaluation at which they were relapse free. Event-free survival will be estimated 
using the method of Kaplan-Meier and summarized by treatment group. Differences between the 
treatment groups will be assessed with the log rank test stratified by age (<60 vs ≥60 years) and 
choice of anthracycline in induction (daunorubicin vs idarubicin). Overall survival will be 
analyzed in a similar manner. 
An independent Data Monitoring Committee (DMC), consisting of two expert hematologists, 
and one expert biostatistician, will monitor emerging safety and efficacy data from this trial on 
an ongoing basis. The DMC will provide a suitable recommendation to the Sponsor for 
appropriate study direction. Such direction may include continuation of the trial as planned, 
modification of study conduct/design or early termination for safety or futility. A DMC charter 
delineates the responsibilities of the DMC and its interactions with other trial components. Data 
monitoring committee analyses will be focused on safety and efficacy endpoints and will be 
conducted regularly as outlined in the DMC charter. 


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2.0  
Introduction 
2.1  
Acute Myeloid Leukemia - Diagnosis, Classification, Prognosis, and 
Treatment in the Frontline Setting 
Acute Myeloid Leukemia (AML) is an aggressive malignancy arising from hematopoietic 
progenitors in the bone marrow (Löwenberg 1999) and is the most common acute leukemia in 
adults, accounting for approximately 80% of cases. Clonal neoplastic myeloid progenitors 
proliferate in the bone marrow and in some cases, in extramedullary sites, causing failure of normal 
hematopoiesis and leading to cytopenias. Most patients diagnosed with AML present with 
symptoms related to bone marrow failure including fatigue, headaches, or shortness of breath from 
anemia, excessive or unexplained bleeding or bruising due to thrombocytopenia, or infections 
related to neutropenia. The categories of adult AML defined by the World Health Organization 
(WHO) include AML with recurrent genetic abnormalities, AML with myelodysplasia-related 
changes, therapy-related myeloid neoplasms, AML not otherwise specified, and myeloid sarcoma 
(Arber 2016). 
Important prognostic factors in AML include clinical variables (age, performance status, 
comorbidities, antecedent history of myelodysplastic or myeloproliferative disorder, or prior 
treatment with DNA damaging chemotherapy), as well as cytogenetic and molecular features. The 
European Leukemia Network (ELN) classifies recurring cytogenetic abnormalities and mutations 
as conferring favorable, intermediate, or adverse risk (Döhner 2017) based on their prognostic 
implications. Genetic alterations not only represent independent prognostic markers, but also may 
constitute targets for specific therapeutic intervention. The percentage of patients in each risk 
category and their 5-year overall survival (OS), based on a retrospective analysis of 1116 newly 
diagnosed AML patients treated with intensive induction chemotherapy (Herold 2020), are shown 
in Table 1. According to this analysis, approximately one-third of patients < 60 years of age in the 
favorable risk category will die of their disease within 5 years. Although this is a substantially 
superior outcome compared to patients in the intermediate or adverse risk categories, it highlights 
an urgent need for more effective therapies for AML including among favorable risk patients. 


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Table 1: 
ELN Classification of Genetic Abnormalities and Mutations by Risk 
Categories and Corresponding Five-year Survival Estimates 
Risk 
 Category 
 Genetic Abnormality 
% of Patients 
5 Year OS (%)a 
Age < 60 Age ≥ 60 Age < 60 Age ≥ 60 
Favorable 
t(8;21)(q22;q22.1); RUNX1-RUNX1T1 
inv(16)(p13.1q22) or 
t(16;16)(p13.1;q22); CBFB-MYH11; 
Mutated NPM1 without FLT3-ITD or 
with FLT3-ITDlow; biallelic mutated 
CEBPA 
41.3 
27.7 
64 
37 
Intermediate 
Mutated NPM1 and FLT3-ITDhigh; wild-
type NPM1 without FLT3-ITD or with 
FLT3-ITDlow (without adverse-risk 
genetic lesions); t(9;11)(p21.3;q23.3); 
MLLT3-KMT2A; cytogenetic 
abnormalities not classified as favorable 
or adverse 
27.6 
21.0 
42 
16 
Adverse 
t(6;9)(p23;q34.1); DEK-NUP214; 
t(v;11q23.3); KMT2A rearranged; 
t(9;22)(q34.1;q11.2); BCR-ABL1 
inv(3)(q21.3q26.2) or 
t(3;3)(q21.3;q26.2); 
GATA2,MECOM(EVI1);-5 or del(5q); -7; 
-17/abn(17p); complex karyotype, 
monosomal karyotype; wild-type NPM1 
and FLT3-ITDhigh; Mutated RUNX1; 
Mutated ASXL1; Mutated TP53 
31.1 
51.3 
20 
6 
Abbreviations: ELN, The European Leukemia Network; ITD, internal tandem duplication; OS, overall survival. 
a Source: Herold 2020 
Frontline treatment for newly diagnosed AML is based on the age and fitness of subjects, or the 
presence or absence of comorbidities, and generally includes a remission induction phase, 
followed by a consolidation phase. Standard induction chemotherapy for subjects < 60 years old 
and older fit subjects typically involves 1 cycle of cytarabine administered by continuous infusion 
over 7 days plus 3 consecutive days of an anthracycline, such as daunorubicin or idarubicin (7 + 3). 
In the US, subjects with residual leukemia post-induction Cycle 1 generally receive a second 
induction cycle consisting of cytarabine (either by bolus or continuous infusion) with or without 
additional anthracycline. Elsewhere, “double induction” (ie, 2 cycles of induction for all subjects 
without regard for remission status post-induction Cycle 1) is generally the norm. The goal of 
induction is to achieve a complete response (CR), defined as fewer than 5% blasts in the bone 
marrow and recovery of normal hematopoiesis. CR rates after intensive induction chemotherapy 


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generally range from 40 to 60% in older adults (≥ 60 years of age); rates as high as 80% have been 
reported in younger subjects with favorable prognostic features (Döhner 2017). Subjects who fail 
to achieve a CR have a very grim prognosis with a 4-year survival of 23% (Othus 2015). For 
subjects who achieve CR, the standard of care typically includes consolidation chemotherapy, 
generally consisting of age-adjusted, intermediate, or high dose cytarabine, with or without 
additional anthracycline, or allogeneic hematopoietic stem cell transplantation (HSCT) if a suitable 
donor is available.  
Elderly subjects (> 75 years of age) or younger subjects with comorbidities are generally not 
considered candidates for intensive induction and consolidation due to high risk of treatment-
related morbidity and mortality. Therapeutic options for these subjects have historically been 
limited to low dose cytarabine with an associated CR rate of 13% and median overall survival 
(OS) of 4.9 months, or hypomethylating agents such as 5-azacytidine (AZA) or 5-aza-2-
deoxycytidine (DAC) with a 25% to 30% CR rate and median OS less than one year (Walter 2015). 
The outlook for older AML patients has improved with the recent approval of the BCL-2 inhibitor, 
VENCLEXTA (venetoclax), and the inhibitor of the smoothened transmembrane protein, 
DAURISMO (glasdegib). The combination of venetoclax and AZA resulted in a composite CR 
rate of 66.4% and a median OS of 14.7 months and is rapidly becoming the standard of care for 
newly diagnosed, elderly or unfit AML patients (DiNardo 2020). DAURISMO when added to low 
dose cytarabine led to a CR rate of 18% and median OS of 8.3 months (DAURISMO US 
prescribing information). 
NPM1-mutated AML: Effects on Expression of HOXA9/MEIS1 Transcription Factors 
The nucleophosmin-1 (NPM1) gene encodes a protein that shuttles between the nucleus and the 
cytoplasm, and plays a key role in histone chaperoning, centrosome duplication, and ribosome 
biogenesis. Mutations in NPM1 cause a reading frame shift that creates an aberrant cytoplasmic 
localization signal peptide at its carboxyl terminus (Falini 2020). These are founder mutations in 
the leukemogenic pathway, detected exclusively in the leukemic clone and not in normal 
progenitors or mature hematopoietic precursors, and nearly always retained at the time of relapse. 
Cytoplasmic NPM1 sequesters the myeloid lineage master transcription factor PU.1 away from the 
nucleus, resulting in transcriptional repression of granulocyte and monocyte differentiation 
programs (Gu 2018). One of the consequences of cytoplasmic NPM1 is the persistent epigenetic 
activation of the genes for the homeodomain-containing transcription factors, HOXA9 and MEIS1 
via their super enhancers (Brunetti 2018). HOXA9 and MEIS1 function together to drive a gene 
expression program that defines primitive myeloid progenitors (Collins and Hess 2016). As these 
progenitors differentiate into mature myeloid cells, the expression of HOXA9 and MEIS1 is 
normally downregulated. Through a variety of mechanisms, this downregulation fails to occur in 
subjects with NPM1-mutated AML. As a consequence, NPM1 mutations are associated with 
consistently high expression levels of HOXA9 and MEIS1 (Tyner 2018; Figure 1) resulting in 
perpetuation of the primitive myeloid progenitor phenotype. Reports have demonstrated that the 
overexpression of HOXA9/MEIS1 is an adverse prognostic marker in AML (Gao 2016; 
Zangenberg 2009).  


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Figure 1: 
Expression of HOXA9 and MEIS1 mRNA in Bone Marrow Blasts From 
AML Patients With NPM1 Mutations vs Wild-Type NPM1  
 
Abbreviations: AML, acute myeloid leukemia; mRNA, messenger RNA; NPM1, Nucleophosmin 1; RPKM, reads per 
kilobase mapped.  
Gene expression data from Tyner 2018. NPM1 mutations (blue box and whiskers) vs wild-type NPM1 (gray box and 
whiskers).  
High HOXA9/MEIS1 Expression Creates a Dependence on Spleen Tyrosine Kinase  
Spleen tyrosine kinase (SYK), a nonreceptor tyrosine kinase expressed in hematopoietic cells, is 
involved in cellular proliferation, differentiation, and survival (Ruzza 2009). The loss of SYK 
expression in AML cell lines is associated with differentiation and expression of mature myeloid 
cell surface markers, suggesting that SYK plays a role in counteracting the differentiation of 
leukemic cells (Hahn 2009).  
Multiple converging lines of evidence support the hypothesis that high HOXA9 and MEIS1 
expression in AML creates a dependence on SYK signaling that can be exploited therapeutically. 
A comparison of AML proteomes with normal or high expression of HOXA9 and MEIS1 revealed 
that SYK protein was significantly more abundant in AML blasts with high HOXA9/ MEIS1 
expression (Mohr 2017). Moreover, there was an increase in SYK activation as a result of MEIS1 
driven Fc receptor and integrin-related signaling. This aberrant SYK signaling acts to drive the 
expression of genes necessary for cytokine independent growth and reinforces the MEIS1 driven 
gene expression program through a positive feedback loop. The first-generation SYK inhibitor, 


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R788 (fostamatinib), was shown to have anti-leukemic activity and prolong survival in mouse 
models of HOXA9/MEIS1 driven AML, including in patient-derived xenograft models. A 
publication from the Leukemia and Lymphoma Society’s (LLS) Beat AML program explicitly 
established the link between NPM1 mutation and dependency on SYK (Tyner 2018). 
2.2 
Preclinical and Clinical Rationale for the Investigation of Entospletinib 
in NPM1-mutated AML 
Entospletinib (ENTO, formerly GS-9973) is a second generation, orally administered, selective 
ATP-competitive inhibitor of SYK. Kinase selectivity profiling has shown > 14-fold selectivity of 
ENTO for SYK vs other kinases compared with the less selective SYK inhibitor, fostamatinib 
(Braselmann 2006). In the aforementioned LLS study (Tyner 2018), bone marrow specimens from 
572 newly diagnosed AML patients were genomically and transcriptomically profiled and tested 
ex vivo for sensitivity to 122 small molecule drugs including ENTO. Sensitivity to ENTO showed 
a statistically significant correlation with the presence of NPM1 mutations (Figure 2). 
 
Figure 2: 
Sensitivity of Primary Patient-derived AML Blasts to Ex Vivo Treatment 
With ENTO is Associated With NPM1 Mutation  
Abbreviations: AML, acute myeloid leukemia; ENTO, entospletinib; NPM1, Nucleophosmin 1 


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Note: X-axis is the fold change in sensitivity of the mutant vs the wild-type. The Y-axis shows the -log10 of the t-test 
False Discovery Rate-corrected p-value comparing drug response for the mutant vs wild-type subjects (Leukemia and 
Lymphoma Society Beat AML program, Brian Druker, personal communication). 
Phase 1b/2 Study of ENTO in AML (Study GS-US-339-1559) 
Between July 2015 and September 2019, a Phase 1b/2 Study of ENTO in AML (GS-US-339-1559, 
NCT 02343939) enrolled 148 subjects in the US, Canada, and Germany into 3 treatment groups. 
One arm of this trial (Arm A) enrolled 53 previously untreated AML patients who were eligible 
for intensive induction. The median age for this cohort was 60 years and 30 subjects (57%) were 
in the ELN intermediate II or adverse prognostic category. Fourteen subjects, including 6 of 15 
subjects with NPM1 mutations had secondary AML. Subjects received a course of ENTO 
monotherapy for a 14-day lead-in period followed by the combination of ENTO with continuous 
infusion cytarabine for 7 consecutive days plus bolus daunorubicin for 3 consecutive days (7 + 3) 
induction and high-dose cytarabine consolidation. Doses of 200 mg twice daily (BID) and 400 mg 
BID were evaluated in the Phase 1b portion of the study (N = 12). ENTO was generally well-
tolerated in combination with intensive induction chemotherapy. A maximally tolerated dose was 
not defined (there were no dose-limiting toxicities at either dose tested) and 400 mg BID was 
selected for study in the Phase 2 portion (N = 41) based on the limited incremental exposure at 
higher doses in earlier studies.  
All 53 subjects across the Phase 1b and Phase 2 portions of the study were considered evaluable 
for efficacy. Thirty-seven subjects (70%) subjects achieved a CR or CR with incomplete recovery 
of neutrophil or platelet counts (CRi), including 13 of 15 NPM1-mutated subjects (87%). Among 
10 subjects with rearrangement of the MLL gene (MLL-r), a mutation also associated with high 
baseline expression of HOXA9 and MEIS1, 9 (90%) experienced a CR or CRi, including one 
patient who achieved a cytogenetic and morphologic CR after the ENTO monotherapy lead-in 
period. In contrast, the CR + CRi rate for the remaining 28 MLL and NPM1 wild-type subjects was 
54%. An exploratory retrospective analysis of HOXA9 and MEIS1 mRNA levels at baseline was 
performed for 34 subjects with available samples. Subjects with expression levels of 
HOXA9/MEIS1 above the median for the overall group experienced superior overall survival 
compared to those with expression levels below the median (hazard ratio, 0.32; 95% confidence 
intervals, 0.100 to 0.997, p = 0.038) (Figure 3). Despite the small sample size and single-arm 
design of this study, higher CR/CRi rates in NPM1-mutated subjects and superior overall survival 
in the HOXA9/MEIS1 high expressing subset are consistent with the hypothesis that SYK is a 
therapeutic dependency in this subset of AML and warrants further study. 
The combination of ENTO with 7 + 3 induction and high dose cytarabine consolidation was 
generally well-tolerated with skin rash, liver transaminase elevations, and indirect 
hyperbilirubinemia being the most commonly reported ENTO-related toxicities (Section 2.4; 
Walker 2020).  
 
 


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Figure 3: 
Overall Survival in Newly Diagnosed AML Patients Treated With 7+3 and 
ENTO Induction. 
Abbreviations: AML, acute myeloid leukemia; ENTO, entospletinib 
Note: K-M curve in gray represents all 34 subjects. Light blue line represents subjects with HOXA9/MEIS1 mRNA 
expression above the median level of expression (N = 17). The pink line is subjects with expression below the median 
(N = 17). OS is censored on the last date the subject was known to be alive (Walker 2020). 
Phase 2 Study of ENTO in NPM1-mutant/FLT-3 Wild -Type AML Patients (Study BAML-
16-001-S6) 
The activity of ENTO is currently being evaluated in the LLS Beat AML Master Trial, BAML-
16-0001 (NCT03013998). This biomarker-based trial of newly diagnosed AML assigns subjects 
to treatment arms on the basis of their mutational profiles or other features.  
Substudy 6, Cohort A (S6A) of this master protocol is evaluating the efficacy and safety of ENTO 
in subjects with NPM1-mutated/FLT3 wild-type AML at a dose of 400 mg BID in combination 
with intensive induction therapy (7 + 3). Cohort 6A uses a Simon 2-stage design to reject the null 
hypothesis of a composite CR rate (CR + CR with partial hematologic recovery [CRh] + CR with 
incomplete hematologic recovery [CRi]) of 65% versus an alternative composite CR rate of 85%. 
To date, the safety profile of ENTO with 7 + 3 in this study has been generally consistent with that 
reported in the above-described GS-US-339-1559 study (Section 2.4).  


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2.3 
Study Rationale 
Given the role of SYK signaling in HOXA9/MEIS1-driven leukemic cell proliferation, the 
association between NPM1 mutation and HOXA9/MEIS1 dysregulation, and the preliminary 
promising results in early phase studies, the Sponsor will evaluate the efficacy and safety of ENTO 
in combination with intensive induction and consolidation chemotherapy in previously untreated 
AML patients with mutations in NPM1.  
2.4 
Benefit/Risk Assessment 
NPM1-mutated AML constitutes a genetically defined subset of AML comprising approximately 
30% of newly diagnosed subjects and is recognized as a distinct disease entity in the 2017 WHO 
classification of myeloid neoplasms and acute leukemia (Patel 2012, Arber 2016). NPM1 mutation 
is commonly associated with normal cytogenetics in subjects < 60 years of age. In the absence of 
concurrent FLT-3 internal tandem duplication (ITD) (or presence at low allelic ratio), or other 
adverse cytogenetic abnormalities, subjects with NPM1 mutation are thought to be in the favorable 
risk category (Table 1) with CR rates of 86 to 88% with current standards of care (Angenendt 
2019). Concurrent FLT-3 ITD at high allelic ratio confers ELN intermediate risk status (Patel 2012, 
Dohner 2017). NPM1-mutated AML patients with additional adverse cytogenetic features are 
usually older than 60 years of age and/or have a history of myelodysplastic syndrome, and poorer 
prognosis with CR rates of 66.3% and a 5-year OS of 19.5% (Angenendt 2019).  
As of 31 January 2021, 20 clinical studies of ENTO have been conducted in which approximately 
1259 subjects received ENTO either alone or in combination with other agents. Detailed 
descriptions of ENTO clinical studies conducted to date including results, where available, may 
be found in the Investigator’s Brochure (Section 4.0, Clinical Studies). 
In the GS-US-339-1559 study, ENTO alone or in combination with 7 + 3 chemotherapy was 
generally well-tolerated. Most treatment-emergent adverse events (TEAEs) were consistent with 
those expected following treatment with intensive induction and consolidation chemotherapy as 
well as from complications of underlying AML. Commonly reported TEAEs/laboratory 
abnormalities are listed in Table 2.  


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Table 2: 
Common Treatment-emergent Adverse Events Reported in Study GS-US-
339-1559 Regardless of Causality  
TEAEs 
Total  
n (%) 
Grade 3 or 4 
n (%) 
Any TEAE  
53 (100) 
53 (100) 
Nonhematologic AEs/laboratory abnormalities reported in > 25% of subjects 
Nausea 
37 (70) 
1 (2) 
Diarrhoea 
35 (66) 
5 (9) 
Oedema peripheral 
31 (59) 
0 
Alanine aminotransferase increased 
30 (57) 
3 (6) 
Blood bilirubin increased 
26 (49) 
6 (11) 
Rash (maculopapular) 
23 (43) 
7 (13) 
Decreased appetite 
22 (42) 
2 (4) 
Constipation 
21 (40) 
0 
Headache  
21 (40) 
0 
Dyspnoea  
20 (38) 
2 (4) 
Aspartate aminotransferase increased  
19 (36) 
2 (4) 
Cough  
18 (34) 
0 
Vomiting  
18 (34) 
0 
Chronic kidney disease (decreased creatinine clearance) 
17 (32) 
1 (2) 
Hypokalaemia  
16 (30) 
1 (2) 
Insomnia  
16 (30) 
0 
Fatigue  
15 (28) 
3 (6) 
Abdominal pain  
14 (26) 
0 
Creatinine increased 
14 (26) 
3 (6) 
Dizziness  
14 (26) 
0 
Hematologic AEs/laboratory abnormalities in > 25% of subjects 
WBC count decreased  
49 (92) 
49 (92) 
Febrile neutropenia  
44 (83) 
44 (83) 
Platelet count decreased  
41 (77) 
41 (77) 
Lymphocyte count decreased  
34 (64) 
17 (32) 
Anaemia  
28 (53) 
28 (53) 
Neutrophil count decreased  
19 (36) 
19 (36) 
Abbreviations: AE: adverse event; TEAE, treatment-emergent adverse events; WBC, white blood cell. 
Source: Walker 2020 
Grade ≥ 3 nonhematologic TEAEs reported in > 10% of study subjects included lung infection 
(n = 11, 21%), device-related infection (n = 9, 17%), hypoxia (n = 9, 17%), maculopapular rash 
(n = 7, 13%), hypertension (n = 6, 11%), and hyperbilirubinemia (n = 6, 11%).  


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Any grade rash was observed in 23 (43%) subjects (Table 2) including grade 3 rash in seven (13%) 
subjects. The rash was characterized as erythematous, diffuse, and morbilliform. Withholding 
ENTO improved the rash to Grade 1 within 10 days. Topical steroids and additional supportive 
care were used as deemed appropriate. The rash recurred in one of four subjects after rechallenge 
leading to discontinuation of ENTO. Hyperbilirubinemia was predominantly indirect, consistent 
with ENTO’s known inhibitory effects on UDP-glucuronosyltransferase 1A1 (UGT1A1) leading 
to reversible increases in unconjugated bilirubin. Both rash and indirect hyperbilirubinemia were 
attributed to ENTO (Walker 2020). 
Interim results from 26 patients treated with the combination of ENTO with 7 + 3 induction 
enrolled in the ongoing Study BAML-16-001-S6 (Cohort A) are also available through 01 October 
2021. The median (range) duration of ENTO exposure for this cohort is 118 days (10, 613). The 
composite CR rate is 76% based on 25 patients evaluable for response. Safety data are generally 
consistent with those reported for Study GS-US-339-1559. Table 3 lists Grade ≥ 3 TEAEs reported 
in more than 1 subject. Two subjects experienced Grade 5 events, cerebrovascular accident and 
intracranial hemorrhage occurred in 1 subject each. 
 
Table 3: 
Grade ≥3 TEAEs Reported in > 1 Subject from Study BAML-16-001-S6A 
 No. of treated patients, n (%) 
26 (100) 
Any Grade ≥ 3 TEAE  
21 (81) 
Nonhematologic TEAEs/laboratory abnormalities 
Device-related infection 
3 (12) 
Blood bilirubin increased 
5 (19) 
Sinusitis 
2 (8) 
Hyponatremia 
3 (12) 
Hypophosphatemia 
4 (15) 
Alanine aminotransferase increased 
2 (8) 
Alkaline phosphatase increased 
2 (8) 
Hypokalaemia 
3 (12) 
Sepsis 
2 (8) 
Hematologic TEAEs/laboratory abnormalities 
Febrile neutropenia 
13 (50) 
Anemia 
9 (35) 
Platelet count decreased 
8 (31) 
White blood cell count decreased 
9 (35) 
Neutrophil count decreased 
6 (23) 
Neutropenia 
4 (15) 
Thrombocytopenia 
3 (12) 
Lymphocyte count decreased 
5 (19) 
Leukopenia 
2 (8) 
Abbreviations: TEAE, treatment-emergent adverse events. 


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In summary, both the spectrum and frequency of TEAEs reported in association with the 
combination of ENTO and 7 + 3 induction and cytarabine consolidation were generally as 
expected for the underlying disease and treatment with intensive induction/consolidation 
chemotherapy. Rash, indirect hyperbilirubinemia, and transaminase elevations are specifically 
attributed to ENTO (Investigator’s Brochure, Section 6.2.5). Toxicities observed to date with 
ENTO plus intensive induction/consolidation can be readily monitored and managed with close 
attention to standard safety assessments (eg, blood counts, electrolytes, liver function studies, fluid 
and electrolyte balance, and careful surveillance, treatment, and follow-up for infectious 
complications). The type and frequency of safety assessments described for the proposed study 
have been modeled to conform with those employed in Study GS-US-339-1559 and are in 
accordance with National Comprehensive Cancer Network (NCCN) supportive care 
recommendations. All are generally consistent with the standards of care for newly diagnosed 
AML patients undergoing intensive induction and consolidation chemotherapy. 
Considering measures that are undertaken to minimize the risk to prospective study subjects, the 
potential risks identified in association with the combination of ENTO and intensive induction and 
consolidation chemotherapy are justified by the anticipated benefits that may be afforded to 
subjects with NPM1-mutated AML. 
More detailed information about the known expected adverse drug reactions of ENTO may be 
found in the Investigator’s Brochure (Section 6.1.2.2; Section 6.2). 
2.4.1 
COVID-19 Considerations 
Patients undergoing systemic chemotherapy for cancer and leukemia have an increased risk of 
severe complications, some leading to death, following infection with coronavirus disease 2019 
(COVID-19). This includes patients who have been fully vaccinated against the virus. The extent 
(if any) to which concurrent treatment with ENTO may increase the magnitude of risk is 
currently unknown. Prospective trial subjects including those who have been vaccinated against 
COVID-19, should be counseled to employ social distancing measures including the regular use 
of face coverings and avoidance of indoor congregant environments, especially those that 
include others for whom the vaccination and/or COVID-19 infection status are unknown.  
Consult Appendix 9 for additional risk mitigation procedures potentially associated with clinical 
trial conduct in the COVID-19 pandemic era. 
 






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Questionnaire-Core 30; EQ-5D-5L, European Quality of Life 5 Dimensions Questionnaire; MRD, measurable residual 
disease; MUGA, multi-gated acquisition; NPM1-m, nucleophosmin-1 mutated; PK, pharmacokinetics; pSYK, 
phosphorylated spleen tyrosine kinase. 


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4.0 
Study Design 
 
4.1 
Overall Design 
This will be a multi-center, international, double-blind, placebo-controlled study in previously 
untreated subjects with AML harboring NPM1 mutations. Upon fulfillment of all eligibility 
criteria, subjects will be randomized 1:1 to receive intensive chemotherapy in combination with 
either the SYK inhibitor, ENTO, or placebo. Randomization will be stratified by age (< 60 vs 
≥ 60 years) and anthracycline administered during induction (daunorubicin vs idarubicin). The 
study will consist of Screening, Induction, Consolidation, End-of-Treatment, and Long-term 
Follow-up phases. 
Subjects will undergo a screening bone marrow aspiration within 14 days prior to Cycle 1, Day 1 
(C1D1) of induction for confirmation of diagnosis, morphology assessment (spicule prep), 
detection of cytogenetic abnormalities by cytogenetics/fluorescence in situ hybridization (FISH), 
and biomarker assessments (including NPM1 and FLT3 mutation status). In cases in which an 
adequate bone marrow aspirate cannot be obtained at Screening (eg, due to dry tap, hypocellularity 
or hemodilution), a trephine bone marrow biopsy is mandated.  
NPM1 and FLT3 mutational status will be assessed in a central laboratory designated by the 
sponsor. Mutation results obtained during a patient’s routine diagnostic workup by the 
investigational site will be accepted for enrollment purposes as long as an appropriate sample is 
provided to the central testing facility selected by the Sponsor for companion diagnostic 
development AND the site can provide appropriate documentation pertaining to local assay 
performance characteristics and test validation prior to initiating enrollment in the study. 
ENTO (400 mg) or placebo will be administered continuously BID beginning on C1D1 of 
induction chemotherapy (Table 4) through completion of consolidation (Table 5), including while 
awaiting blood count recovery.  


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Table 4: 
Induction Chemotherapy 
 
Age < 60 years 
Age ≥ 60 years 
Cycle 1: 
Cytarabinea 
100 mg/m2 by continuous 
infusion, Days 1-7 
100 mg/m2 by continuous 
infusion, Days 1-7 
Anthracycline 
Daunorubicin, 60 mg/m2 slow 
IV push, Days 1-3  
OR 
Idarubicin, 12 mg/m2 slow IV 
push, Days 1-3 
Daunorubicin, 60 mg/m2  
slow IV push, Days 1-3  
OR 
Idarubicin, 12 mg/m2 slow IV 
push, Days 1-3 
Cycle 2 (if administered): 
Cytarabine 
1.0 g/m2, BID Days 1-6  
1.0 g/m2, BID Days 1-6  
Anthracycline 
Daunorubicin, 60 mg/m2 slow 
IV push, Days 1-3  
OR 
Idarubicin, 12 mg/m2 slow IV 
push, Days 1-3 
N/A 
Abbreviations: BID, twice daily; IV, intravenous; N/A, not administered. 
a Subjects who are candidates for continuous infusion of cytarabine in Cycle 1 at doses higher than 100 mg/m2/day 
are ineligible. 
Subjects will undergo bone marrow examination no later than Day 42 of Induction Cycle 1 for 
assessment of response.  Subjects with ≥5% residual leukemic blasts in bone marrow will receive 
Induction Cycle 2 as outlined in Table 4, which may be administered prior to blood count recovery. 
Subjects with <5% residual blasts will receive Consolidation Cycle 1 as outlined in Table 5 upon 
recovery of peripheral blood counts (absolute neutrophil count [ANC] > 1.0 x 109/L; platelet count 
> 100 x 109/L). After completion of Induction Cycle 2 or Consolidation Cycle 1 (hereafter referred 
to collectively as Chemotherapy Cycle 2), subjects will undergo bone marrow examination for 
assessment of remission status at the investigative site (bone marrow biopsy is mandated if 
sufficient or adequate aspirate cannot be obtained, eg, due to dry tap, hemodilution or 
hypocellularity). Bone marrow examination should await recovery of ANC to > 1.0 x 109/L and 
platelet count to > 100 x 109/L no later than Day 42 of Chemotherapy Cycle 2, unless leukemic 
progression is suspected. Subjects who achieve or remain in morphologic CR after Chemotherapy 
Cycle 2 will undergo MRD assessment in peripheral blood and bone marrow aspirate in a central 
laboratory designated by the Sponsor. Subjects who have not achieved morphologic CR after the 
last cycle of induction (whether it be Induction Cycle 1 or Induction Cycle 2) will be deemed 
treatment failures. Figure 4 provides a schematic representation of the study treatment plan from 
Cycle 1, Day 1 through completion of Chemotherapy Cycle 2. 


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Figure 4  
Treatment Phase: Cycle 1, Day 1 through Completion of Chemotherapy 
Cycle 2: 
 
Subjects who achieve MRD negative CR post-Chemotherapy Cycle 2 will undergo retrospective 
MRD assessments in peripheral blood every 3 months until morphologic relapse.  
All subjects who achieve morphologic CR, CRh, or CRi upon completion of Chemotherapy 
Cycle 2 may initiate or continue consolidation therapy in combination with ENTO or placebo (in 
accordance with their original randomized treatment assignment), as outlined in Table 5 at the 
investigator’s discretion either instead of or as a bridge to hematopoietic stem cell transplant.  


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Table 5: 
Treatment Phase –Consolidation 
 
Age < 60 years 
Age ≥ 60 years 
Cytarabine 
3.0 g/m2, BID over 3 hours  
on Days 1, 3 and 5 every 
28-35 days for up to 
3 cycles* 
1.5 g/m2, BID over 3 hours 
on Days 1, 3 and 5 every 
28-35 days for up to 
3 cycles* 
For subjects with < 5% residual blasts post-Induction Cycle 1, Consolidation Cycle 1 will consist of Chemotherapy 
Cycle 2. For patients with ≥5% residual blasts post-Induction Cycle 1, Induction Cycle 2 (Table 4) will consist of 
Chemotherapy Cycle 2 with consolidation beginning thereafter. All subjects are eligible to receive up to 3 cycles of 
high dose cytarabine after Chemotherapy Cycle 2.    
All subjects will undergo an End-of-Study Treatment Visit 30 ± 7 days after the last study 
treatment (either ENTO/placebo or chemotherapy, whichever is later) or prior to initiation of 
follow-on therapy (eg, maintenance therapy, HSCT), if sooner than 30 ± 7 days after last study 
treatment. 
All subjects regardless of their post-remission status will be followed monthly for 3 months after 
the End-of-Study Treatment Visit and thereafter at least once every 3 months for 
progression/relapse, first salvage therapy, and survival until study termination. Unscheduled study 
visits at other time points are permitted in the setting of suspected leukemic recurrence or for 
evaluation and management of post-treatment sequelae. 
4.2 
Justification for Dose of ENTO 
The dose of ENTO that will be investigated in this study is 400 mg orally (PO) every 12 hours, 
consistent with that employed in aforementioned early phase studies in AML (see Section 2.2).  
Pharmacokinetic (PK) data derived from healthy volunteers demonstrated significantly less than 
dose-proportional increases in exposure when comparing 800 mg and 400 mg BID dosing 
schedules, suggesting a plateau in exposures that is likely due to solubility-limited absorption of 
ENTO. The median maximal concentration (Cmax) and area under the concentration time curve at 
steady state (AUCss) were approximately 30% and 23% higher when comparing 800 mg BID with 
400 mg BID doses, respectively, in healthy subjects.  
Preliminary safety exposure-response analyses, which included a total of 191 subjects from Studies 
GS-US-339-0102 in subjects with relapsed or refractory hematologic malignancies (Section 4.2.1 
of the IB) and GS-US-339-1559, who received ENTO monotherapy or in combination with 7 + 3 
chemotherapy, showed that the exposure distributions were similar in subjects who experienced 
any grade adverse events (AEs), except for a higher median AUCss observed in subjects with any 
grade alanine aminotransferase increase or hyperbilirubinemia. Since ENTO is an inhibitor of the 
UGT1A1 enzyme, the Sponsor investigated the exposure-response relationship between the 
maximal change from baseline in total bilirubin, and the maximal and minimal change from 
baseline in direct bilirubin. While there was no clear exposure-response relationship for the 
minimal or maximal change from baseline in direct bilirubin, exploratory modeling suggests that 
a linear exposure-response relationship exists between ENTO AUC and the maximal change from 


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baseline in total bilirubin, consistent with the effects of UGT1A1 inhibition on the levels of indirect 
(unconjugated) bilirubin. These observations are consistent with an earlier analysis in chronic 
lymphocytic leukemia subjects, where no clinically relevant trends were observed between ENTO 
exposure and safety (either clinical adverse events or laboratory abnormalities), except for a trend 
towards higher total bilirubin levels with higher ENTO exposures (Gupta 2017).  
In the Phase 1 study GS-US-245-0101 in healthy volunteers and subjects with rheumatoid arthritis 
(Section 4.1.1. of the IB), increasing pharmacodynamic modulation of CD63 and pSYK (Y525) 
was observed with increasing dose and ENTO exposures until reaching a plateau in exposure in 
healthy volunteers. 
4.3 
End of Study Definition 
The study will be completed when all enrolled subjects either relapse, die, or after the last subject 
enrolled completes 5 years of follow-up, whichever is earliest. 


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5.0 
Study Population 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Adults 18 to 74 years with previously untreated de novo AML, AML with MDS features, 
or therapy-related AML, who are candidates for intensive induction therapy. 
2. NPM1-mutated disease documented in a local or the Sponsor’s central testing facility.  
Note: Subjects with local test results for NPM1-m (and/or FLT3 mutational status) may 
enroll, provided appropriate samples are sent to the Sponsor’s central testing facility for 
NPM1-m companion diagnostic development (see Section 4.1).  
3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0, 1, or 
2. 
4. Adequate hepatic and renal function defined as:  
a. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 
times the upper limit of normal (ULN), except those with hepatic involvement by 
AML, as documented by either computed tomography (CT) or ultrasound, in whom 
levels of AST and ALT < 5 times ULN are acceptable; total bilirubin < 1.5 times 
ULN unless elevated due to Gilbert’s Disease or hemolysis. 
b. Calculated creatinine clearance > 40 mL/min or serum creatinine < 1.5 times ULN. 
5. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international 
normalized ratio (INR) ≤ 1.5 x ULN unless receiving therapeutic anticoagulation. Note: 
Transition from a Vitamin K or Factor Xa antagonist to a low-molecular weight heparin 
preparation is recommended prior to the start of induction chemotherapy (see Appendix 
8 for guidelines on anticoagulation management). 
6. Left ventricular ejection fraction ≥ 45% confirmed by echocardiogram (ECHO) or 
multi-gated acquisition (MUGA) scan. 
7. Negative serum ß-HCG test in women of childbearing potential (WOCBP). 
8. For WOCBP, willingness to abstain from heterosexual intercourse OR to use a protocol-
recommended method of contraception from 7 days prior to C1D1 throughout the study 
treatment period and for 90 days following the last dose of ENTO/placebo or as 
recommended in the prescribing information for other co-administered study drugs 
(whichever is later). See Appendix 3 for contraceptive guidance. 
9. For male subjects with female sexual partners of childbearing potential, willingness to 
abstain from heterosexual intercourse OR use a protocol recommended method of 
contraception beginning 7 days prior to C1D1 throughout the study treatment period and 
for 90 days following the last dose of ENTO/placebo or as recommended in the 
prescribing information for other co-administered study drugs (whichever is later), AND 
to refrain from sperm donation from the start of study treatment throughout the study 


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treatment period and for 90 days following the last dose of ENTO/placebo or as 
recommended in the prescribing information for other co-administered study drugs 
(whichever is later). See Appendix 3 for contraceptive guidance. 
10. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
11. Willingness to comply with scheduled study visits, procedures, and treatment plan. 
 
 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. Isolated myeloid sarcoma (ie, participants must have peripheral blood and/or bone 
marrow involvement by AML) or acute promyelocytic leukemia. 
2. Concurrent FLT3 mutation (either TKD or ITD). 
3. Known central nervous system (CNS) involvement with leukemia. 
4. Is a candidate for more intensive treatment than specified in this protocol. 
5. Either not a candidate for any anthracycline therapy or a candidate for induction therapy 
with a higher dose of daunorubicin (eg. 90 mg/m2). 
6. Is a candidate for daily doses of cytarabine > 100 mg/m2 in Induction Cycle 1. 
7. Active infection with hepatitis B, C, or uncontrolled human immunodeficiency virus 
(HIV). 
Note: Subjects who are positive for hepatitis B surface antigen (HBsAg) are ineligible. 
Those who are seropositive for hepatitis B core antibody (anti-HBc) may enroll but must 
agree to receive hepatitis B virus (HBV) prophylaxis during the study treatment period 
and undergo regular surveillance for HBV reactivation at least once every 3 months. 
Subjects who have received curative therapy for prior HCV infection and who are 
seropositive for hepatitis C antibody (anti-HCV), may enroll, however must undergo 
regular surveillance monitoring for HCV reactivation. 
Note:  At the discretion of the investigator and in accordance with institutional as well as 
local health authority guidelines and regulations regarding participation of HIV + 
patients in clinical trials, HIV + patients may enroll in this study if all of the following 
parameters are fulfilled: 
• CD4+ lymphocyte count >350 cells/µL 
• 
Patient is receiving highly active antiretroviral therapy (HAART) for a period of at 
least 4 weeks prior to initiation of study treatment AND has an HIV viral load of 
<400 viral copies/mL. 


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• Commitment by the patient to continue HAART for the duration of study treatment. 
Please note that components of some anti-retroviral therapy combinations may 
pose a risk for drug interactions with ENTO.  For example, combinations that include 
ritonavir may not be concurrently administered with ENTO because ritonavir is a 
moderate inducer of CYP2C9.  Since CYP3A is a minor pathway for ENTO metabolism, 
concurrent use of HAART combinations that include cobicistat are allowed.  Before 
considering an HIV + patient who meets the above entry criteria for enrollment, 
investigators are encouraged to consult with either the Sponsor or a pharmacist at their 
institution in order to ensure that potential trial subjects are not subjected to the risk of 
unwanted interactions between the study medication and the patient’s anti-retroviral 
therapy. 
8. Known active coronavirus disease 2019 (COVID-19) either symptomatic or 
asymptomatic, as determined by nasopharyngeal swab for severe acute respiratory 
syndrome (SARS) coronavirus 2 (SARS CoV-2) RNA or antigen. 
Note: Subjects with a history of SARS-CoV-2 nasopharyngeal carriage (either with or 
without symptoms), who have subsequently tested negative on follow-up 
nasopharyngeal swab and are without signs or symptoms of COVID-19 may enroll. 
Subjects who are fully vaccinated against SARS-CoV-2 may enroll.  
9. Disseminated intravascular coagulation with active bleeding or signs of thrombosis. 
10. History of prior allogeneic hematopoietic stem cell transplant or solid organ transplant. 
11. History of non-myeloid malignancy except for the following: adequately treated 
localized 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 (which 
may be continued while on study) and with normal prostate specific antigen for > 1 year 
prior to start of study therapy; or any other cancer that has been in complete remission 
without treatment for ≥ 3 years prior to enrollment. 
Note: Subjects who are on adjuvant hormonal therapy and ≥ 3 years from definitive 
therapy for their primary tumor are eligible to enroll. 
12. Current (within 30 days of study enrollment) drug-induced liver injury, chronic active 
hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cholangitis 
with inadequate response to ursodeoxycholic acid or other health-authority approved 
therapy, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal 
hypertension. 
13. Ongoing (within 6 weeks of study enrollment) hepatic encephalopathy. 
14. Treatment with proton pump inhibitors (PPIs) from 7 days prior to enrollment until 48 
hours after completion of ENTO or placebo.  
Note: PPIs are likely to interfere with ENTO absorption, thus requiring a 7-day washout 
period prior to the initiation of study medication. For management of acute 
gastrointestinal bleeding during the study treatment period (such as that related to 


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chemotherapy), short term concurrent use of PPIs is permitted for up to 10 consecutive 
days. If longer durations of PPI exposure are required, subjects should discontinue study 
medication.  H2 receptor antagonists and antacids are allowed throughout the study 
treatment period.   
15. Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of 
leukemia. 
Note: Subjects may not receive AML-directed therapy prior to enrollment other than 
hydroxyurea or leukapheresis for acute management of hyperleukocytosis. 
16. Concurrent (within 14 days of study enrollment) participation in an investigational drug 
study with therapeutic intent. 
17. Clinical signs/symptoms of leukostasis that have failed therapy including hydroxyurea 
and/or leukapheresis of at least 3 days duration. 
18. Clinically significant heart disease defined as: 
a. New York Heart Association Class 3 or 4 congestive heart failure, 
b. Acute myocardial infarction ≤ 6 months before enrollment, 
c. Symptomatic cardiac ischemia/unstable angina ≤ 3 months before enrollment,  
d. History of clinically significant arrhythmias (eg, ventricular tachycardia or 
fibrillation; Torsades de Pointe) including Mobitz type II 2nd degree or 3rd degree 
heart block without a permanent pacemaker in place. 
19. Subjects with a corrected QT interval (using the Fredericia formula, QTcF) > 480 msec 
or Long QT Syndrome 
20. Evidence of ongoing, uncontrolled systemic bacterial, fungal, or viral infection at the 
time of study treatment initiation, including but not limited to persistent fever or positive 
cultures in the setting of appropriate antimicrobial therapy. Patients who are afebrile for 
≥48 hours may enroll even while continuing antimicrobial therapy. 
21. Pregnant or breastfeeding women. 
22. Alcohol or drug addiction as determined by investigator. 
23. Unable to swallow tablets or concurrent disease affecting gastrointestinal function such 
as, malabsorption syndrome, gastric or small bowel resection, bariatric surgery, 
inflammatory bowel disease, or bowel obstruction. 
24. Any prior or ongoing condition that, in the opinion of the investigator, could adversely 
affect the safety of the subject or impair the assessment of study results. 
25. Known hypersensitivity to ENTO, cytarabine, daunorubicin, or idarubicin, their 
metabolites, or formulation excipient. 
 
 


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5.3 
Lifestyle Considerations 
No lifestyle changes or restrictions are required for clinical trial participation. 


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6.0 
Study Treatment and Concomitant Therapy 
6.1 
Study Treatment Administered 
Study medication (ENTO, 400 mg or placebo) will be administered orally approximately every 
12 hours and should be taken at approximately the same time each day while in the fasted state 
(≥ 2 hours after and at least 1 hour before a meal) with 8 ounces of water. Tablets should be 
swallowed whole. Subjects who have a delay of < 6 hours in administration of a dose of study 
medication should take the planned dose as soon as possible after the intended time of 
administration. For subjects who have a delay of ≥ 6 hours, the missed dose should not be taken 
and the time frame for the subsequent dose of study medication should be maintained. Vomited 
doses should not be repeated except if the tablets are clearly visible in the vomitus. 
For cytarabine and daunorubicin or idarubicin, follow the currently approved prescribing 
information and institutional guidelines when administering. 
6.2 
Preparation/Handling/Storage/Accountability 
ENTO is available as 200 mg film-coated tablets (entospletinib bis-methanesulfonate monohydrate 
spray-dried dispersion formulation or ENTO SDD). ENTO tablets or placebo-to-match tablets are 
packaged in a white, high-density polyethylene bottle with silica gel desiccant and polyester 
packing material. Each bottle is enclosed with a white, continuous-thread, child-resistant, 
polypropylene screw cap fitted with an induction-sealed, aluminum-faced liner. The study 
medication should not be transferred into a container other than that in which it was supplied in 
order to ensure its stability. Study medication should be stored at 15°C to 30°C (59°F to 86°F). 
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all study medication and any discrepancies are reported and resolved 
before use. Only participants enrolled in the study may receive study medication and only 
authorized site staff may supply or administer it. 
All study medication must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff. Measures that minimize medication contact with the 
body should always be considered during handling, preparation, and disposal procedures. Any 
unused study medication should be disposed of per the local requirements. The investigator, 
institution, or the head of the medical institution (where applicable) is responsible for study 
medication accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and 
final disposition records). 
Further guidance and information for the final disposition of unused study medication are provided 
in the Study Reference Manual. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
All subjects who sign informed consent will be registered through an Interactive Voice/Web 
Response System (IxRS). Subjects who subsequently meet all eligibility requirements will be 
randomly assigned 1:1 to study medication (ENTO or placebo) using the IxRS. The randomization 


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will be stratified by age (< 60 vs ≥ 60 years) and anthracycline administered during induction 
(daunorubicin or idarubicin). All subjects, study site personnel, and the Sponsor’s clinical trial 
management staff (and their designees) will be blinded to treatment assignment.  
Members of the Data Monitoring Committee (DMC; Section 9.5) may be unblinded to treatment 
assignment for individual subjects or treatment arm in order to better assess safety and efficacy 
trends that could potentially underlie the basis for specific recommendations to modify the study. 
The criteria and procedures for unblinding at the DMC are outlined in the DMC Charter. 
Investigators will also have the ability to unblind the study medication assignment for individual 
patients in cases of medical emergency or where this information is critical for the assessment and 
management of specific adverse events (eg. suspected, unexpected, serious adverse reactions 
[SUSARs]) including Grade 5 AEs assessed as at least possibly related to study medication. The 
investigator will have the capability to unblind the study medication assignment without prior 
authorization from the study medical monitor or Sponsor and will access study medication 
assignment via the IxRS. Upon unblinding the medication assignment for a specific patient, the 
investigator must notify the study’s medical monitor as soon as possible.  
6.4 
Compliance with Study Medication Regimen 
Compliance with the study medication dosing schedule will be documented at each study visit via 
diary cards placed in the subject’s medical record and entered in the electronic case report form 
(eCRF) at each scheduled visit. Deviation(s) from the prescribed dosing schedule will be recorded. 
6.5 
Dose Modification 
Toxicity management and dose modifications for chemotherapy should follow institutional 
standards of care in accordance with health authority guidelines as outline in the relevant 
prescribing information for each country. 
6.5.1 
ENTO/Placebo  
Hematologic toxicity: There will be no dose modifications for hematologic toxicity except in 
subjects who achieve a CR with count recovery followed by recurrence of cytopenias that are not 
attributable to subsequent chemotherapy or other causes. In this setting, performance of a bone 
marrow aspirate and/or biopsy to confirm AML has not recurred is mandated. Interrupt study 
medication for Grade 4 neutropenia or thrombocytopenia attributed to study medication until 
counts return to Grade 2 or better. Study medication may then be restarted at a 50% reduced dose 
twice daily. If Grade 4 neutropenia or thrombocytopenia recurs, the total daily dose may be further 
reduced to 50% once daily. No further dose level reductions beyond this are permitted and subjects 
should be removed from study medication if Grade 4 neutropenia or thrombocytopenia recurs. If 
blood counts remain stable for 1 month after dose reduction, investigators may attempt to increase 
the dose of study medication by one dose level. 
Dose modifications for non-hematologic toxicities are described in Table 6. 


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Table 6:   
Study Treatment Modifications for Non-hematologic Toxicities 
Liver function abnormalities: 
• For Grade 1-2 abnormalities, continue study medication 
at full dose.  
• For Grade ≥ 3 AST/ALT elevations, interrupt study 
medication and recheck transaminase levels at least 
weekly. 
• When AST, ALT levels return to Grade 1 or baseline, 
restart study medication at a 50% reduced dose twice 
daily. 
• If there is no recurrence of Grade ≥ 3 transaminase 
elevation after 2 weeks of reduced dose, escalation to full 
dose may be attempted.  
• For Grade ≥ 3 increased blood bilirubin not attributed to 
increased indirect bilirubin levels, or liver function 
abnormalities that meet the criteria for Hy’s law**, 
permanently discontinue therapy. 
Note: ENTO is an inhibitor of UGT1A1 and reversible 
increases in unconjugated (indirect) bilirubin values have 
occurred in healthy subjects receiving ENTO. In the 
absence of symptoms or other liver function abnormalities, 
study medication dose modification is not required for 
elevated indirect bilirubin levels. 
Dermatologic abnormalities: 
• For all Grade 1 to 2 abnormalities that are clinically 
manageable with topical steroids, continue study 
medication. 
• For Grade 3 rash, interrupt study medication until rash 
resolves to Grade 1. At this time, restart at a 50% reduced 
dose twice daily. 
• If Grade 3 rash does not recur after 2 weeks of reduced 
dose study medication, escalation to full dose may be 
attempted. 
• Permanently discontinue study medication in subjects 
with Grade 4 rash or those with recurrent Grade 3 rash 
despite dose reduction. 
Gastrointestinal toxicity: 
• For Grade 3 diarrhea attributed to study medication, anti-
diarrheal medication should be initiated in an effort to 
achieve improvement. If this does not control diarrhea 
then study medication should be interrupted until 
diarrhea resolves to Grade 1 or less. Study medication 
may then be restarted at a 50% reduced dose twice daily. 
• If Grade 3 diarrhea does not recur after 2 weeks of 
reduced dose study medication, escalation to full dose 
may be attempted.  


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• For Grade 4 diarrhea, permanently discontinue study 
medication. 
Pneumonitis: 
Note: Non-infectious pneumonitis is a diagnosis of exclusion 
and a thorough evaluation for infectious etiologies is 
mandated.  
• If Grade 1 non-infectious pneumonitis develops, it is 
acceptable to observe closely while continuing study 
medication.  
• If Grade 2 pneumonitis develops, interrupt study 
medication until Grade 1 or less. A short course of 
prednisone or methylprednisolone may be given for 
Grade 2 pneumonitis.  
• Following resolution to Grade 1, restart study medication 
at a 50% reduced dose twice daily. This dose level should 
be maintained without attempt to escalate to full dose.  
• If Grade 3 or 4 pneumonitis develops, study medication 
should be discontinued permanently. 
Other non-hematologic 
toxicities:* 
• Subjects who experience other Grade ≥3 nonhematologic 
toxicity assessed as at least possibly related to study 
medication, interrupt until the toxicity resolves to 
Grade 1, and then restart at 50% reduced dose twice daily 
and continue through the end of the cycle.  
• If toxicity recurs at this lower dose, study medication will 
be discontinued permanently.  
*  Excluded from this requirement are electrolyte disturbances, nausea, vomiting, or diarrhea that are reversible with 
supportive care within 48 hours. Since subjects will be receiving the study medication daily, low grade chronic 
side effects, such as nausea, fatigue, and diarrhea, while not meeting the above criteria for dose modification, may 
not be tolerable when experienced for long periods of time. Following discussion with the medical monitor, dose 
reduction may be permitted if low grade chronic side effects cannot be managed effectively with supportive care, 
as long as they are attributed to study medication. 
**  A Hy’s law case is one in which liver aminotransferase levels ≥3x ULN are accompanied by an elevation of total 
bilirubin to >2x ULN without initial findings of cholestasis (e.g. elevated serum alkaline phosphatase levels), for 
which no other reason can be found to explain the combination of increased transaminase levels and total bilirubin, 
such as viral hepatitis A, B or C; pre-existing or acute liver disease; or another drug capable of causing the observed 
liver injury. 
If the following signs or symptoms are medically manageable, they are not to be a consideration 
with respect to the subject’s study medication dose or continuation of study treatment: nausea, 
mild vomiting, diarrhea, drug-related fever or chills, transient and correctable laboratory test 
abnormalities, line associated thrombosis, or alopecia. Subjects who are intolerant of study 
medication beyond Induction Cycle 1, may either permanently discontinue it or interrupt study 
medication in consultation with the medical monitor until the toxicity or laboratory abnormality 
has resolved to Grade 1 or baseline following which, dose reduction may be considered.  


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6.5.2 
Cytarabine Consolidation Therapy Dose Modifications 
In the setting of neurotoxicity attributed to cytarabine, contributions of concomitant medications 
should be assessed, and other medications discontinued if possible. For neurotoxicity Grade ≥ 2 
due to cytarabine therapy, discontinue cytarabine for the remainder of the cycle. Resumption of 
cytarabine may be considered at the next chemotherapy cycle at a reduced dose per institutional 
standards of care if the toxicity has resolved. For a second occurrence of neurotoxicity Grade ≥ 2, 
cytarabine should be permanently discontinued. 
6.5.3 
Retreatment Criteria 
Resumption of study medication at a later date is not permitted in subjects who permanently 
discontinue. 
6.6 
Continued Access to Study Medication After the End of the Study 
Study medication will be discontinued for all subjects no later than at the completion of 
consolidation. 
6.7 
Treatment of Overdose 
Any dose of study medication greater than the dose assigned is considered an overdose. Adverse 
events associated with an overdose will be recorded on the AE eCRF log. Events that meet the 
criteria for seriousness must be reported immediately, without undue delay, after awareness via 
the serious adverse event (SAE) reporting process (see Appendix 2). In the event of an overdose, 
contact the medical monitor immediately. The subject must be monitored for evidence of toxicity 
and standard supportive treatment should be provided, as necessary. It is unknown whether ENTO 
can be removed by dialysis. There is no known antidote for ENTO. In the case of symptomatic 
overdose, the subject should receive standard treatment for overdose and supportive therapy based 
on the subject’s signs and symptoms. 
6.8 
Concomitant Therapy 
All concomitant medications will be recorded beginning on C1D1 through 30 ± 7 days after 
treatment completion. The medical monitor should be contacted if there are any questions 
regarding concomitant or prior therapies.  
Subjects should receive full supportive care including transfusions of blood and blood products, 
antibiotics, antiemetic and antifungal medications, allopurinol, etc., as appropriate. Patients should 
receive prophylactic antimicrobial therapy in accordance with institutional standards of care. No 
other direct antileukemic therapy is permitted except for hydroxyurea prior to Induction Cycle 1 
to control hyperleukocytosis, as required. The use of myeloid growth factors is permitted according 
to guidelines for use in AML but is generally discouraged during induction. For consolidation 
therapy, GM-CSF or G-CSF may be used in accordance with National Comprehensive Cancer 
Network guidelines (NCCN Guidelines) or per institutional standards of care.  
Adrenocortical replacement therapy, ie, ≤ 10 mg/day prednisone or equivalent, is allowed. Short 
term administration of dexamethasone for prophylaxis against chemotherapy-induced nausea and 


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vomiting or toxicities associated with high dose cytarabine is also permitted as is administration 
of “stress” doses of steroids for management of sepsis with or without hypotension. Non-systemic 
(eg, topical, intraocular) steroids are permitted, as needed. 
Recombinant erythropoietin is not permitted at any time during the study. Palliative radiation 
therapy may not be administered while the subject is on study except for the management of 
localized skin lesions.  
Subjects should NOT receive a PPI during therapy with study medication except if required for 
management of acute gastrointestinal bleeding and only for a period of up to 10 consecutive days 
(Section 5.2). If longer durations of PPI exposure are required, subjects should discontinue study 
medication. H2 receptor antagonists and agents such as locally acting antacids (eg, TUMS) and 
carafate are allowed to control symptoms of gastritis.  
ENTO is a substrate of CYP2C9 and CYP3A. Co-administration of rifampin (a strong CYP3A and 
moderate CYP2C9 inducer) resulted in an approximately 70% decrease in ENTO exposure 
(Section 6.1.2.1, Investigator’s Brochure). As such, co-administration of strong CYP3A and 
CYP2C9 inducers, and moderate CYP2C9 inducers must be avoided beginning 14 days prior to 
study drug administration and throughout the study treatment period (Appendix 7). 
Co-administration with fluconazole, a CYP2C9 inhibitor, increased ENTO exposure by 
approximately 40%. Caution should be exercised when co-administering drugs that are moderate 
to strong inhibitors of CYP2C9. Neither itraconazole nor posaconazole are inhibitors of CYP2C9 
and can be safely co-administered orally with study medication, if clinically indicated. 
ENTO is expected to produce asymptomatic and transient elevations of unconjugated (indirect) 
bilirubin due to inhibition of UGT1A1. The elevations in indirect bilirubin in previous studies were 
generally self-limited and did not result in discontinuation of ENTO (Section 6.1.2.2, 
Investigator’s Brochure). 
ENTO marginally increased the exposure of the P-glycoprotein substrate, digoxin, thus caution 
should be exercised when co-administering medications that are transported by P-glycoprotein. 
ENTO increased the exposure of the OATP1B1, OATP1B3, and BCRP substrate, rosuvastatin, by 
approximately 3.8-fold, which may theoretically increase the risk of rhabdomyolysis. In reviewing 
the safety of subjects who have received an HMG-CoA reductase inhibitor concurrently with 
ENTO, there have been no reports of rhabdomyolysis nor a difference in adverse events profile. 
As a precautionary measure, reduce doses of HMG-CoA reductase inhibitors administered 
concurrently with study medication as outlined in Appendix 7. In general, caution should be 
exercised when co-administering medications that are transported by OATP1B1, OATP1B3, or 
BCRP; dose adjustment may be necessary, if clinically indicated (Section 6.1.2.1, Investigator’s 
Brochure). 
For HIV + patients who meet all criteria for enrollment outlined in Section 5.2, sites are encouraged 
to consult with the Sponsor or their institutional pharmacist in order to assess the potential for 
adverse interactions between the study medication and one or more components of their anti-
retroviral therapy combination, before enrolling the patient. 
 


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7.0 
Discontinuation of Study Treatment/Participation  
7.1 
Discontinuation of Study Treatment 
Subjects may discontinue study medication at any time at his/her own request or may be 
discontinued at the discretion of the investigator for safety, behavioral, or compliance reasons. 
Subjects must discontinue study medication for the following reasons: 
• Recurrence of leukemia after a response  
• Failure to achieve (or maintain) CR, CRh or CRi post-Chemotherapy Cycle 2 
• Death 
• Withdrawal of consent 
• An AE or intercurrent illness that precludes further administration of protocol therapy or 
participation in the study 
• Need for, or use of a prohibited concomitant medication 
• Hematopoietic stem cell transplantation 
• Pregnancy 
If study treatment is permanently discontinued for any reasons, subjects shall remain in the study 
for long-term follow-up. See Table 7 for assessments required for the End-of-Treatment evaluation 
and long-term follow-up. 
7.2 
Discontinuation from the Study 
Subjects may withdraw from the study at any time at his/her own request or may be withdrawn at 
the discretion of the investigator for safety, behavioral, or compliance reasons. Subjects must 
discontinue study participation for the following reasons: 
• Death 
• The study is terminated by the Sponsor 
7.3 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
The site must attempt to contact the participant and reschedule the missed visit as soon as possible 
and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the participant wishes to and/or should continue in the study. 
Before a participant is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the participant (where possible, telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record. 


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Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 


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8.0 
Study Assessments and Procedures 
The schedule of study assessments and procedures is summarized in Table 7. 
All study visits should be scheduled relative to the C1D1 date regardless of any treatment 
interruptions. Acceptable windows for study visits/assessments after C1D1 are ± 1 day. 
Unscheduled study visits may be required as clinically indicated for evaluation of AEs or suspected 
leukemic relapse/progression. Results of diagnostic evaluations performed as part of an 
unscheduled study visit must be entered into the Unscheduled Visit eCRF.  
 


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Table 7: 
Schedule of Assessments and Procedures 
Study Phase 
Screening 
Induction (up to 2 Cycles)*  
At Recovery of Blood 
Counts/Assessment of 
Remission Status (Post-
Induction Cycle 1,  
Post-Chemotherapy 
Cycle 2)/ 
At Relapse 
Consolidation 
(up to 3 Cycles)*  
End-of-
Study 
Treatment 
Long-Term 
Follow-up x 
Study Visit Day a 
-14 to 0 
1 
3  7  14  
15  
until 
blood 
count 
recovery 
 
1 
3 
 5 
28 
to 
35 
30 ± 7 
days after 
last study 
treatment 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IxRS registration/ 
randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/smoking history/ 
prior medications/AML 
baseline characteristics b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Safety assessments 
Vital signs c 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Physical examination d 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
X 
 
Height/weight e 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
ECG f 
X 
 
ECHO/MUGA g 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
ECOG PS (Appendix 6) 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
AEs/concomitant 
medications h 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Hematology i 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Clinical chemistries/ 
LFTs j 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
 
Coagulation k 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Urinalysis l 
X 
 
ß-HCG/FSH m  
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
HBV/HCV/HIV 
serologies n 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Phase 
Screening 
Induction (up to 2 Cycles)*  
At Recovery of Blood 
Counts/Assessment of 
Remission Status (Post-
Induction Cycle 1,  
Post-Chemotherapy 
Cycle 2)/ 
At Relapse 
Consolidation 
(up to 3 Cycles)*  
End-of-
Study 
Treatment 
Long-Term 
Follow-up x 
Study Visit Day a 
-14 to 0 
1 
3  7  14  
15  
until 
blood 
count 
recovery 
 
1 
3 
 5 
28 
to 
35 
30 ± 7 
days after 
last study 
treatment 
 
Induction therapy 
Study medication 
(ENTO/Placebo) o 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Cytarabine  
 
 
 
 
 
 
 
 
 
 
 
 
 
Daunorubicin or 
Idarubicin 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consolidation therapy 
Study medication 
(ENTO/Placebo) p 
 
 
 
 
 
 
 
 
 
 
 
 
 
Age-adjusted, high-dose 
cytarabine  
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow evaluations 
Aspirate q 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
NPM1-m MRD 
assessments r 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X  
Pharmacokinetics s 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
Peripheral blood  
biomarker assessments t 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
 Bone marrow aspirate 
biomarker assessments u 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Pharmacogenomics (whole 
blood) v 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient reported outcomes w 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Follow-up for relapse, first 
salvage therapy, OS x 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Abbreviations: AEs, adverse events; AML, acute myeloid leukemia; β-HCG, beta human chorionic gonadotropin; ECG, electrocardiogram; ECHO, echocardiogram; ECOG PS, 
Eastern Cooperative Oncology Group Performance Status; FSH, follicle stimulating hormone; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; 
LFTs, liver function studies; MUGA, multi-gated acquisition; NPM1-m, Nucleophosmin 1-mutated;  MRD, measurable residual disease; OS, overall survival. 
* Subjects with ≥5% residual leukemic blasts in bone marrow aspirate between Days 14 and 28 of Induction Cycle 1 will receive Induction Cycle 2 as outlined in Table 4, which 
may be administered prior to blood count recovery. Subjects who have achieved a complete response (CR) either with or without full hematologic recovery (CRh, CRi) or a 
morphologic-free leukemia state (MFLS) will proceed to Consolidation Cycle 1 (Table 5) upon recovery of peripheral blood counts (absolute neutrophil count [ANC] ≥ 1.0 x 109/L; 
platelet count ≥ 50 x 109/L). After completion of Induction Cycle 2 or Consolidation Cycle 1 (ie.  Chemotherapy Cycle 2), subjects will undergo bone marrow examination for 
assessment of remission status at the investigative site.  Patients in morphologic CR post-Chemotherapy Cycle 2 will undergo MRD assessment (see footnote “r” below). 
a Acceptable windows for study visits/assessments after C1D1 are ± 1 day; however, study treatment must be administered on the days indicated (eg, Days 1-7 for cytarabine, and 
Days 1-3 for daunorubicin or idarubicin in Induction Cycle 1).   
b The following details minimally, regarding the diagnosis of AML will be collected and recorded on the eCRF: age and date of diagnosis (month, day, year); AML subtype (de 
novo; AML with myelodysplasia-related changes; therapy associated AML); history of myelodysplastic or myeloproliferative (eg, chronic myelomonocytic leukemia [CMML] 
syndrome; history of prior exposure to leukemogenic agents (eg. alkylating agents, topoisomerase II inhibitors); cytogenetic abnormalities identified by conventional cytogenetic 
testing and/or FISH; complete blood count (CBC) with differential; percent blasts (peripheral blood and bone marrow); NPM1 mutation subtype (A, B, D, other); FLT-3 mutational 
status (wild-type; internal tandem duplication [ITD] mutation, tyrosine kinase domain [TKD] mutation, or both).  
c Vital signs include measurement of blood pressure, respiratory rate, pulse, temperature, and oxygen saturation level by pulse oximetry. After discharge from hospital, assess vital 
signs at each of the designated time points.  
d Perform a complete physical examination including neurological exam at Screening. After discharge from the hospital, a targeted physical exam may be performed at each of the 
designated time points. Subjects ≥60 years old receiving intermediate dose cytarabine or those with impaired renal function are at risk for cerebellar toxicity. Monitor for the 
occurrence of nystagmus, slurred speech, or dysmetria on each day of cytarabine dosing during Induction Cycle 2 and consolidation. Follow dose modification guidelines outlined 
in Section 6.5.2 or in accordance with institutional care standards in the setting of neurotoxicity. 
e Height and weight will be measured at Screening. Only weight will be measured thereafter at designated time points.   
f ECG is required at Screening and thereafter as clinically indicated during treatment. 
g An echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan must be performed at Screening and at the End-of-Treatment Visit. Consider repeating ECHO or MUGA 
within 48 hours prior to Induction Cycle 2 for subjects receiving anthracycline in Cycle 2 and at increased risk for cardiac toxicity.  
h Record all adverse events and concomitant medications through 30 ± 7 days after treatment completion. Thereafter, record only serious adverse events assessed as study medication 
related. 
i Includes hemoglobin, hematocrit, WBC and platelet counts, and WBC differential (neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, blasts). At times not 
designated in Table 7, monitor CBC and WBC differential in accordance with institutional care standards until ANC is >1.0 x 109/L or persistent leukemia is documented. Monitor 
platelet counts at times designated in Table 7 and at other times, per institutional care standards until the platelet count is >100 x 109/L or persistent leukemia is documented. Monitor 
CBC and platelet count twice weekly during consolidation and at other times, as clinically indicated. 
j Includes electrolytes (sodium, potassium, chloride, total CO2 and/or bicarbonate, calcium, phosphate), liver function studies (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], total and direct bilirubin), lactate dehydrogenase (LDH), alkaline phosphatase, blood urea nitrogen [BUN] or serum urea, creatinine, uric acid, glucose, 
amylase, and lipase. Include total creatine phosphokinase (CPK) at Screening, Day 14 of each induction cycle, and End of Study Treatment. At times not designated in Table 7, 
monitor electrolytes, LFTs, BUN, creatinine, uric acid, and phosphate in accordance with institutional care standards until the risk of tumor lysis syndrome has abated.  For subjects 


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receiving nephrotoxic antimicrobial agents, closer monitoring of renal function throughout the period of hospitalization is recommended, consistent with institutional standards of 
care.  
k Includes prothrombin time, activated partial thromboplastin time and international normalized ratio. Perform coagulation panel twice per week during Induction. For subjects with 
evidence of disseminated intravascular coagulation (DIC), coagulation parameters including fibrinogen should be monitored in accordance with institutional care standards until 
resolution. 
l Includes dipstick evaluation for pH, glucose, protein, blood, leukocyte esterase and microscopic evaluation for red and white blood cells.  After Screening, perform urinalysis as 
clinically indicated. 
m A negative serum pregnancy test is required for female subjects (unless surgically sterile or postmenopausal) at Screening. Female subjects with medically documented ovarian 
failure must also have serum FSH levels within the institutional postmenopausal range at Screening. A urine pregnancy test will be performed for all females (unless surgically sterile 
or postmenopausal) on Day 1 of each cycle of induction and consolidation and at the End-of-Treatment Evaluation. 
n HBV/HCV/HIV serology tests include HBsAg, anti-HBs, anti-HBc, anti-HCV, and anti-HIV.  
o Study medication will be administered orally every 12 hours during Induction Cycles 1 and Induction Cycle 2, if administered (see Table 4). Subjects are to continue receiving 
study medication while awaiting blood count recovery and response assessment results. 
p Subjects who achieve CR, CRh or CRi post-Chemotherapy Cycle 2 may receive consolidation chemotherapy in combination with study medication (see Table 5). Subjects are to 
continue receiving study medication while awaiting blood count recovery. The number of cycles of consolidation (up to 3) will be at the investigator’s discretion.  
q A bone marrow aspirate will be performed at Screening (within 14 days before the first administration of study treatment) for confirmation of diagnosis, morphology (spicule prep), 
cytogenetics/FISH and NPM1 and FLT-3 mutational status. In cases in which an adequate bone marrow aspirate cannot be obtained at Screening (eg, due to dry tap, 
hypocellularity or hemodilution), a trephine bone marrow biopsy is mandated. Bone marrow aspirates are required in Induction Cycle 1 (up to but no later than Day 42) and 
again post-Chemotherapy Cycle 2 (no later than Day 42) to assess remission status.  Thereafter, perform bone marrow examination for confirmation of suspected leukemic relapse. 
r NPM1-m allelic frequency will be assessed in peripheral blood and bone marrow aspirate in a central laboratory at the following time points:  Screening; post-Chemotherapy Cycle 
2 for subjects in CR (no later than Day 42, for MRD assessment); and at the End of Study Treatment visit (peripheral blood only). MRD will be assessed retrospectively on 
peripheral blood in subjects who achieve MRD negative CR post-Chemotherapy Cycle 2, every 3 months during long term follow-up until morphologic relapse. 
s Blood sampling for pharmacokinetic assessments will be performed at the following time points: Cycle 1 (Induction): Day 1 between 2- and 4-hours post-study medication dose, 
Day 7 predose only, Day 14 predose and between 2- and 4-hours post-study medication dose; Cycle 3 (Consolidation): Day 1 predose and between 2- and 4-hours post-study 
medication dose, Day 28-35 predose and between 2- and 4-hours post-study medication dose. All predose samples must be obtained within 60 minutes before the first daily dose of 
study medication (Section 8.7). 
t Blood samples for biomarker assessments including (but not limited to) other somatic mutations will be obtained at Screening; Cycle 1 (Induction), Day 1 (predose and 2 hours 
post-dose), Day 7 and Day 14 (predose only) prior to the first daily dose of study medication; Cycle 3 (Consolidation) Day 1 (predose) and Day 28-35 (predose); at time of post-
Chemotherapy Cycle 2; relapse; and End of Study Treatment. See Section 8.9 for a description of planned biomarker assessments. 
u Bone marrow aspirate samples for biomarker assessments including (but not limited to) other somatic mutations will be obtained at Screening; post-Chemotherapy Cycle 2; and at 
relapse. 
v Whole blood will be collected during Screening for evaluation of CYP2C9 and cytidine deaminase polymorphisms. Examinations of other germline genes implicated in 
leukemogenesis may be conducted for comparison with corresponding genes in the leukemic clone. See Section 8.9 for additional details. 
w Includes the European Quality of Life 5 Dimensions Questionnaire (EQ-5D-5L) and the European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC-QLQ 30). 


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x All subjects regardless of post-remission status will be followed monthly for 3 months after the End-of-Treatment Visit and thereafter at least once every 3 months for 
progression/relapse, first salvage therapy, and overall survival until study termination.  


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8.1 
Informed Consent 
Study site personnel must obtain signed informed consent before any study-specific procedures 
(including central laboratory screening for the presence of NPM1 and FLT3 mutations) are 
conducted unless these are part of the standard of care and must document the informed consent 
process in the patient’s medical record. Consent must be obtained using the most current version 
of ICF approved by the study site’s Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC). Once the patient signs the ICF, that will signal the beginning of the 14-day 
Screening Period. Selected screening assessments may be repeated once for final eligibility 
determination if thought to be out-of-range due to artifact or transient abnormality. These include 
the following: ECG, ECHO, clinical chemistries/liver function studies, coagulation screening 
studies and HBV/HCV/HIV serologies. 
8.2 
Confirmation of Eligibility 
All screening assessments and relevant medical history must be available and reviewed by the 
investigator before eligibility can be confirmed. Eligibility waivers will not be granted. After the 
investigator determines that a patient is eligible, study site personnel will complete an enrollment 
authorization form to be sent to the medical monitor for review/approval. Written authorization by 
the medical monitor is required before a patient can be officially enrolled and begin study 
treatment. 
8.3 
Medical and Leukemia History 
Clinically significant medical and surgical history not pertaining to the underlying malignancy 
under study that started prior to informed consent will be collected. “Clinically significant” is 
generally regarded as any diagnosis requiring on-going treatment intervention and follow-up. 
Signs and symptoms of concurrent medical conditions must be adequately documented at 
Screening in order to establish baseline severities. Clinically relevant prior and current medical 
and surgical history will be reported on the Medical and Surgical History eCRF.  
Smoking history (never smoker; former smoker; current smoker) will also be recorded. 
The following details minimally regarding the diagnosis of AML will be collected and recorded 
on the eCRF: age and date of diagnosis (month, day, year); AML subtype (de novo; AML with 
myelodysplasia-related changes; therapy associated AML); history of myelodysplastic or 
myeloproliferative (eg, chronic myelomonocytic leukemia [CMML]) syndrome; history of prior 
exposure to leukemogenic agents (eg. alkylating agents, topoisomerase II inhibitors); cytogenetic 
abnormalities identified by conventional cytogenetic testing and/or FISH; CBC with differential; 
percent leukemic blasts (peripheral blood and bone marrow); NPM1 mutation subtype (A, B, D, 
other); FLT-3 mutational status (wild-type; internal tandem duplication [ITD] mutation, tyrosine 
kinase domain [TKD] mutation, or both).  
8.4 
Study Medication Dispensation 
During periods of hospitalization, study medication (ENTO or placebo) will be dispensed by the 
in-patient pharmacy and administered by in-patient medical/nursing staff. Study medication for 


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outpatient use will be dispensed by study center personnel to ensure adequate drug supply for home 
administration throughout the treatment phase in accordance with details outlined in the Pharmacy 
Manual. Instructions will be provided to subjects for dosing, storage, and disposition of unused 
study drug. 
8.5 
Efficacy Assessments 
Assessments that define the quality of response to study treatment will include physical 
examination, peripheral blood counts, and bone marrow examination. All assessments of response 
will be made by the investigator in accordance with ELN 2017 criteria (Döhner 2017) with minor 
modification for neutrophil and platelet count thresholds that define CR per the International 
Working Group (IWG) criteria (Cheson 2003). See Appendix 4 for criteria that define each 
response category.  
8.5.1 
Bone Marrow Examination 
A bone marrow aspirate will be performed at Screening (within 14 days before the first 
administration of study treatment) for confirmation of diagnosis, morphology (spicule prep), 
cytogenetics/FISH and NPM1 and FLT3 mutational status. In cases in which an adequate bone 
marrow aspirate cannot be obtained at Screening (eg, due to dry tap, hypocellularity or 
hemodilution), a trephine bone marrow biopsy is mandated. Bone marrow aspirates are 
required in Induction Cycle 1 (up to but no later than Day 42) and again post-Chemotherapy Cycle 
2 (no later than Day 42) to assess remission status. Thereafter, perform bone marrow examination 
for confirmation of suspected leukemic relapse. 
Additional biomarker assessments including (but not limited to) the presence of other somatic 
mutations at each of the aforementioned timepoints will be conducted (see Section 8.8). 
8.5.2 
Measurable Residual Disease 
NPM1-m MRD assessments on peripheral blood and bone marrow aspirate will be conducted in a 
central laboratory post-Chemotherapy Cycle 2 for subjects in CR, no later than Day 42. 
Additionally, NPM1-m will be assessed as part of a broader panel of AML somatic mutations on 
peripheral blood only at End of Study Treatment, and every 3 months during long term follow-up 
in subjects who achieve MRD negative CR post-Chemotherapy Cycle 2, until morphologic 
relapse. 
8.6 
Safety Assessments 
8.6.1 
Physical Examination and Vital Signs 
A complete physical examination that includes a neurological exam must be performed at 
Screening. Thereafter, a targeted physical exam may be performed at each of the designated time 
points in Table 7. Height and weight will be measured at Screening. Only weight will be measured 
thereafter at designated time points. 


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Vital signs include measurement of blood pressure, respiratory rate, pulse, temperature, and 
percent oxygen saturation by pulse oximetry. After discharge from hospital, assess vital signs at 
each of the designated time points indicated in Table 7. 
Blood pressure and pulse should be measured at least 5 minutes after rest in a quiet setting without 
distractions. To the extent possible, measure vital signs prior to blood collection for laboratory 
assessments. 
Subjects ≥ 60 years of age or those with impaired renal function receiving cytarabine at doses 
specified in this study are at risk for cerebellar toxicity. Monitor for the occurrence of nystagmus, 
slurred speech, or dysmetria on each day of cytarabine dosing during induction and consolidation. 
Follow dose modification guidelines outlined in Section 6.5.2 or those consistent with institutional 
care standards in the setting of neurotoxicity. 
8.6.2 
Electrocardiogram 
A triplicate, 12-lead ECG will be obtained as outlined in Table 7. ECG is required at Screening 
and thereafter as clinically indicated during treatment. 
8.6.3 
Echocardiography/Multi-gated Acquisition Scan 
An echocardiogram (ECHO) or multigated acquisition (MUGA) scan must be performed at 
Screening and at the End-of-Treatment Visit. For subjects receiving anthracycline in Induction 
Cycle 2, consider repeating an ECHO or MUGA scan within 48 hours prior to Cycle 2, Day 1 in 
subjects at increased risk for cardiotoxicity. 
8.6.4 
Laboratory Assessments  
See Table 7 for the list of clinical laboratory tests to be performed and their timing and frequency. 
The investigator must review results for protocol-specified laboratory assessments, document 
his/her review, and record any clinically significant changes from baseline, defined as the value 
most proximate to initiation of study treatment, as an AE. If laboratory abnormalities from non-
protocol specified laboratory tests require a change in subject management or are considered 
clinically significant (eg, requiring treatment modification), these must also be recorded as an AE. 
Laboratory reports must be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered clinically 
significant unless judged by the investigator to be more severe than expected for the underlying 
condition. Clinically significant laboratory abnormalities should be reassessed during the study, 
up to 30 days after the last dose of study treatment until the results return to normal or baseline or 
are no longer considered clinically significant by the investigator or medical monitor. If clinically 
significant abnormalities do not return to normal/baseline within a time period judged reasonable 
by the investigator, the etiology should be identified, and the Sponsor notified.  
Hematology: 
Includes hemoglobin, hematocrit, white blood cell (WBC) and platelet counts, and WBC 
differential (neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, blasts). At times 
not designated in Table 7, monitor CBC and WBC differential in accordance with institutional care 


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standards until ANC is >1.0 x 109/L or persistent leukemia is documented. Monitor platelet counts 
at times designated in Table 7 and at other times, per institutional care standards until the platelet 
count is >100 x 109/L or persistent leukemia is documented. Monitor CBC and platelet count twice 
weekly during consolidation and at other times, as clinically indicated. 
Clinical Chemistries: 
Includes electrolytes (sodium, potassium, chloride, total CO2 and/or bicarbonate, calcium, 
phosphate), liver function studies (AST, ALT, total and direct bilirubin), lactate dehydrogenase, 
alkaline phosphatase, blood urea nitrogen (BUN) or serum urea, creatinine, uric acid, glucose, 
amylase, and lipase. Include total creatine phosphokinase at Screening, Day 14 of each Induction 
cycle, and at the End of Study Treatment. At times not designated in Table 7, monitor electrolytes, 
LFTs, BUN, creatinine, uric acid, and phosphate in accordance with institutional care standards 
until the risk of tumor lysis syndrome has abated. For subjects receiving nephrotoxic antimicrobial 
agents, closer monitoring of renal function throughout the period of hospitalization is 
recommended, consistent with institutional standards of care.  
Coagulation Parameters: 
Includes prothrombin time, activated partial thromboplastin time and international normalized 
ratio. Perform coagulation panel twice per week during induction. For subjects with evidence of 
disseminated intravascular coagulation, coagulation parameters including fibrinogen should be 
monitored until resolution. 
Hepatitis/HIV Serologies: 
Includes HBsAg, anti-HBs, anti-HBc, anti-HCV, and anti-HIV. Patients who are seropositive for 
HBsAg are excluded. HIV + patients may be considered for enrollment if they meet all criteria 
outlined in Section 5.2 and for whom the risk of adverse interactions between anti-retroviral 
therapy and the study medication is assessed as minimal to none. 
Urinalysis: 
Includes dipstick evaluation for pH, glucose, protein, blood, leukocyte esterase and microscopic 
evaluation for red and white blood cells. After Screening, perform urinalysis as clinically 
indicated. 
8.6.5 
Pregnancy testing 
A negative serum pregnancy test is required for female subjects (unless surgically sterile or 
postmenopausal) at Screening. Female subjects with medically documented ovarian failure must 
also have serum follicle stimulating hormone (FSH) levels within the institutional postmenopausal 
range at Screening. A urine pregnancy test will be performed for all females (unless surgically 
sterile or postmenopausal) on Day 1 of each cycle of induction and consolidation and at the End-
of-Treatment evaluation. 


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8.7 
Pharmacokinetic Assessments 
Whole blood will be collected for measurement of plasma concentrations of ENTO at the 
following time points using a validated liquid chromatography mass spectrometry (LC-MS/MS) 
method:  
Cycle 1 (Induction): 
• Day 1, between 2 and 4 hours after study medication dose  
• Day 7 predose only 
• Day 14 predose and between 2 and 4 hours after study medication dose 
Cycle 3 (Consolidation): 
• Day 1 predose and between 2 and 4 hours after study medication dose 
• Day 28-35 predose and between 2 and 4 hours after study medication dose 
All predose samples must be obtained within 60 minutes before the first daily dose of study 
medication. The actual date and time (24-hour clock time) of each blood draw will be recorded. 
Details concerning the processing and handling of PK samples, including labeling and shipping 
instructions will be provided in the Laboratory Manual. 
8.8 
Biomarker Assessments 
Whole blood for biomarker testing will be obtained at the following time points: 
• Screening, 
• Cycle 1 (Induction), Day 1 (pre- and 2 hours postdose), Day 7 and Day 14 (predose), 
• Post-Chemotherapy Cycle 2 
• Cycle 3 (Consolidation), Day 1 (predose) and Days 28-35 (predose), 
• At relapse, and 
• End of Study Treatment.  
All predose samples must be obtained within 60 minutes before the first daily dose of study 
medication. The actual date and time (24-hour clock time) of each blood draw will be recorded. 
The extent of ENTO target engagement as measured by quantitation of pSYK and other 
phosphoproteins of interest as well as expression levels of relevant genes comparing baseline and 
on treatment blood samples will be explored. Additional targeted protein/phosphoprotein profiling 
(eg, pSYK expression) in leukemic cells specifically will be assessed at baseline. Biomarker 
assessments will also include baseline expression levels of HOXA9/MEIS1 transcription factors 
and other relevant genes in leukemic cells from peripheral blood and bone marrow aspirate using 
standard expression profiling platforms (eg, Nanostring®) or next-generation sequencing. 
Mutational profiling in leukemic cells using standard platforms like next generation sequencing 
both at baseline and following study treatment will be explored. Results of all biomarker 
assessments will be evaluated for potential correlations with response and leukemic progression. 


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Details concerning the processing and handling of biomarker samples, including labeling and 
shipping instructions will be provided in the Laboratory Manual. 
8.9 
Pharmacogenomic Assessments 
A whole blood sample will be collected at Screening for assessments of CYP2C9 and cytidine 
deaminase (the enzyme primarily responsible for cytarabine metabolism) polymorphisms. 
CYP2C9 polymorphisms will be evaluated in relationship to ENTO exposures (AUC, Cmax) and 
as a potential covariate in population PK analyses. Cytidine deaminase polymorphisms will be 
evaluated for potential correlations with selected safety and efficacy outcomes. Examinations of 
selected germline genes implicated in leukemogenesis may be conducted for comparison with the 
corresponding genes in the leukemic clone. 
8.10 
Patient Reported Outcomes 
Includes the European Quality of Life 5 Dimensions Questionnaire (EQ-5D-5L) and the European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 
(EORTC-QLQ 30) collected at baseline, post-Chemotherapy Cycle 2, at End-of-Treatment and 
every 3 months thereafter until progression/relapse or death (whichever is earlier). 
8.11 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
Definitions for AEs and SAEs as well as methods for evaluating and reporting AEs and SAEs can 
be found in Appendix 2. 
8.11.1 
Time Period for Reporting AEs and SAEs  
During the period from signing informed consent for this study until initiation of study treatment, 
only SAEs will be reported. Beginning on Day 1 of Cycle 1 all AEs, and SAEs will be reported 
through 30 days after treatment completion. Thereafter, only SAEs that are study medication 
related as assessed by the investigator will be reported. 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities are met. All SAEs will be reported to the sponsor or 
designee immediately, without undue delay, as outlined in Appendix 2. The investigator will 
submit any updated SAE data to the sponsor immediately, without undue delay. 
8.11.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when eliciting information on the occurrence of AEs and/or 
SAEs. Open-ended and non-leading verbal questioning of the participant is the preferred method 
to inquire about AEs. Investigators are not obligated to actively seek information on AEs or SAEs 
after the End-of-Treatment evaluation. However, if the investigator learns of any SAE, including 
a death, at any time after a subject has discontinued study treatment, and he/she considers the event 
to be reasonably related to the study medication or study participation, he/she must promptly notify 
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8.11.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All AEs, including SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Appendix 2. 
8.11.4 
Regulatory Reporting Requirements for SAEs 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study medication under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
regulatory authorities, IRB/IEC, and investigators. 
Investigators who receive a safety report describing an SAE or other safety information (eg, 
summary or listing of SAEs) from the Sponsor will review and then file it with the applicable 
reference safety information and will notify the IRB/IEC, if appropriate, according to local 
requirements. For this study, the reference safety information for the study medication, ENTO, is 
the Investigator’s Brochure (Edition 11.0). For all chemotherapy agents (cytarabine, daunorubicin, 
idarubicin), the reference safety information is the local health authority-approved prescribing 
information. 
Safety reports must be prepared for SUSARs in accordance with local regulatory requirements and 
Sponsor policy and forwarded to study investigators, as necessary. 
8.11.5 
Reporting Pregnancy 
If a female patient or the partner of a male patient becomes pregnant while receiving or within 
3 months of discontinuing study treatment, a pregnancy report form must be completed and 
submitted to the sponsor within 24 hours of learning of the pregnancy (after obtaining the 
necessary signed informed consent from the female partner of a male patient) to facilitate outcomes 
follow-up. 
While pregnancy itself is not considered an AE, any pregnancy complications (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) or elective termination 
of a pregnancy for medical reasons will be reported as a SAE. For pregnancies taken to term, 
details on the status of the mother and the child will be forwarded to the sponsor, with follow-up 
generally no longer than 6 to 8 weeks after the delivery date. Any female participant who becomes 
pregnant while participating in the study will discontinue study treatment but may continue to be 
followed for leukemic progression/relapse, first salvage therapy and survival. 
Any post-study pregnancy-related SAE considered by the investigator at least possibly related to 
the study treatment will be reported to the Sponsor as described in Section 8.11.4. While the 
investigator is not obligated to actively seek this information from former study subjects or 
pregnant female partners of male subjects, he or she may learn of an SAE through spontaneous 
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9.0 
Statistical Considerations 
9.1 
Statistical Hypotheses 
The primary efficacy endpoint is MRD negative CR rate after Chemotherapy Cycle 2. 
The hypothesis of interest is a two-sided test of superiority comparing ENTO to placebo. 
H0: pplacebo = pENTO vs H11: pplacebo ≠ pENTO, 
where pplacebo is the proportion of subjects in the placebo group with MRD negative CR after 
Chemotherapy Cycle 2, and pENTO is the proportion of subjects in the ENTO group with MRD 
negative CR after Chemotherapy Cycle 2. 
9.2 
Sample Size Determination 
Based on a completed study of newly diagnosed AML subjects treated with ENTO, it is anticipated 
that 87% of NPM1-m subjects will achieve CR (Walker 2020). Based on analysis of a historical 
dataset from the Cancer and Leukemia Group B Alliance (Mims et al, 2021) showing a 68% CR 
rate in 107 NPM1-mutated/FLT3-ITD negative patients ≥ 60 years of age treated with 7+3 
induction, a conservative estimate of 70% CR rate for placebo is assumed for sample size 
determination. The MRD negative rate among placebo subjects achieving CR is assumed to be 
60% (Ivey et al, 2016). Alternatively, it is hypothesized that 80% of subjects with CR receiving 
ENTO will be MRD negative. A sample size of 90 subjects per group (total of 180 subjects) will 
provide > 97% power to detect a difference in the MRD negative CR rate of 28% (87% x 80% = 
70% for ENTO vs 70% x 60% = 42% for placebo) with a 2-sided alpha level of 0.05 (PASS 2008: 
Two sample test of Proportion Module). Up to 10% over enrollment is allowable in order to 
account for technical or logistical barriers (eg. inadequate bone marrow aspirate or poor sample 
quality) related to the ascertainment of MRD status in patients who achieve CR post-
Chemotherapy Cycle 2. 
Assuming the two-year EFS rate for the control group is 63% (hazard rate of 0.231), a total of 
124 events (70 in the placebo arm, 54 in the ENTO arm) would be sufficient to provide 80% power 
to detect a hazard ratio of 0.6 for EFS (PASS 2008: log rank tests (Lakatos) [Hazard Rate] module) 
assuming 2-sided alpha = 0.05 and a total study duration of 60 months.  
9.3 
Analysis Sets 
Population 
Definition 
Intent-to-Treat Analysis Set 
All subjects randomized. 
Safety Analysis Set 
All subjects randomized who receive at least one dose of 
study medication. 
PK Analysis Set 
All subjects with at least 1 ENTO plasma concentration  
Biomarker Analysis Set 
All subjects with at least 1 biomarker assessment result 


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9.4 
Statistical Analyses 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP). Described below is a summary of the planned 
statistical analyses of the primary and key secondary endpoints. 
9.4.1 
General Considerations 
Summary statistics and listings will be used to analyze the study data. Continuous variables will 
be summarized by means, standard deviations, medians, interquartile ranges, minimal and 
maximal values. Categorical variables will be summarized by number and percentage. Any 
statistical testing will be conducted at the alpha = 0.05 level (2-sided). 
Unless otherwise specified, data summaries and analyses described below will be reported by 
treatment group.  
9.4.2 
Primary Endpoint 
Measurable Residual Disease Negative Complete Response 
The primary efficacy endpoint is the proportion of subjects who achieve CR without MRD (MRD 
negative [<0.01%] CR rate) Post-Chemotherapy Cycle 2 as defined by the absence of NPM1-m 
alleles in bone marrow aspirate based on a molecular assay (eg, next generation sequencing) in a 
central reference laboratory designated by the Sponsor.   
9.4.2.1 
Statement of Estimand 
The population for the trial is defined through appropriate inclusion/exclusion criteria to reflect 
the targeted patient population for approval, adults with previously untreated NPM1-m AML who 
are candidates for intensive induction/consolidation chemotherapy. The analysis population is 
based on the Intent-to-treat Analysis set and includes subjects who have been randomized.  
The treatments of interest are ENTO or placebo in combination with intensive induction and 
consolidation chemotherapy. 
The variable of interest is the MRD negative CR rate post-Chemotherapy Cycle 2. 
The ability to evaluate treatment effect using the variable may be impacted by intercurrent 
events. Death, use of additional leukemic treatments, and premature discontinuation of study 
drug may all impact the interpretation of treatment effect. Given that death equates to a poor 
outcome, a composite strategy will be implemented including all available data through the 
evaluation of response post-Chemotherapy Cycle 2; subjects who die before the end of  
Chemotherapy Cycle 2 will be considered as not having achieved MRD negative CR.   
The population level summary measure is the risk difference (difference in the proportion of 
subjects with MRD negative CR Post-Chemotherapy Cycle 2). 
 


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Primary Endpoint Analysis 
The primary evaluation of the primary analysis endpoint will be conducted utilizing the estimand 
as described in Section 9.4.2.1. Subjects with a missing evaluation of MRD post-Chemotherapy 
Cycle 2 will be imputed as failures for the analysis. Additional information on the handling of 
missing data, planned sensitivity measures, and supportive analyses will be detailed in the SAP.  
Risk difference will be estimated using stratum-adjusted Mantel-Haenszel proportions, and 95% 
confidence intervals around the treatment difference will be calculated. The differences are 
weighted by the harmonic mean of the sample size in each treatment group per stratum 
(age < 60 vs ≥ 60 years; daunorubicin vs idarubicin anthracycline). If n1h and n2h are the sample 
sizes of the two treatment groups for a given comparison, say treatment groups 1 and 2, in any 
given stratum, called stratum h, then the weight in stratum h is given by, 
h
h
h
h
h
n
n
n
n
w
2
1
2
1
+
=
Let dh=p1h-p2h be the difference in the proportion of subjects with MRD negative CR in treatment 
group 1 and treatment group 2 in stratum h. The stratum-adjusted Mantel-Haenszel proportion is 
given by, 
∑
∑
=
h
h
h
h
h
w
d
w
d
The continuity corrected variance is given by, 
(
)
(
)
2
2
*
2
*
2
1
*
1
*
1
2
1
1
1
1
var












−
−
+
−
−
=
∑
∑
h
h
h
h
h
h
h
h
h
h
w
n
p
p
n
p
p
w
where
1
5.0
1
1
*
1
+
+
=
h
h
h
n
m
p
,  
1
5.0
2
2
*
2
+
+
=
h
h
h
n
m
p
,  m1h and m2h are the number of subjects with MRD 
negative CR in treatment groups 1 and 2, respectively.  
9.4.3 
Secondary Endpoint(s) 
The secondary endpoint variables and their population level summary measures will be described in 
each of the following sections. The evaluation of the population for the trial, treatments of 
interest, and the possible intercurrent events are as described in Section 9.4.2.1. All secondary 
endpoints will include death as part of definition of the variable. Intercurrent events of additional 
leukemic therapy and premature study treatment discontinuation will be ignored for the primary 
evaluation of these endpoints. Additional information on the handling of missing data and 
sensitivity analyses will be detailed in the SAP. 
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Event-free survival 
Event-free survival (EFS) is defined as time from randomization to the earliest of induction 
treatment failure (ITF), relapse for those who achieve CR, or death from any cause. ITF is failure 
to achieve morphological CR after completion of the last cycle of induction chemotherapy (no 
later than Day 42 of the last cycle of induction). Subjects who experience ITF will be treated as 
events at Day 1. 
Subjects who do not experience an event (ITF, relapse from CR, or death) will be censored at their 
last study evaluation at which they were relapse free. Event-free survival will be estimated using 
the method of Kaplan-Meier (K-M) and summarized by treatment group. Differences between the 
treatment groups will be assessed with the log rank test stratified by age (<60 vs ≥60 years) and 
choice of anthracycline in induction (daunorubicin vs idarubicin). The population level summary 
measure will be the adjusted hazard ratio as calculated from a Cox proportional hazards model 
with effects for treatment, age, and choice of anthracycline in induction. 
Relapse free survival  
For subjects who achieve CR, relapse free survival (RFS) is defined as the time from CR to 
morphologic relapse as assessed by the study site investigator or death from any cause, whichever 
comes first. Subjects who do not experience a relapse or death will be censored at the last study 
evaluation at which they were relapse free. RFS will be estimated using the K-M method and 
summarized by treatment group. The population level summary measure will be the adjusted 
hazard ratio as calculated from a Cox proportional hazards model with effects for treatment, age, 
and choice of anthracycline in induction. 
Overall survival  
Overall survival is defined as the time from randomization to death from any cause. Subjects 
who are alive at last contact will be censored at their date of last contact. Overall survival will be 
estimated using the K-M method and summarized by treatment group. Differences between the 
treatment groups will be assessed with the log rank test stratified by age (< 60 vs ≥ 60 years) and 
choice of anthracycline in induction (daunorubicin vs idarubicin). The population level summary 
measure will be the adjusted hazard ratio as calculated from a Cox proportional hazards model 
with effects for treatment, age, and choice of anthracycline in induction. 
Categorical secondary endpoints will be analyzed similarly to the primary efficacy endpoint, and 
other time-to-event secondary endpoints will be analyzed similarly to EFS. To avoid inflation of 
Type I error for the secondary endpoints, statistical comparisons will be made at the time of the 
confirmatory analysis using a hierarchical approach with EFS tested first followed by RFS, and 
then overall survival. Details of the hierarchical analysis will be provided in the SAP.  
9.4.4 
Safety Analysis 
All safety analyses will be conducted on the Safety Analysis Set. 
Treatment-emergent adverse events (TEAEs) defined as all events beginning or worsening from 
Cycle 1, Day 1 through 30 days following study treatment completion, will be coded according to 
the most current version of the Medical Dictionary for Regulatory Activities (MedDRA) and will 


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be summarized by treatment group, system organ class, and preferred term. Unless otherwise 
specified, only TEAEs will be reported in safety summaries and listings.  
Additional summaries by seriousness, severity, causality, and outcomes will also be prepared. 
Adverse events leading to ENTO dose reduction or discontinuation as well as those with an 
outcome of death will be summarized with descriptive statistics. Changes from baseline in selected 
laboratory assessments of interest will be summarized by treatment group and severity grade. 
9.5 
Timing of Analyses 
9.5.1 
Data Monitoring Committee 
An independent DMC, consisting of two expert hematologists and one expert biostatistician will 
monitor emerging safety and efficacy data from this trial on an ongoing basis. The DMC will 
provide a suitable recommendation to the Sponsor for appropriate study direction. Such direction 
may include continuation of the trial as planned, modification of study conduct/design or early 
termination based on safety or futility. A DMC charter delineates the responsibilities of the DMC 
and its interactions with other trial components. Data monitoring committee analyses will be 
focused on safety and efficacy endpoints and will be conducted regularly as outlined in the DMC 
charter. 
9.5.2 
Blinded Review of EFS Events 
Prior to unblinding for the primary endpoint analysis, the sponsor will review the number of EFS 
events achieved. If the rate of events is slower than anticipated, the sponsor may propose an 
increase in sample size in order to achieve the events necessary for the confirmatory analysis of 
EFS. The increase will be based on the original sample size assumptions for hazard ratio and 
two-year EFS rate of the placebo group. The proposed sample size increase will be shared with 
the DMC and appropriate regulatory agency prior to implementation. Given that the review will 
be conducted in a blinded fashion, no adjustment for Type 1 error is proposed. 
9.5.3 
Primary Endpoint Analysis 
The primary endpoint analysis will be conducted once 180 subjects complete Chemotherapy 
Cycle 2 (or discontinue study participation prior to the assessment) and the resulting database is 
cleaned and locked.  
9.5.4 
EFS Analysis 
A final EFS analysis will be conducted once the pre-specified number of events have been reported 
and the resulting database is cleaned and locked. 
 


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10.0 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
o Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
o Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The protocol and protocol amendments will be submitted to the regulatory agencies by the 
Sponsor, as applicable.  
• The protocol and any substantial amendments to the protocol will require health authority 
approval prior to initiation, where applicable, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC. 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations. 
10.1.2 
Financial Disclosure 
Investigators are required to provide the sponsor with complete and accurate financial information 
in accordance with regulations to allow the sponsor to submit disclosure or certification of the 
absence of certain financial interest or to disclose those financial interests as required, to the 
appropriate health authorities. This is to ensure that financial interests and arrangements between 


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clinical investigators and Kronos Bio, which could affect the reliability of data submitted to health 
authorities, are identified, and disclosed. Investigators are responsible for providing information 
about their financial interests before their participation in the study and to update this information 
if any relevant changes occur during the study and for 1 year after completion of the study. 
10.1.3 
Informed Consent Process 
The investigator is responsible for obtaining written, informed consent from each prospective 
study subject using the IRB/IEC-approved consent form, after adequately explaining the 
objectives, methods, and potential hazards of study participation and before conducting study-
related procedures or assessments. Each informed consent form will be signed and dated by the 
subject or, where permissible by local laws and regulations, the subject’s legally authorized 
representative and the person obtaining consent.  
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study. A copy of the ICF(s) must be provided to the subject or their legally authorized 
representative. The process of obtaining informed consent and contents of the informed consent 
form will be in accordance with the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, and the 
IRB/IEC or study center. 
If a subject chooses to withdraw from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. If the subject 
withdraws consent for disclosure of future information, the sponsor may retain and continue to use 
any data collected before withdrawal of consent. 
10.1.4 
Data Protection 
Subjects will be assigned a unique identifier by the Sponsor. Any subject’s records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject’s names or any information 
which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection laws. The level of disclosure must also be explained to 
the subject who will be required to give consent for their data to be used as described in the 
informed consent. 
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, appropriate IRB/IEC 
members, and inspectors from regulatory agencies. 
10.1.5 
Dissemination of Clinical Study Data 
A clinical study report will be prepared detailing the outcomes of this study and provided to 
regulatory authorities including the US FDA and others, as applicable. Kronos Bio will ensure that 
this report meets the standards set out in the ICH Guideline for Structure and Content of Clinical 
Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain cases. 


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Results from this study will be published or presented at scientific meetings in a timely and 
objective manner regardless of the outcome of the study in a manner consistent with good science, 
industry and regulatory guidance, and in accordance with the terms of the applicable clinical study 
agreement.  Data generated in this clinical study are the exclusive property of the sponsor and will 
remain confidential until such time as they are publicly disclosed. As this is a multicenter study, 
the first publication or disclosure of study results shall be a joint, multicenter publication or 
disclosure coordinated by the sponsor or its designee. Thereafter, any secondary publications will 
reference the first (original) publication. Authorship shall be determined by mutual agreement and 
all authors must meet the criteria for authorship established by the International Committee of 
Medical Journal Editors Uniform Requirements for manuscripts or alternatively, stricter local 
criteria (International Committee of Medical Journal Editors, 2013). 
No communication, presentation or publication will include Kronos Bio’s confidential 
information. 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor prior to submission for peer-review or 
presentation in accordance with the terms outlined in the clinical study agreement. This will allow 
the sponsor to protect proprietary information, provide comments based on information from other 
studies that may not yet be available to the investigator and ensure scientific and clinical accuracy. 
The procedure for reviewing manuscripts and presentations that are based on results from this 
study is detailed in the investigator’s clinical study agreement. Each investigator acknowledges 
and agrees that in accordance with the clinical study agreement, a delay in publication/presentation 
may be requested by the sponsor to allow for patent filings in advance of the latter or deletion of 
sponsor’s confidential information. 
10.1.6 
Data Quality Assurance 
Data required by the study protocol will be entered into eCRFs in an EDC system that is compliant 
with all regulatory requirements. All study-related data collected or received by the investigator or 
study team shall be promptly entered into the eCRFs after the data is collected or received by the 
investigator or study team in a time frame consistent with what is stipulated in the study site 
contract. 
Data recording onto eCRFs must follow the data entry instructions provided in the eCRF 
completion guidelines. The investigator has ultimate responsibility for the collection and reporting 
of all clinical data. The investigator or his/her designee in the “Statement of Investigator Form” at 
the front of this protocol must sign the completed casebooks to attest to their accuracy, authenticity, 
and completeness. 
All final patient data recorded onto eCRFs as well as external data (eg, central laboratory 
assessments) collected in accordance with this protocol will be stored at Kronos Bio or a 
designated off-site facility at the end of the study. Data will be reviewed for the presence of 
potential outliers or inconsistencies as well as for logic and completeness. Standard procedures 
including data review guidelines, computerized validation for query generation and maintenance 
of an audit file that includes database modifications will be followed to ensure accurate data 
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10.1.7 
Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the eCRF. During the course of the study, a study monitor will make regular visits to 
the study site or engage with the study site via videoconference or through other digital media to 
review protocol compliance, compare data entered onto eCRFs with individual study subjects’ 
medical records (ie, source data verification) and ensure that the study is being conducted in 
accordance with pertinent regulatory requirements. The source data verification process will be 
conducted in a manner to ensure that the confidentiality of study subjects is maintained. Direct 
access to source data will also be required for inspections and audits and be carried out with due 
consideration to data protection and confidentiality. 
10.1.8 
Study/Site Termination 
The sponsor or designee reserves the right to close a study site(s) or terminate the study at any 
time for any reason at its sole discretion. Study sites will be closed upon study completion. A study 
site is considered closed when all required documents and study supplies have been collected and 
a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to: 
For study termination: 
• Discontinuation of all evaluation of the study’s objectives and endpoints. 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects by 
the investigator 
• Total number of subjects enrolled is earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform study subjects and assure the 
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10.1.9 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a coordinating investigator 
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10.3 
Appendix 3: Contraceptive and Barrier Guidance 
10.3.1 
Definitions 
Women in the following categories are not considered Women of Childbearing potential (WOCBP) 
1. Premenopausal female with one of the following: 
• Documented hysterectomy. 
• Documented bilateral salpingectomy. 
• Documented bilateral oophorectomy. 
Documentation can come from a review of the patient’s medical records, medical examination, 
or medical history interview. 
2. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy (HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonhormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
10.3.2 
Contraception Guidance 
Male subjects 
Male subjects with female partners of child-bearing potential are eligible to participate if they 
agree to the following during the study:  
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinence on a long term and persistent basis) and agree to remain abstinent for the 
duration of study and for at least 3 months after the last dose of study medication. 
• Female partner is using a highly effective contraceptive method, including one of the highly 
effective contraceptives listed in the table below.  
• Agree to use a male condom.   
• Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a condom during the study.  
• Refrain from donating sperm for the duration of study and for at least 3 months after the 
last dose of study medication. 
 


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Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly,a  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulation.b  
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation.b  
• 
Oral  
• 
Injectable  
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP, and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred 
and usual lifestyle of the patient.  
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local 
regulations regarding the use of contraceptive methods for subjects participating in clinical studies.  
b) Based on current knowledge, drug-drug interactions are not expected between ENTO and hormonal contraceptives that 
could potentially reduce their effectiveness in pregnancy prevention. Nevertheless, WOCBP using one of the highly 
effective, hormonal contraceptives described above (either birth control pills or implantable devices) will be required to 
also employ a barrier method of contraception (eg. condom use by a male partner, diaphragm, or cervical cap) for at least 
3 months after the last dose of study treatment.  
Female subjects 
Female subjects of reproductive potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in the table above in 
combination with a barrier method (eg, condom use by a male partner, diaphragm, or cervical cap), 
as noted above.  
10.3.3 
Pregnancy Testing  
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test at Screening and a negative urine pregnancy test on Day 1 of each 
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10.3.3.1 
Collection of Pregnancy Information  
Male subjects with partners of reproductive potential who become pregnant  
• The investigator will attempt to collect pregnancy information on any female partner of a male 
study subject who becomes pregnant while participating in this study. This applies only to 
subjects who receive study treatment. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor or designee within 24 hours of learning of the partner’s pregnancy.  
• The partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the sponsor or designee.  
• Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
Female subjects who become pregnant  
• The investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  
• Information will be recorded on the appropriate form and submitted to the sponsor or designee 
within 24 hours of learning of a subject’s pregnancy.  
• The subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow up information on the subject and the neonate, which will be forwarded to the 
sponsor or designee. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. 
• Any termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure.  
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. 
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• Any SAE occurring as a result of a post-study pregnancy that is considered reasonably related 
to the study treatment by the investigator, will be reported to the sponsor or designee.  While 
the investigator is not obligated to actively seek this information in former study subjects, he 
or she may learn of an SAE through spontaneous reporting.  
Any female subject who becomes pregnant while participating will discontinue study treatment 
but may continue to be followed for leukemic progression/relapse, first salvage therapy and 
survival. Further treatment options will be discussed. 
 
 


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10.4 
Appendix 4: Response Criteria  
Complete Response (CR)* 
CR requires all the following: 
• 
Bone marrow blasts < 5% 
• 
Absence of circulating blasts and blasts with Auer rods 
• 
Absence of extramedullary disease (ie, leukemia outside of bone marrow confirmed by 
biopsy) 
• 
Absolute neutrophil count > 1.0 x 109/L (1000/μL) 
• 
Platelet count > 100 x 109/L (100,000/μL) 
Note: *MRD positive or unknown 
Complete Response with Hematologic Improvement (CRh)** 
CRh requires all the CR criteria, except for residual thrombocytopenia and/or neutropenia and is 
defined as:  
• 
Bone marrow blasts < 5% 
• 
Absence of circulating blasts and blasts with Auer rods 
• 
Absence of extramedullary disease  
• 
Absolute neutrophil count > 0.5 x 109/L (500/μL) 
• 
Platelet count > 50 x 109/L (50,000/μL) 
Complete Response with Incomplete Blood Count Recovery (CRi)** 
CRi requires all the CR criteria, except for residual neutropenia or thrombocytopenia and is defined 
as: 
• 
Bone marrow blasts < 5% 
• 
Absence of circulating blasts and blasts with Auer rod 
• 
Absence of extramedullary disease 
• 
Absolute neutrophil count ≤ 1.0 x 109/L (1000/μL) or platelet count ≤ 100 x 109/L 
(100,000/μL) 
Note: **If subjects meet criteria for both CRh and CRi, they should be classified as CRh 
Morphologic Leukemia Free State (MLFS)*** 
• 
Bone marrow blasts < 5% 
• 
Absence of blasts with Auer rods 
• 
Absence of extramedullary disease 
• 
No hematologic recovery required 
Note: *** Marrow should not be merely “aplastic”; at least 200 cells should be enumerated or 
cellularity on bone marrow biopsy should be at least 10% of normal. 
Partial Response (PR) 
PR meets all hematologic criteria of CR: 
• 
Absolute neutrophil count > 1.0 x 109/L (1000/μL) 


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• 
Platelet count > 100 x 109/L (100,000/μL), and 
• 
Residual bone marrow blast percentage of 5% to 25% 
• 
Reduction of bone marrow blast percentage by ≥ 50% compared with pretreatment 
Stable Disease (SD) 
Absence of MRD negative CR, CR, CRh, CRi, PR, MLFS and criteria for PD not met.  
Progressive Disease (PD) 
Evidence for an increase in bone marrow blast percentage and/or circulating blast counts as defined 
by at least one of the following: 
• 
> 50% increase in bone marrow blasts over baseline (a minimal absolute 15% increase 
is required in cases with < 30% blasts at baseline), or 
• 
Persistent bone marrow blast percentage > 70% over ≥ 3 months without at least a 
100% improvement in ANC to an absolute level > 0.5 x 109/L (500/μL) and/or platelet 
count to > 50 x 109/L (50,000/μL) without transfusion, or 
• 
> 50% increase in circulating blasts to > 25 x 109/L (>25,000/μL) in the absence of 
Differentiation Syndrome,**** or 
• 
New extramedullary disease 
**** Certain targeted therapies, for example, those inhibiting mutant IDH proteins, other kinase 
or targets may cause a transient increase in the percentage of bone marrow blasts accompanied by 
an increase in circulating blasts (differentiation syndrome). In the setting of therapy with such 
compounds, an increase in blasts may not necessarily indicate progressive disease. Such instances 
should be discussed with the study medical monitor on a case-by-case basis.  
Recurrence 
Recurrence for subjects with prior MRD-CR, morphological CR, CRh, CRi, or MLFS is defined 
as: 
Morphologic relapse as defined by the reappearance of circulating blasts or ≥ 5% blasts in the bone 
marrow not attributable to any other cause.  
Note: In the setting of recent treatment, if there are no circulating blasts and the bone marrow 
contains 5 to 20% blasts, a bone marrow aspirate/biopsy should be repeated within 1 week to 
distinguish relapse from bone marrow regeneration. 
Reappearance of cytologically or biopsy documented extramedullary disease, including new CNS 
disease or other new sites of extramedullary involvement.  
Note: The reappearance of a cytogenetic or molecular abnormality would be considered a 
cytogenetic or molecular relapse. In the absence of morphologic relapse, this would not be 
considered a recurrence. 
 


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10.5 
Appendix 5: New York Heart Association Classification 
 
 
 
 
 
 
 
 
 
 
 
Source: The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnoses of Diseases of the 
Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co;1994:253-256. 
 
 


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10.6 
Appendix 6: ECOG Performance Status Scale 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Not confined to bed more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
Adapted from: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5:649-655. 
 
 


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10.7 
Appendix 7: Potential for Drug-Drug Interactions 
Concomitant administration of study treatment with medications listed below could result in drug-
drug interactions that potentially lead to reduced activity or enhanced toxicity of the concomitant 
medication and/or ENTO. 
The following list of prohibited medications is not comprehensive and only meant to be used as a 
guide. 
Proton pump inhibitors* 
Omeprazole, esomeprazole, pantoprazole, lansoprazole, 
rabeprazole, dexlansoprazole 
Strong CYP3A inducers 
Rifampin, mitotane, avasimibe, rifapentine, apalutamide, 
ivosidenib, phenytoin, carbamazepine, enzalutamide, St 
John’s wort, lumacaftor, phenobarbital 
Strong CYP2C9 inducers 
(none reported) 
Moderate CYP2C9 inducers 
Rifampin, enzalutamide, ritonavir, carbamazepine 
*Short term PPI use during the study treatment period (for up to 10 consecutive days) is permitted for management of 
acute gastrointestinal bleeding.  Any requirement for longer exposures should prompt discontinuation of study 
medication per Section 7.1 (Need for or use of a prohibited concomitant medication). 
 
A more comprehensive listing of strong CYP3A inducers, and strong or moderate CYP2C9 
inducers to avoid can be found at: Flockhart DA. Drug Interactions: Cytochrome P450 Drug 
Interaction 
Table, 
Indiana 
University 
School 
of 
Medicine 
(2007). 
https://drug-
interactions.medicine.iu.edu 
The following table lists dose adjustment requirements for concurrently administered HMG-CoA 
reductase inhibitors. 
HMG-CoA Reductase Inhibitor 
Dose Adjustment Required 
Atorvastatin 
Maximum dose 20 mg QD 
Rosuvastatin 
Maximum dose 10 mg QD 
Pravastatin 
Maximum dose 40 mg QD 
Simvastatin 
Maximum dose 20 mg QD 
Lovastatin 
Maximum dose 20 mg QD 
Fluvastatin 
Maximum dose 20 mg BID or 40 mg QD 
Pitavastatin 
Maximum dose 1 mg QD 


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10.8 Appendix 8: Recommended Adjustments to Anti-Platelet and Anti-
Coagulant Therapy in AML 
1. If aspirin is administered for primary prevention of cerebrovascular events, discontinue. If 
given for secondary prevention of cerebrovascular events, interrupt when platelets count is 
< 30,000/μL. Resume when platelet count is ≥ 30,000/μL. 
 
2. Coronary artery stents (bare metal and drug eluting): Work closely with a consulting 
cardiologist to adjust anti-platelet therapy especially within first month of bare stent 
placement and first year of drug eluting stent placement. Consider holding aspirin and 
Plavix® when platelet count is < 20,000/μL and then resume when ≥ 20,000/μL if supported 
by cardiology consult recommendations, especially within first year of stent placement. 
 
3. Atrial fibrillation: If patient is on aspirin only, hold when platelet count is < 50,000/µL and 
restart when consistently ≥ 50,000/μL. If patient is on anti-coagulant therapy (eg,  Factor 
Xa antagonist), treat with therapeutic doses of low molecular weight heparin (LMWH) 
until platelet count is < 50,000/μL, treat with prophylactic doses for platelet counts between 
20-50,000/μL and hold for platelet counts < 20,000/μL. 
 
4. Mechanical heart valves: Work closely with a consulting cardiologist. Treat with 
therapeutic doses of LMWH until platelet count < 40,000/μL. Treat with prophylactic 
doses when platelet count is between 20-40,000/μL. Consider holding for platelet counts < 
20,000/μL. Alternatively, consider platelet transfusions in order to allow continuation of 
anti-coagulant therapy, based on a recommendation from cardiology consultation. 
  
5. Acute events: 
a. Catheter thrombosis: Remove catheter, consider anticoagulation if symptomatic 
and platelet count ≥ 50,000/μL. 
b. Distal thrombosis: Follow-up scans in 3 days and every week for 6 weeks to make 
sure thrombosis does not progress.  
c. Proximal thrombosis and pulmonary embolism: Treat with therapeutic doses of  
LMWH if platelet count is ˃40,000/μL, prophylactic doses if platelet count is 
20-40,000/μL and retrievable inferior vena filter if platelet count is < 20,000/μL on 
a case-by-case basis after discussion with cardiology consult and the medical 
monitor. 
6. Acute coronary syndrome: administer aspirin to all subjects, regardless of platelet count. 
Individualize therapy based on cardiology consultation (patient may need to discontinue 
study participation after discussion with medical monitor). 
 
 


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10.9 
Appendix 9: Guidance on the Management of Clinical Trials During 
COVID-19 Pandemic 
FDA Guidance on the Conduct of Clinical Trials of Medical Products During the COVID-19 
Public Health Emergency 
EU Guidance on the Management of Clinical Trials During COVID-19 Pandemic 
Supplementary Recommendations to EU Guidance on the Management of Clinical Trials 
During the COVID-19 (Coronavirus) Pandemic 


Contains Nonbinding Recommendations 
Conduct of Clinical Trials of 
Medical Products During the 
COVID-19 Public Health 
Emergency 
Guidance for Industry, 
Investigators, and Institutional 
Review Boards 
March 2020 
Updated on August 30, 2021 
For questions on clinical trial conduct during the COVID-19 pandemic, please 
email 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
Oncology Center of Excellence (OCE) 
Office of Good Clinical Practice (OGCP) 


Contains Nonbinding Recommendations 
Preface
Public Comment
This guidance is being issued to address the Coronavirus Disease 2019 (COVID-19) public 
health emergency.  This guidance is being implemented without prior public comment because 
the Food and Drug Administration (FDA or Agency) has determined that prior public 
participation for this guidance is not feasible or appropriate (see section 701(h)(1)(C) of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 371(h)(1)(C)) and 21 CFR 
10.115(g)(2)).  This guidance document is being implemented immediately, but it remains 
subject to comment in accordance with the Agency’s good guidance practices. 
Comments may be submitted at any time for Agency consideration.  Submit written comments to 
the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.  Submit electronic comments to https://www.regulations.gov.  
All comments should be identified with the docket number FDA-2020-D-1106 and complete title 
of the guidance in the request. 
Additional Copies
Additional copies are available from the FDA web page titled “COVID-19-Related 
Guidance Documents for Industry, FDA Staff, and Other Stakeholders,” available at 
https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/covid-19-related-
guidance-documents-industry-fda-staff-and-other-stakeholders, and the FDA web page 
titled “Search for FDA Guidance Documents,” available at https://www.fda.gov/
regulatory-information/search-fda-guidance-documents.  You may also send an email 
request to
 to receive an additional copy of the 
guidance.  Please include the docket number FDA-2020-D-1106 and complete title of the 
guidance in the request. 
Questions
For questions about this document, contact us via email at 
 


Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I. 
INTRODUCTION ...............................................................................................................1 
II. 
BACKGROUND..................................................................................................................2 
III. 
DISCUSSION ......................................................................................................................3 
IV. 
ADDITIONAL RESOURCES ...........................................................................................6 
APPENDIX:  QUESTIONS AND ANSWERS ............................................................................7 
 
 
 




Contains Nonbinding Recommendations 
2 
This policy is intended to remain in effect only for the duration of the public health emergency 
related to COVID-19 declared by the Secretary of Health and Human Services (HHS) on January 
31, 2020, effective January 27, 2020, including any renewals made by the HHS Secretary in 
accordance with section 319(a)(2) of the Public Health Service Act (PHS Act) (42 U.S.C. 
247d(a)(2)). 
Given this public health emergency, and as discussed in the Notice in the Federal Register of 
March 25, 2020 (85 FR 16949), titled “Process for Making Available Guidance Documents 
Related to Coronavirus Disease 2019,” available at https://www.govinfo.gov/content/pkg/FR- 
2020-03-25/pdf/2020-06222.pdf, this guidance is being implemented without prior public 
comment because FDA has determined that prior public participation for this guidance is not 
feasible or appropriate (see section 701(h)(1)(C) of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) and 21 CFR 10.115(g)(2)).  This guidance document is being implemented 
immediately, but it remains subject to comment in accordance with the Agency’s good guidance 
practices. 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract.  This document is 
intended only to provide clarity to the public regarding existing requirements under the law.  
FDA guidance documents, including this guidance, should be viewed only as recommendations, 
unless specific regulatory or statutory requirements are cited.  The use of the word should in 
FDA guidances means that something is suggested or recommended, but not required. 
II.
Background
There is currently an outbreak of respiratory disease caused by a novel coronavirus.  The virus 
has been named “SARS-CoV-2” and the disease it causes has been named “Coronavirus Disease 
2019” (COVID-19).  On January 31, 2020, HHS issued a declaration of a public health 
emergency related to COVID-19 and mobilized the Operating Divisions of HHS.2  In addition, 
on March 13, 2020, there was a Presidential declaration of a national emergency in response to 
COVID-19.3   
FDA recognizes that the COVID-19 public health emergency may impact the conduct of clinical 
trials of medical products.  Challenges may arise, for example, from quarantines, site closures, 
travel limitations, interruptions to the supply chain for the investigational product,4 or other 
considerations if site personnel or trial participants become infected with COVID-19.  These 
challenges may lead to difficulties in meeting protocol-specified procedures, including 
2 Secretary of Health and Human Services, Determination that a Public Health Emergency Exists (originally issued 
Jan. 31, 2020, and subsequently renewed), available at 
https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx. 
3 Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) 
Outbreak (Mar. 13, 2020), available at https://trumpwhitehouse.archives.gov/presidential-actions/proclamation-
declaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/.    
4 For the purposes of this guidance, the term investigational product refers to human drugs and biological 
products, as well as medical devices. 


Contains Nonbinding Recommendations 
 
3 
 
administering or using the investigational product or adhering to protocol-mandated visits and 
laboratory/diagnostic testing.  FDA recognizes that protocol modifications may be required, and 
that there may be unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 
public health control measures.  Although the necessity for, and impact of, COVID-19 public 
health control measures on trials will vary depending on many factors, including the nature of 
disease under study, the trial design, and in what region(s) the study is being conducted, FDA 
outlines the following general considerations to assist sponsors in assuring the safety of trial 
participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to 
trial integrity.  The appendix further explains those general considerations by providing answers 
to questions about conducting clinical trials that the Agency has received during the COVID-19 
public health emergency. 
 
 
III. Discussion 
 
A. 
Considerations for ongoing trials: 
 
• Ensuring the safety of trial participants is paramount.  Sponsors should consider 
each circumstance, focusing on the potential impact on the safety of trial 
participants, and modify study conduct accordingly.  Study decisions may include 
those regarding continuing trial recruitment, continuing use of the investigational 
product for patients already participating in the trial, and the need to change 
patient monitoring during the trial.  In all cases, it is critical that trial participants 
are kept informed of changes to the study and monitoring plans that could impact 
them. 
 
• Sponsors, in consultation with clinical investigators and Institutional Review 
Boards (IRBs)/Independent Ethics Committees (IECs), may determine that the 
protection of a participant’s safety, welfare, and rights is best served by 
continuing a study participant in the trial as per the protocol or by discontinuing 
the administration or use of the investigational product or even participation in the 
trial.  Such decisions will depend on specific circumstances, including the nature 
of the investigational product, the ability to conduct appropriate safety 
monitoring, the potential impact on the investigational product supply chain, and 
the nature of the disease under study in the trial.  
 
• Since trial participants may not be able to come to the investigational site for 
protocol-specified visits, sponsors should evaluate whether alternative methods 
for safety assessments (e.g., phone contact, virtual visit, alternative location for 
assessment, including local labs or imaging centers) could be implemented when 
necessary and feasible, and would be sufficient to assure the safety of trial 
participants.  Sponsors should determine if in-person visits are necessary to fully 
assure the safety of trial participants (for example, to carry out procedures 
necessary to assess safety or the safe use of the investigational product 
appropriately); in making the decision to continue use or administration of the 
investigational product, the sponsor should consider whether the safety of trial 


Contains Nonbinding Recommendations 
 
4 
 
participants can be assured with the implementation of the altered monitoring 
approach. 
 
• In some cases, trial participants who no longer have access to investigational 
product or the investigational site may need additional safety monitoring (e.g., on 
withdrawal of an active investigational treatment). 
 
• The need to put new processes in place or to modify existing processes will vary 
by the protocol and local situation.  For example, this assessment could include 
consideration of whether it is appropriate to delay some assessments for ongoing 
trials, or, if the study cannot be properly conducted under the existing protocol, 
whether to stop ongoing recruitment, or even withdraw trial participants. 
 
• COVID-19 screening procedures that may be mandated by the health care system 
in which a clinical trial is being conducted do not need to be reported as an 
amendment to the protocol, even if done during clinical study visits, unless the 
sponsor is incorporating the data collected as part of a new research objective.  
 
• Changes in a protocol are typically not implemented before review and approval 
by the IRB/IEC, and in some cases, by FDA.  Sponsors and clinical investigators 
are encouraged to engage with IRBs/IEC as early as possible when urgent or 
emergent changes to the protocol or informed consent are anticipated as a result 
of COVID-19.  Such changes to the protocol or investigational plan to minimize 
or eliminate immediate hazards or to protect the life and well-being of research 
participants (e.g., to limit exposure to COVID-19) may be implemented without 
IRB approval or before filing an amendment to the investigational new drug 
(IND) or investigational device exemption (IDE), but are required to be reported 
afterwards.5  FDA encourages sponsors and investigators to work with their IRBs 
to prospectively define procedures to prioritize reporting of deviations that may 
impact the safety of trial participants.  
 
• The implementation of alternative processes should be consistent with the 
protocol to the extent possible, and sponsors and clinical investigators should 
document the reason for any contingency measures implemented.  Sponsors and 
clinical investigators should document how restrictions related to COVID-19 led 
to the changes in study conduct and duration of those changes, indicate which trial 
participants were impacted, and how those trial participants were impacted. 
 
• Changes in study visit schedules, missed visits, or patient discontinuations may 
lead to missing information (e.g., for protocol-specified procedures).  It will be 
important to capture specific information in the case report form that explains the 
basis of the missing data, including the relationship to COVID-19, for missing 
protocol-specified information (e.g., from missed study visits or study 
 
5 See 21 CFR 56.108(a)(4), 56.104(c), 312.30(b)(2)(ii), and 812.35(a)(2). 


Contains Nonbinding Recommendations 
 
5 
 
discontinuations due to COVID-19).  This information, summarized in the clinical 
study report, will be helpful to the sponsor and FDA.  
 
• If scheduled visits at clinical sites will be significantly impacted, certain 
investigational products, such as those that are typically distributed for self-
administration, may be amenable to alternative secure delivery methods.  For 
other investigational products that are normally administered in a health care 
setting, consulting FDA review divisions on plans for alternative administration 
(e.g., home nursing or alternative sites by trained but non-study personnel) is 
recommended.  In all cases, existing regulatory requirements for maintaining 
investigational product accountability remain and should be addressed and 
documented. 
 
• With respect to efficacy assessments, FDA recommends consultation with the 
appropriate review division regarding protocol modifications for the collection of 
efficacy endpoints, such as use of virtual assessments, delays in assessments, and 
alternative collection of research-specific specimens, if feasible.  For individual 
instances where efficacy endpoints are not collected, the reasons for failing to 
obtain the efficacy assessment should be documented (e.g., identifying the 
specific limitation imposed by COVID-19 leading to the inability to perform the 
protocol-specified assessment).   
 
• If changes in the protocol will lead to amending data management and/or 
statistical analysis plans, the sponsor should consider doing so in consultation 
with the applicable FDA review division.  Prior to locking the database, sponsors 
should address in the statistical analysis plan how protocol deviations related to 
COVID-19 will be handled for the prespecified analyses. 
 
• If planned on-site monitoring visits are no longer possible, sponsors should 
consider optimizing use of central and remote monitoring programs to maintain 
oversight of clinical sites.  
 
B. 
In general, and if policies and procedures are not already in place for 
applicable trials: 
 
• Sponsors, clinical investigators, and IRBs should consider establishing and 
implementing policy and procedures, or revise existing policy and procedures, to 
describe approaches to be used to protect trial participants and manage study 
conduct during possible disruption of the study as a result of COVID-19 control 
measures at study sites.  Changes to policy and procedures could address, but not 
be limited to, impact on the informed consent process, study visits and 
procedures, data collection, study monitoring, adverse event reporting, and 
changes in investigator(s), site staff, and/or monitor(s) secondary to travel 
restrictions, quarantine measures, or COVID-19 illness itself.  Policy and 
procedures should be compliant with applicable (regional or national) policy for 
the management and control of COVID-19.  Depending upon the nature of the 


Contains Nonbinding Recommendations 
6 
changes described above, a protocol amendment may be required under the 
applicable regulations.6   
C. 
For all trials that are impacted by the COVID-19 public health emergency: 
Sponsors should describe in appropriate sections of the clinical study report (or in a separate 
study-specific document): 
1. Contingency measures implemented to manage study conduct during disruption of the
study as a result of COVID-19 control measures.
2. A listing of all participants affected by the COVID-19 related study disruption by unique
trial participant number identifier and by investigational site, and a description of how the
individual’s participation was altered.
3. Analyses and corresponding discussions that address the impact of implemented
contingency measures (e.g., trial participant discontinuation from investigational product
and/or study, alternative procedures used to collect critical safety and/or efficacy data) on
the safety and efficacy results reported for the study.
Robust efforts by sponsors, investigators, and IRBs/IECs to maintain the safety of trial 
participants and study data integrity are expected, and such efforts should be documented.  As 
stated above, FDA recognizes that protocol modifications may be required, including 
unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 control measures.  
Efforts to minimize impacts on trial integrity, and to document the reasons for protocol 
deviations, will be important. 
IV. Additional Resources
For further questions on clinical trial conduct during the COVID-19 public health 
emergency, please email
 
Contact information for FDA’s review divisions is as follows: 
CDER:  https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/office-
new-drugs. 
CBER:  https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/
contacts-center-biologics-evaluation-research-cber#indcont. 
CDRH:  https://www.fda.gov/about-fda/cdrh-offices/cdrh-management-directory-organization. 
6 See 21 CFR 312.30(b) and 812.35(a).  Under applicable Federal regulations, investigators must engage with the 
Drug Enforcement Administration when amending protocols for research involving Schedule I substances under the 
Controlled Substances Act by requesting a modification to a site-specific investigator registration (see 21 CFR 
1301.18). 


Contains Nonbinding Recommendations 
 
7 
 
Appendix:  Questions and Answers 
 
Q1. 
Deciding whether to suspend, continue, or initiate trials ......................................................8 
Q2. 
Deciding whether to continue administering product appearing to provide benefit .............9 
Q3. 
Managing protocol deviations and amendments .................................................................10 
Q4. 
Submitting changes to IND and IDE protocol ....................................................................11 
Q5. 
Conducting remote (virtual) clinic visits .............................................................................11 
Q6. 
Capturing data on protocol and process deviations .............................................................12 
Q7. 
Delivering low-risk investigational products to home ........................................................12 
Q8. 
Disposal of unused investigational product .........................................................................13 
Q9. 
Changing site for delivering high-risk investigational product ...........................................14 
Q10. Alternative monitoring approaches .....................................................................................14 
Q11. Obtaining informed consent for patients in isolation ..........................................................15 
Q12. Obtaining informed consent from legally authorized representatives .................................17 
Q13. Obtaining informed consent when electronic and paper forms cannot be provided ...........18 
Q14. Remote clinical outcome assessments .................................................................................20 
Q15. Remote site monitoring visits ..............................................................................................22 
Q16. Challenges and temporary waivers for eCTDs ....................................................................24 
Q17. Shipping investigational product to local provider ‒ Form 1572 and accountability .........25 
Q18. Use of commercial vs. investigational products ..................................................................26 
Q19. Scheduling of meetings with review divisions ....................................................................27 
Q20. Use of alternative laboratory or imaging centers ................................................................28 
Q21. Use of video conferencing for trial visits ............................................................................28 
Q22. Postmarketing requirements for drugs, biologics, and devices ...........................................29 
Q23. Reporting serious adverse events for approved drugs used to treat COVID-19 .................31 
Q24. Reporting serious adverse events associated with COVID-19 in a non-COVID trial ........32 
Q25. Reviewing IND safety reports .............................................................................................33 
Q26. Collecting electronic signatures and Part 11 compliance ....................................................34 
Q27. Exclusion criteria for “investigational medical products” ..................................................35 
Q28. Re-monitoring after pandemic-related restrictions are lifted ..............................................36 
 
 


Contains Nonbinding Recommendations 
 
8 
 
Q1. 
What are some of the key factors that a sponsor should consider when deciding 
whether to suspend or continue an ongoing study or to initiate a new study during 
the COVID-19 public health emergency? 
 
Central to any decision should be ensuring that the safety of clinical trial participants can be 
maintained.  Sponsors, in consultation with clinical investigators and Institutional Review 
Boards (IRBs)/Independent Ethics Committees (IECs), should assess whether the protection of a 
participant’s safety, welfare, and rights is best served by continuing a study participant in the 
trial as per the protocol or by discontinuing the administration or use of the investigational 
product or even participation in the trial.  Such decisions will depend on specific circumstances, 
including the nature of the investigational product, the ability to conduct appropriate safety 
monitoring, the potential impact on the investigational product supply chain, and the nature of 
the disease under study in the trial.  As part of this assessment, sponsors should carefully 
consider the following aspects of clinical trial conduct when deciding how or whether to proceed 
with a clinical trial: 
 
• Assessing whether the limitations imposed by the COVID-19 public health 
emergency on protocol implementation pose new safety risks to trial participants, 
and whether it is feasible to mitigate these risks by amending study processes 
and/or procedures.   
 
• Assessing the continued availability of the clinical investigator/sub-investigators 
to provide oversight of the trial and properly assess and manage safety issues that 
may emerge.   
 
• Assessing whether there will be sufficient clinical trial support staff given the 
evolving COVID-19 situation and its impact on staff availability.  Are there 
appropriately trained staff that could be available to handle the expected tasks?  Is 
there adequate equipment and materials for clinical trial support staff? 
 
• Assessing whether clinical investigator sites will remain open to trial participants 
for required in-person assessments or whether the clinical investigator has the 
ability to provide required in-person assessments at an acceptable alternate 
location(s), or whether such protocol-specified, in-person assessments can instead 
be conducted virtually.   
 
• Assessing the continued availability of clinical trial supplies and continued 
operations of vendors, especially related to supply of the investigational product 
and/or to clinical trial supplies that are essential to maintaining appropriate safety 
monitoring or other key trial procedures.  This should include consideration of 
product stability (shelf life) if the treatment schedule is revised, or if the clinical 
site is unable to properly store the product for the needed duration. 
 
• Assessing the continued availability of, and support for, information technology 
systems and any other technological tools that are needed to support the trial.  Are 
current contingency plans adequate for the types of disruptions that might be 


Contains Nonbinding Recommendations 
 
9 
 
anticipated?  What other plans can be put in place to minimize any potential 
disruptions?  
 
• Assessing whether there will be continued operations of, and adequate 
communications with, IRB/IEC and Data Monitoring Committee (DMC) staff, if 
applicable, to support trial needs. 
 
• Assessing whether it is feasible to conduct the trial in light of any COVID-19 
public health measures implemented by Federal and State authorities to control 
the virus.  
 
Involvement of a study’s DMC, if one has been established, can provide support for the 
assessments discussed above.  Since a primary responsibility of the DMC is assuring the safety 
of participating trial participants, the DMC’s assessment of the impact of modifications of trial 
conduct due to COVID-19 on patient safety is important to consider.   
 
The risks and benefits of continuing a trial are likely different than a decision to initiate a trial 
(other than trials intended to evaluate investigational treatments or vaccines for COVID-19).  
Given the evolving situation, with likely increasing impacts on investigators, staff, and supply 
chains, sponsors should carefully consider the ability to effectively mitigate risks such that 
patient safety and trial integrity are assured.  In addition, it is important to consider whether 
initiation of the trial could interfere with public health measures implemented by Federal and 
State authorities to control the virus.  
 
Q2. 
What key factors should sponsors consider when deciding whether to continue 
administering or using an investigational product that appears to be providing 
benefit to the trial participant during the COVID-19 public health emergency?   
 
There may be circumstances in which an investigational product (either a drug, biological 
product, or medical device) appears to be providing benefit to the trial participant.  A sponsor 
deciding whether to continue administering or using such a product during the COVID-19 public 
health emergency should carefully consider context-dependent issues, including whether a trial 
participant appears to be benefitting from treatment with the investigational product, whether 
there are reasonable alternative treatments, the seriousness of the disease or condition being 
treated, and the risks involved in switching to an alternative treatment if necessary.  FDA 
recognizes that in some circumstances it may be necessary (e.g., based on lack of product supply 
or inability to administer or ensure the safe use of the investigational product) to discontinue 
investigational product administration in a trial.  If there are individual trial participants for 
whom discontinuing the investigational product might present a substantial risk (e.g., trial 
participants perceived by the investigator as having a clinical benefit from the investigational 
product), the sponsor should consider amending the protocol, after discussion with the relevant 
review division, to limit investigational product use to those patients with apparent benefit and 
discontinue investigational product use to other participants.  In all cases, if a trial participant is 
discontinued from an investigational therapy, it is important that there be appropriate 
management after discontinuation.   
 


Contains Nonbinding Recommendations 
 
10 
 
Q3. 
How should sponsors manage protocol deviations and amendments to ongoing trials 
during the COVID-19 public health emergency? 
 
FDA recognizes that during the COVID-19 public health emergency, sponsors of clinical trials 
may need to modify protocol-specified procedures.  As is discussed in the main body of this 
guidance, for protocol deviations necessitated by the impact of the current COVID-19 public 
health emergency, the sponsor should document the specific protocol deviation and the reason 
for the deviation.  The sponsor can document protocol deviations using its standard processes, or 
given the larger expected number of such deviations, use alternative documentation approaches.  
For example, if visits are to be conducted by telephone/video contact rather than at the 
investigational site as specified in the protocol, documentation that provides a listing of all study 
visits (e.g., listing study reference number, patient ID, date of visit) that are deviations from the 
protocol due to the current COVID-19 situation generally would be acceptable.  Protocol 
deviations should be included in final study reports and may also be included in annual reports.  
 
For a study-wide change in protocol conduct, under the IND regulations protocol amendments 
that are necessary to prevent imminent hazards to trial participants can generally be immediately 
implemented with subsequent submission and formal approval by the IRB and notification to 
FDA through filing a protocol amendment to the IND.7 
 
For studies under an IND, 21 CFR 312.30(b) specifies that sponsors must submit a protocol 
amendment to the IND describing any change in a phase 1 protocol that significantly affects the 
safety of trial participants or any change in a phase 2 and 3 protocol that significantly affects the 
safety of trial participants, the scope of the investigation, or the scientific quality of the study.  
Pausing enrollment in a trial to decrease potential exposure to COVID-19 would not generally be 
expected to significantly affect trial participant safety, the scope of the investigation, or the 
scientific quality of the study; therefore, submitting a protocol amendment would not be required 
under the regulation for such a pause.   
 
Protocol amendments that are not required to prevent imminent safety risks to patients can be 
implemented after they are submitted to FDA and IRB approval has occurred.8  
 
FDA recognizes that during the rapidly evolving circumstances of the current COVID-19 public 
health emergency, a sequence of changes may be needed to address those circumstances.  
Clinical investigators must document as protocol deviations any modifications to protocol-
specified procedures that occur prior to IRB approval and submission of the protocol amendment 
implementing the modification.9  Consolidating several protocol modifications in a single 
protocol amendment would be acceptable but should be submitted expeditiously.   
 
For studies under an IDE, 21 CFR 812.35(a) generally requires prior FDA approval before 
implementing changes to the investigational plan.  These requirements do not apply to changes 
made to protect the life or physical well-being of a trial participant in an emergency, including 
 
7 See 21 CFR 56.108(a)(4) and 312.30(b)(2)(ii). 
8 See 21 CFR 312.30(b)(2).  
9 See 21 CFR 312.62. 


Contains Nonbinding Recommendations 
 
11 
 
study-wide changes, but such deviations must be reported to FDA within 5 working days.10  In 
addition, under 21 CFR 812.35(a)(3), changes to the protocol that the sponsor determines, based 
on credible information, do not affect the validity of the results from the study, the likely patient 
risk-to-benefit relationship, the scientific soundness of the investigational plan, or the rights, 
safety, or welfare of the trial participants may be made without prior FDA approval, if the 
sponsor reports the modifications to the agency within 5 days of implementing the changes.  
Because of the unique and evolving circumstances surrounding the impact of COVID-19, we 
understand that it may be challenging to submit 5-day reports/notices within the required 
timeframe.  Sponsors may consolidate implemented changes when submitting 5-day 
reports/notices and should update the IDE as soon as possible.    
 
Q4. 
How should a sponsor submit a change in protocol that results from challenges 
related to the COVID-19 public health emergency? 
 
For IND studies, the sponsor should submit a formal amendment to its IND, with the following 
information added to the cover letter in the subject line:   
 
     PROTOCOL AMENDMENT – COVID-19 
 
     TITLE OF PROTOCOL 
 
Sponsors should summarize the major changes made to the protocol related to COVID-19 in the 
cover letter and should include a tracked changes version of the protocol to facilitate review.  As 
with other protocol amendments, sponsors may implement protocol amendments due to COVID-
19 upon submission to FDA if approved by the IRB.  Sponsors seeking FDA input prior to 
implementation should indicate that in the cover letter.    
 
For IDE studies, the sponsor should submit a supplement to its existing IDE, with the following 
information added to the cover letter in the subject line: 
 
     CHANGE IN PROTOCOL SUPPLEMENT – COVID-19 or  
     NOTICE OF IDE CHANGE – COVID-19, as applicable 
 
     TITLE OF PROTOCOL 
 
The submission to the IDE should contain a tracked changes version of the protocol to facilitate 
review.  
 
Q5. 
Can a sponsor initiate virtual clinical trial visits for monitoring patients without 
contacting FDA if there is an assessment by the sponsor and investigator that these 
visits are necessary for the safety of the trial participant and it will not impact data 
integrity? 
 
FDA regulations allow for changes to be made to the investigational plan or protocol without 
prior FDA review or approval, if the change is intended to eliminate an apparent immediate 
 
10 See 21 CFR 812.35(a)(2). 


Contains Nonbinding Recommendations 
 
12 
 
hazard or to protect the life and well-being of trial participants.11  Therefore, changes in protocol 
conduct necessary to immediately assure patient safety, such as conducting telephone or video 
contact visits for safety monitoring rather than on-site visits, can be immediately implemented 
with subsequent review by the IRB and notification to FDA.  Since this reflects a protocol 
deviation (until the amendment is approved), documentation of the required deviations, as 
described above, would generally be acceptable (i.e., a document that lists each deviation, study 
reference ID, patient ID, and date).  For example, documenting that all protocol-specified visits 
will be done by telephone contact rather than on-site visits, and that procedures requiring in-
person visits will either not be conducted, or performed by other means (specified, as 
appropriate).  Since the change to telephone or video contact visits would likely result in some 
protocol-required procedures not being conducted (e.g., vital signs, blood samples for safety 
laboratory studies), the sponsor must evaluate the potential impact on patient safety, and consider 
how to mitigate risks to patients, including the need to discontinue the investigational product.   
 
For IDE studies, sponsors are required to report deviations implemented to address the imminent 
safety risk to FDA within 5 working days after learning of the deviations.  We recognize that 
challenges related to the COVID-19 pandemic may make it difficult to meet this timeframe.  
Sponsors may consolidate implemented deviations when submitting 5-day reports and should 
update FDA as soon as possible. 
 
Q6. 
With the rapid changes in clinical trial conduct that may occur due to the COVID-
19 public health emergency, including multiple deviations to address patient safety, 
what is the best way for sponsors and investigators to capture these data? 
 
As noted in the main body of this guidance, it is important to capture specific information for 
individual participants that explains the basis for missing protocol-specified information that 
includes the relationship to COVID-19 (e.g., from missed study visits or study discontinuations 
due to COVID-19).  This information, summarized in the clinical study report, will be helpful to 
the sponsor and FDA.  If it is not possible to capture this information in the case report form(s), 
sponsors may develop processes that enable systematic capture of these data across the sites in a 
manner that enables the appropriate analysis when the data are submitted to FDA.  Sponsors may 
also develop processes to capture site-level status, site-level or vendor-level protocol deviations, 
and process deviations. 
 
Q7. 
If patients are currently dispensed investigational product through a pharmacy at 
the clinical trial site for self-administration at home, can a sponsor switch that to 
home delivery without amending the protocol? 
 
If there is concern about risk of exposure to COVID-19, home delivery of investigational product 
that would not raise any new safety risks may be implemented to protect patients from coming to 
clinical trial sites.  In all cases, requirements under FDA regulations for maintaining required 
investigational product storage conditions and investigational product accountability remain; 
these requirements must be addressed and documented.12  If the protocol indicates pharmacy 
dispensing for self-administration at home, and this is changed to direct-to-patient shipments, 
 
11 See 21 CFR 56.108(a)(4), 312.30(b)(2)(ii), and 812.35(a)(2).  
12 See 21 CFR 312.60, 312.62, and 812.140. 


Contains Nonbinding Recommendations 
13 
then a protocol amendment would be required to permit home delivery of investigational 
product.13  If the extent of home delivery is limited to certain participants and not the entire 
population described in the protocol, documenting the change in the mechanisms of distribution 
of investigational product administration through protocol deviations may also be acceptable.  If 
the change in the mechanisms of investigational product distribution is then included in a 
protocol amendment, such a change may be part of a “cumulative” amendment that includes a 
number of changes that accrue, rather than an urgent protocol change.14   
Q8. 
How can the sponsor ensure proper disposal of unused investigational drug product 
if the participant cannot return to the study site?   
FDA regulations outline sponsor and investigator responsibilities for storage conditions and 
accountability of investigational drug products, including disposition of unused investigational  
products (IPs).15  Under 21 CFR 312.59, the sponsor shall assure the return of all unused 
supplies of the investigational drug from each individual investigator.  The regulation further 
provides that the sponsor may authorize alternative disposition of unused supplies of the 
investigational drug provided this alternative does not expose humans to risks from the drug.  
The procedure for disposition is generally considered part of the investigational plan and is 
normally described in the study protocol as a study-specific plan for handling the IPs.  In most 
protocols, such plans involve the participant bringing the unused IP to the clinical trial site and 
then the investigator returning the unused IP to the sponsor or its designee.  During the COVID-
19 public health emergency, if appropriate, a pre-paid shipping package can be used for the 
participant to return IP back to a central location where it can be accounted for and disposed of 
per the protocol, but this approach is not the only way to satisfy the regulatory requirements for 
disposition of unused IP.  Regardless of the chosen disposition method, sponsors and 
investigators must maintain adequate records regarding the disposition of the IP.16 
Sponsors may consider adopting alternative procedures for disposition of IP that permit sponsors 
and investigators to fulfill their requirements for maintaining adequate records of IP disposition 
(including documenting dates, quantity, and use by particpants), provided such procedures do not 
expose humans to risks from the IP.17  For example, it may be possible to provide the 
participants with a way to dispose of  IP at their home (such as with a drug disposal pouch) and 
document such disposal through photo or video that can be transmitted to the investigator or 
sponsor.  FDA does not endorse a particular approach, but the risks involved (e.g., environmental 
considerations) with specific IPs should be considered when selecting a method for disposal.  
FDA has provided a consumer update Where and How to Dispose of Unused Medicines18 that 
provides recommendations to consumers about how to safely dispose of unused FDA-approved 
medication at home.  Sponsors can consider whether any of those recommended methods of 
disposition are appropriate for approved drugs being studied for a new use in a clinical 
13 See 21 CFR 312.30(b) and 812.35(a). 
14 See 21 CFR 312.30(b), 812.35(a), and 812.150(a)(4). 
15 See 21 CFR 312.57, 312.59, 312.60, and 312.62.   
16 See 21 CFR 312.57 and 312.62.  
17 Sponsors should consider whether an information amendment should be submitted pursuant to 21 CFR 
312.31. 
18 See https://www.fda.gov/consumers/consumer-updates/where-and-how-dispose-unused-medicines.  


Contains Nonbinding Recommendations 
 
14 
 
investigation.  As noted in the consumer update, FDA only recommends flushing medications 
that are on the FDA flush list, which currently does not include unapproved IP.   
 
Investigators proposing alternative disposition methods must obtain authorization of those 
methods from the sponsor of the trial.19  Additional restrictions may apply to IPs subject to the 
Controlled Substances Act.20 
 
Q9. 
If patients are currently receiving an investigational product infusion at the clinical 
trial site, can a sponsor switch to home infusion? 
 
Sponsors should consider the safety risk to trial participants who would miss an investigational 
product infusion because of the inability to come to the clinical trial site.  If a sponsor is 
considering providing alternative arrangements for administration of the investigational product 
(e.g., home nursing or alternative sites by trained but non-study personnel), the sponsor is 
expected to perform a risk assessment that considers the nature of the investigational product and 
the potential risks to both the trial participants and the health care providers responsible for 
administering the product at the alternative site.  This risk assessment should include assessment 
of risk mitigation strategies.  Based on this risk assessment, sponsors should consider whether 
consulting the appropriate FDA review divisions regarding plans for alternative arrangements for 
administration of investigational products that are usually administered in a health care setting is 
warranted.  
 
Consulting FDA is strongly advised for complex investigational products (e.g., cellular therapy 
and gene therapy products), where potentially altered storage and handling conditions could 
adversely affect product stability.  In all cases, applicable requirements for maintaining required 
investigational product storage conditions (prior and after reconstitution), investigational product 
reconstitution specifications per the Investigator’s Brochure, and investigational product 
accountability remain and must be addressed and documented.  Storage conditions and 
investigational product accountability should be considered if the protocol is amended to permit 
alternative site infusions.  Defining circumstances when discontinuing investigational product 
administration, while continuing study participation, albeit with potentially delayed assessments, 
may be an appropriate option when suitable alternative arrangements cannot be made.   
 
Q10. Considering that there likely will be delays to on-site monitoring of clinical trials 
during the COVID-19 public health emergency, what are FDA’s expectations in 
such circumstances? 
 
FDA recognizes that monitors may not be able to access the trial sites for on-site visits in a 
timely manner during the COVID-19 public health emergency.  Sponsors should work to find 
alternative approaches to maintain trial participant safety and trial data quality and integrity, such 
as enhanced central monitoring, telephone contact with the sites to review study procedures, trial 
participant status and study progress, or remote monitoring of individual enrolled trial 
participants, where appropriate and feasible.  FDA recognizes that delays in on-site monitoring 
may result in delayed identification of GCP non-compliance (including major protocol 
 
19 See 21 CFR 312.59 and 21 CFR 312.62. 
20 See 21 CFR 312.58(b) and 312.69  




Contains Nonbinding Recommendations 
 
16 
 
3. 
To ensure that patients are approached in a consistent fashion, a standard process should 
be used that will accomplish the following: 
 
• Identification of who is on the call. 
 
• Review of the informed consent document with the patient by the 
investigator/designee and response to any questions the patient may have.  
 
• Verbal confirmation by the patient that their questions have been answered, 
that they would like to participate in the trial, and that they have signed and 
dated the informed consent document that is in their possession. 
 
4. 
The patient (or an individual in the room) takes a photograph of the signed informed 
consent document and sends it to the investigator/designee. 
 
5. 
A trial team member enters the photograph into the trial records along with an attestation 
that states how that photograph was obtained and that it is a photograph of the informed 
consent document signed by the patient.  
 
Method 2:  A witness can attest to the signature, but a photograph of the signed informed 
consent document cannot be transmitted  
 
1. 
An unsigned consent form is provided to the patient by a person who has entered 
the room. 
 
2. 
The investigator/designee arranges a three-way telephone call or video conference 
call with the patient, a witness who is not otherwise connected with the clinical 
investigation, and, if desired and feasible, additional individuals requested by the 
patient (e.g., next of kin).  Alternatively, in lieu of using a witness, a recording of 
the conversation can be made.25 
 
3. 
To ensure that patients are approached in a consistent fashion, a standard process 
should be used that will accomplish the following: 
 
• Identification of who is on the call. 
 
• Review of the informed consent document with the patient by the 
investigator/designee and response to any questions the patient may have. 
 
• Verbal confirmation by the patient that their questions have been answered, 
that they would like to participate in the trial, and that they have signed and 
dated the informed consent document that is in their possession. 
 
 
25 If an investigator wants to record the telephone or video conference call, the investigator/designee should ensure 
that the recording is done in a manner consistent with applicable State and local laws and that all parties agree to 
being recorded. 


Contains Nonbinding Recommendations 
 
17 
 
4. 
When using a witness, documentation in the trial records includes: (1) a signed 
and dated attestation by the witness who participated on the call that the patient 
confirmed their agreement to participate in the trial and signed the informed 
consent document; and (2) a signed and dated attestation by the 
investigator/designee stating why the informed consent document signed by the 
patient was not retained (e.g., due to potential contamination of the document by 
infectious material). 
 
When using a recording in lieu of a witness, documentation in the trial records includes: 
(1) the recording of the conference call; and (2) a signed and dated attestation by the 
investigator/designee who participated on the call stating why the informed consent 
document signed by the patient was not retained (e.g., due to potential contamination of 
the document by infectious material). 
 
When either Method 1 or 2 is used to document informed consent, the resulting documentation 
should be: (1) collected and archived, as either original paper copies or appropriately certified 
electronic copies (e.g., using a validated process for scanning paper copies),26 and (2) retained 
according to applicable FDA record retention requirements as part of the trial record.27 
 
If the patient is unable to provide informed consent and there is a legally authorized 
representative, investigators must obtain written consent from the patient’s legally authorized 
representative in accordance with 21 CFR 50.27(a). 
 
Q12.  How do I obtain informed consent from a patient unable to travel to a clinical trial 
site where electronic informed consent is not an option? 
 
Investigators may also need to obtain informed consent from a potential trial participant or their 
legally authorized representative when these individuals are unable to travel to the site where the 
investigator is located due to COVID-19 illness or travel restrictions.  When investigators do not 
have electronic informed consent (eIC) capabilities,28 methods of obtaining informed consent 
other than a face-to-face consent interview may still be acceptable if those methods allow for an 
adequate exchange of information and documentation, and a method to ensure that the signer of 
the consent form is the person who plans to enroll as a participant in the clinical investigation or 
is the legally authorized representative of the trial participant.  For example, the consent form 
may be sent to the trial participant or their legally authorized representative by facsimile or 
email, and the consent interview may then be conducted by telephone when the trial participant 
or their legally authorized representative can read the consent form during the discussion.  After 
the consent discussion, the trial participant or their legally authorized representative can sign and 
date the consent form.   
 
26 FDA guidance on good clinical practice developed with the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) defines a certified copy as “[a] copy (irrespective of the 
type of media used) of the original record that has been verified (i.e., by a dated signature or by generation through a 
validated process) to have the same information, including data that describe the context, content, and structure, as 
the original.”  See the ICH guidance for industry E6(R2) Good Clinical Practice: Integrated Addendum to ICH 
E6(R1) (March 2018), available on the FDA guidance web page. 
27 See 21 CFR 312.57, 312.62, and 812.140. 
28 See footnote 19.   


Contains Nonbinding Recommendations 
 
18 
 
 
Options for returning the document to the clinical investigator may include facsimile, a 
photographic image sent through electronic means, scanning the consent form and returning it 
through a secure email account, or posting it to a secure Internet address, especially if there are 
concerns about having the participant mail a potentially contaminated consent document.  
Alternatively, the trial participant may bring the signed and dated consent form to his/her next 
visit to the clinical site, if restrictions on traveling to the clinical trial site are alleviated or mail it 
to the clinical investigator.  The case history for each trial participant must document that 
informed consent was obtained prior to participation in the trial.29  In addition, the person 
signing the consent form must receive a copy of the consent form.30  Although FDA regulations 
do not require the trial participant’s copy to be a signed copy, FDA recommends that a copy of 
the signed consent form be provided. 
 
The trial participant or their legally authorized representative must sign and date the informed 
consent form before the investigator may conduct any study-related procedures involving the 
participant.31  Where it is not feasible for investigators to receive the signed consent form prior 
to beginning study-related procedures, the investigators should have the prospective trial 
participant or legally authorized representative confirm verbally during the consent interview 
that the participant or legally authorized representative has signed and dated the form.  In 
addition, the overseeing IRB must review and approve the planned informed consent process.32   
 
Q13.  How can informed consent be obtained and documented from a prospective trial 
participant (or legally authorized representative) when they cannot print and sign a 
paper copy of the consent form provided electronically by the investigator/designee, 
they cannot electronically sign the informed consent form, and providing a paper 
copy of the consent form via mail/courier is not feasible within the time frame for 
enrollment into the clinical trial? 
 
Where a prospective trial participant (or legally authorized representative) is unable to print the 
informed consent document provided electronically by the investigator/designee, an electronic 
signature process is not available, and the prospective trial participant must meet time-sensitive 
eligibility criteria, the investigator may consider using the following alternative process to satisfy 
FDA requirements for obtaining and documenting informed consent: 
 
1. The investigator/designee provides the prospective participant (or legally 
authorized representative) with an electronic version of the informed consent 
document. 
 
2. The investigator/designee arranges a telephone call or video conference call with 
the prospective participant (or legally authorized representative), the 
investigator/designee, a witness who is not otherwise connected with the clinical 
investigation and, if desired and feasible, additional participants requested by the 
 
29 See 21 CFR 312.62(b) and 812.140(a)(3) 
30 See 21 CFR 50.27(a). 
31 See 21 CFR 50.20 and 50.27(a).   
32 See 21 CFR 50.27(a), 56.103(a), and 56.111(a). 


Contains Nonbinding Recommendations 
 
19 
 
prospective participant (e.g., next of kin).  Alternatively, in lieu of using a 
witness, a recording of the conversation can be made.33 
 
3. To ensure that the prospective participant (or legally authorized representative) is 
approached in a consistent fashion, a standard process should be used that will 
accomplish the following:  
 
a. Identification of who is on the call. 
 
b. Review of the informed consent document with the prospective participant (or 
legally authorized representative) by the investigator/designee and response to 
any questions the prospective participant (or legally authorized representative) 
may have. 
 
c. Verbal confirmation by the prospective participant (or legally authorized 
representative) that their questions have been answered and that they would 
like to participate in the trial. 
 
4. Verbal confirmation by the participant (or legally authorized representative) that 
they signed and dated a blank piece of paper with a written statement that they 
voluntarily agree to participate in the protocol, noting both the Protocol 
‘NUMBER’ and brief protocol title.  
 
5. After signing and dating the newly created document, the trial participant (or 
legally authorized representative) sends a photograph of the signed and dated 
statement by facsimile, text message, or email to the investigator/designee; OR 
returns the document to the investigator by mail at a later date, or at a future study 
visit that might occur in person.  
 
6. When using a witness, documentation in the trial records includes a signed and 
dated attestation by the witness who participated on the call that the patient 
confirmed their agreement to participate in the trial and signed the document 
referenced above.   
 
7. When using a recording in lieu of using a witness, documentation in the trial records 
includes the recording of the conference call. 
 
8. After the signed and dated document is received by trial staff, it should be 
appended to a copy of the consent document that was reviewed with the trial 
participant (or their legally authorized representative) and retained in the trial 
records as would normally be done for a signed informed consent document.  
Additionally, a note in the trial records should be made explaining the 
circumstances of why informed consent was obtained through an alternative 
 
33 If an investigator wants to record the telephone or video conference call, the investigator/designee should ensure 
that the recording is done in a manner consistent with applicable State and local laws and that all parties agree to 
being recorded. 




Contains Nonbinding Recommendations 
 
21 
 
should ensure that the methods and conduct of remote assessments are consistent across sites, 
trial participants, and visits to minimize variability in the data.  For example, if a sponsor decides 
that video is their preferred method of remote assessment in a clinical trial, then using different 
methods to conduct assessments (e.g., both telephone and video in the same trial) may increase 
variability.  Maintaining consistency in assessment methods should be balanced, however, 
against the need to minimize missing data and the decision to use different methods should be 
justified in study documentation. 
 
Feasibility of the Assessment Method Within the Context of Use:  Investigators should assess 
the feasibility of conducting a specific type of COA remotely, which will depend on 
corresponding trial goals and needs (e.g., ability to conduct the assessment in a way that captures 
all the data needed to evaluate the endpoint in the trial), given that not all assessments can 
provide an accurate assessment when done remotely.  
 
Documentation and Audit Trails:  Investigators should document, and sponsors should include 
data on related variables in the clinical trial datasets, whether an assessment was conducted in-
person or remotely (including type of technology used), as well as the date of the assessment and 
the person who conducted the assessment.  Sponsors also should ensure that remote data 
acquisition, transmission, and storage are secure, and that the privacy of trial participants is 
protected.  When sponsors use electronic platforms to perform remote assessments that transmit 
data directly into trial records, these platforms should include automated audit trails. 
 
Technology and Technological Support:  Sponsors planning to use remote electronic 
assessments as part of a clinical investigation should use appropriate technology and develop 
procedures for provision of technology and technical support to trial participants, investigators, 
and/or other trial personnel to facilitate those assessments.  For example, sponsors could develop 
a plan to accommodate trial participants who are either already enrolled in a trial or may be 
enrolled in a trial in the future, but who do not have access to appropriate communication 
technology (e.g., cell phones or Internet), by providing trial participants with these services. 
 
Specific considerations for certain COA types are explained below. 
 
PerfO- and Interview-Based ClinRO-Specific Considerations:  For these types of 
assessments, sponsors should consider: (1) appropriateness of remote assessment for the type of 
clinical data to be collected; (2) special investigator training to administer the PerfO or 
interview-based ClinRO assessments remotely; and (3) procedures for assessing and confirming 
the safety of trial participants, their privacy, and appropriate setting and resources to adequately 
complete the assessment.   
 
Recognizing that components of the PerfO and interview-based ClinRO assessment for some 
trials may specify visualization or in-person interactions with trial participants that may be 
difficult to replicate through remote interactions, sponsors should assess whether these 
components can be evaluated in an alternative way that still permits an accurate clinical 
assessment.  When components of the assessment cannot be accomplished in a remote encounter, 
investigators should document, and sponsors should report in the clinical trial datasets, any 
aspects of the assessment they are unable to accomplish remotely.  Sponsors should consider 


Contains Nonbinding Recommendations 
 
22 
 
whether the information that can be collected remotely will be sufficient to reliably assess the 
clinical outcome and support robust conclusions for the study. 
 
PRO- and ObsRO-Specific Considerations:  For these types of assessments, sponsors should 
consider: (1) potential for missing data when switching from in-person assessment to remote 
assessment; (2) whether switching from use of paper- or electronic-based PRO and ObsRO 
assessments completed independently to assessments administered verbally by another person 
may lead to bias of scores (e.g., if trial participants try to please the site staff by offering ratings 
that might not truly reflect their experience); and (3) that data collected with PROs and ObsROs 
through verbal administration should not be considered a substitute for required safety 
monitoring throughout the trial.38 
 
To minimize potential bias resulting from verbal administration of PRO and ObsRO 
assessments, sponsors should ensure interviewer training and use of an interview script.  
Sponsors may also consider using automated virtual interviewers or a trained neutral third-party 
interviewer to administer the assessments remotely. 
 
The potential for missing data is also a limitation when switching from in-person to remote 
assessment using paper-based PRO or ObsRO assessments, if the trial participant or observer 
fails to complete all or part of the questionnaire within a given timeframe.  To mitigate potential 
for missing data, sponsors should consider remote electronic capture of these assessments 
through technologies that can remind trial participants to complete the questionnaires and/or 
verbal administration at the time instructed (assuming appropriate steps are taken to minimize 
bias from verbal administration).  
 
Q15.  I am a study monitor and am unable to conduct on-site monitoring visits due to the 
COVID-19 public health emergency.  May I remotely perform the site monitoring 
visit?  What recommendations does FDA have for how I can remotely perform 
source document review?  
 
FDA regulations require sponsors to monitor the conduct and progress of their clinical 
investigations.39  The regulations are not specific about how sponsors must conduct such 
monitoring and are therefore compatible with a range of approaches to monitoring that may vary 
depending on multiple factors.  Therefore, certain aspects of site monitoring visits may be done 
remotely if technically feasible.  FDA understands that there may be deviations from the timing 
of on-site monitoring visits set forth in the trial monitoring plan and procedures, and that 
sponsors may consider ways to replace on-site monitoring visits with remote monitoring visits 
during the COVID-19 public health emergency.  Further, there may be components of an on-site 
monitoring visit, as outlined in the trial monitoring plan, that cannot be completed remotely.   
 
During the COVID-19 public health emergency, traditional on-site monitoring might be difficult 
for reasons such as (1) sites may not be able to accommodate monitoring visits (e.g., due to 
staffing limitations or site closures) or (2) monitors may not be able to travel to trial sites.  When 
 
38 See 21 CFR 312.32(b), 312.56(c), and 812.46. 
39 See 21 CFR 312.50, 312.53(d), 312.56(a), 812.40, 812.43(d), and 812.46.  


Contains Nonbinding Recommendations 
 
23 
 
planned on-site monitoring visits are not possible, the reason should be documented and 
available for review by the sponsor and during FDA inspections. 
 
The sponsor should consider using a risk-based approach to prioritize sites for remote 
monitoring, including as many study sites as feasible (and with a frequency as close to that 
described in the site monitoring plan as feasible).  The decision regarding which sites to 
prioritize for remote monitoring should be guided by centralized monitoring or other information 
available about site performance (e.g., frequency and severity of protocol deviations previously 
identified during monitoring visits or currently identified by centralized monitoring, number of 
randomized active trial participants, experience of site staff, known history of prior major audit 
or inspection findings).   
 
Remote monitoring should be focused on review of critical study site documentation and source 
data.  If the materials identified for review include participants’ medical records that normally 
would be reviewed at the site (and such a review is consistent with the trial participants’ 
informed consent documents) then, as discussed below, remote review of medical records may 
be explored with trial sites to complete source document review.  When the study monitor cannot 
access the site to review critical source documents, requests for review of source documents that 
may include private health information should be consistent with requirements for source 
document validation and review as described in the current study monitoring plan or other 
appropriate study-specific document.  When remote monitoring processes and procedures have 
not previously been described by the sponsor, these processes and procedures should be 
established (e.g., in a revised study monitoring plan or in updates to existing sponsor policies and 
procedures). 
 
During remote monitoring, the study monitor should focus on trial activities that are essential to 
the safety of trial participants and/or data reliability.  Sponsors and monitors may wish to 
consider one or more of the following options to facilitate remote monitoring access to clinical 
site records: 
 
• If the site can provide appropriate resources and technical capabilities, consider 
establishing a secure remote viewing portal that would permit site staff to provide 
access to the site’s study documentation and/or trial participants’ source 
documents for the study monitor’s review.  In addition, the potential for remote 
access to trial participants’ electronic health records may be explored with trial 
sites. 
 
• Sites could upload certified copies40 of source records to a sponsor-controlled 
electronic system or other cloud-based repository that contains appropriate 
security controls.  In the setting of a blinded or partially blinded study, if source 
documents contain potentially unblind information, controls to protect the study 
blind should be in place prior to transfer of source documents (e.g., use of an 
unblinded study monitor to review source documents, restricted access to folders 
containing copies of source documents).  It is not necessary for the clinical site to 
have control of certified copies of source documents uploaded to such a 
 
40 See footnote 26.  


Contains Nonbinding Recommendations 
 
24 
 
repository; however, the clinical investigator should maintain control of the 
original source records. 
 
Regarding retention of copies of source documents used for remote review, it would not be 
necessary to retain the certified copies of source documents used for remote review, provided the 
clinical investigator retains the original source documents according to FDA regulations for the 
retention of records.41  
 
In addition, processes and procedures should be established for the handling of source document 
copies that were placed in temporary storage locations for remote review and that are no longer 
needed after the remote monitoring has concluded. 
 
Remote monitoring activities, including remote review of source documents, should be 
documented in the same level of detail as on-site monitoring activities, and any resulting actions 
to address issues identified from the remote source document review should be consistent with 
procedures and processes described in the study monitoring plan. 
 
Q16.  I am a sponsor of commercial INDs and electronic common technical document 
(eCTD) requirements cannot be met due to the COVID-19 public health emergency.  
Who do I contact for assistance? 
 
Commercial sponsors may qualify for a short-term waiver from the eCTD requirements under 
section 745A of the FD&C Act in unique and rare circumstances and for a limited duration.  
During the COVID-19 public health emergency, rare circumstances may arise in which a sponsor 
cannot meet eCTD requirements (e.g., if the current COVID-19 public health emergency has 
impacted computer operations).  Companies experiencing technical difficulties with transmission 
of their electronic submissions to FDA should consult FDA’s electronic submission staff (contact 
information provided below) for technical assistance, rather than submitting a waiver request, as 
described in Section III.E of FDA’s guidance for industry Providing Regulatory Submissions in 
Electronic Format—Certain Human Pharmaceutical Product Applications and Related 
Submissions Using the eCTD Specifications (February 2020, Revision 7): 
 
FDA may grant temporary waivers of the requirement for eCTD submission if one or more of the 
following events or circumstances exist: 
 
• 
Extraordinary events or circumstances occur that are beyond the control of the 
submitter that justify a waiver, including but not limited to, natural disasters that 
impact computer operations. 
 
• 
An unplanned long-term Internet disruption or other unplanned event occurs that 
would preclude the sponsor from submitting in eCTD format (e.g., malware attacks). 
 
• 
The sponsor intends to request a withdrawal of an application that has not yet 
converted to eCTD format. 
 
 
41 See 21 CFR 312.62 and 812.140(a) 


Contains Nonbinding Recommendations 
25 
•
The sponsor submitted a request for withdrawal and has not yet received FDA’s
acknowledgement of the withdrawal.42
The guidance also states: 
The sponsor or applicant’s request to waive the eCTD electronic format requirement must 
include all of the following as supporting documentation to justify the waiver: 
(a) A description of the circumstances or event–including the anticipated duration of the 
circumstance or event–giving rise to the need for a waiver 
(b) The requested duration of the waiver 
(c) A description of the proposed alternative submission format the sponsor or applicant 
will be using for the duration of the waiver 
The request should reference all products that are to be covered by the waiver.  The waiver 
request should be clearly titled “WAIVER REQUEST–eCTD REQUIREMENTS” in 
bold capital letters at the top of the first page of the submission.43 
Waiver requests for new drug applications (NDAs), biologics license applications (BLAs), 
abbreviated new drug applications (ANDAs), drug master files (DMFs), and commercial INDs 
may be sent to FDA electronic submission staff via email to CDER 
 or 
CBER
.  If a waiver is granted, FDA intends to provide information 
in the response letter on how to transmit the submission.  FDA intends to encourage sponsors 
and applicants to send submissions electronically in an alternative electronic format (e.g., PDF 
files following the eCTD structure). 
Q17. During the COVID-19 public health emergency, certain patients may no longer be 
able to travel to a central location for protocol-based treatment that is scheduled on 
a recurring basis.  Can the investigational product intended for infusion be shipped 
to a local health care provider who is not a sub-investigator to administer the 
infusion to a patient while still maintaining integrity of the trial?  If so, what else 
would be needed regarding trial monitoring and institutional review board (IRB) 
oversight? 
Specific circumstances for a given clinical trial would affect the feasibility and appropriateness 
of shipping investigational products (IP) to locations other than clinical trial sites as specified 
under an IND, as well as administering the IP.  If the IPs being evaluated in the trial are 
administered by infusion, then it would be important that any alternative infusion center have 
appropriately trained personnel and oversight by physicians with sufficient experience regarding 
42 See the guidance for industry Providing Regulatory Submissions in Electronic Format—Certain Human 
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (February 2020, 
Revision 7), available on the FDA guidance web page.  To the extent that the guidance provides criteria for waivers 
and exemptions from the eCTD reporting requirements under section 745A(a) of the FD&C Act, it has binding 
effect pursuant to statute.  
43 Ibid. 


Contains Nonbinding Recommendations 
 
26 
 
the class of products involved to assure trial participant safety comparable to administration at a 
trial site.   
 
For the purposes of this guidance, local health care providers (HCPs) who are administering 
drugs in a manner that does not differ from their normal clinical practices would not be 
considered sub-investigators and need not be listed on Form FDA 1572.44  FDA recommends 
that these HCPs be listed in site records, such as a log of activities delegated by the investigator.  
Any changes to a trial protocol to permit an HCP to administer the investigational drug generally 
must be reviewed and approved by an IRB.45 
 
The above paragraph described administration of the investigational product by local HCPs who 
are practicing medicine within their scope of practice.  In contrast, if a sponsor will be asking 
local HCPs to perform study-specific research procedures or assessments that represent a direct 
and significant contribution to the clinical data for the study (e.g., assessing drug response for a 
patient or performing a procedure unique to the study and not part of routine medical care), these 
HCPs would be considered sub-investigators and should be listed on Form FDA 1572.  
 
IP may be shipped from a central distribution site directly to an HCP, provided that such 
shipping is done under the supervision of the investigator using procedures that assure 
accountability and product quality (i.e., that storage conditions, as defined in the protocol, for the 
IP were maintained during shipping, and the drug packaging was intact upon receipt).   
 
If the HCP administering the IP is not considered a sub-investigator, the investigator should 
ensure that they can obtain records regarding administration of the IP by requesting that the trial 
participants provide consent to allow access to medical records from their local HCPs involving 
trial-related data such as measuring vital signs, and results of evaluations of any symptoms or 
signs occurring with the infusion.  Communicating the intent to request such records from the 
HCP in advance may facilitate this process.   
 
Consulting the appropriate FDA review division(s) on plans for alternative administration is also 
recommended as per Q9 above. 
 
Q18. If a trial participant is unable to receive the investigational drug from the trial site 
but the product is FDA-approved for other uses, can the patient or health care 
provider secure the product commercially or is this considered the sponsor charging 
for the investigational drug under 21 CFR 312.8?  Can the sponsor reimburse trial 
participants for their out of pocket expenses in getting the drug commercially? 
 
If the product(s) under investigation in a clinical trial is FDA-approved, and the study does not 
require blinding, then local sourcing of the product(s) would be acceptable to FDA (e.g., by 
having the local physician write a prescription for the product instead of shipping the product 
 
44 For the definition of a sub-investigator, see 21 CFR 312.3(b); for the requirement to list sub-investigators on the 
FDA Form 1572, see 21 CFR 312.53(c)(1). 
45 As noted in the response to Q3 above, changes to a protocol necessary to eliminate an apparent immediate hazard 
to trial participants may be implemented before FDA and IRB review and approval (see 21 CFR 56.108(a)(4) and 21 
CFR 312.30(b)(2)(ii)). 


Contains Nonbinding Recommendations 
27 
directly to the patient).  FDA does not consider a trial participant’s commercial procurement of 
the study drug when unable to secure it from the trial site during the COVID-19 public health 
emergency to be a sponsor charging for an investigational drug under an IND per FDA 
regulations at 21 CFR 312.8.  FDA also would not object if the sponsor reimburses the patient 
for any costs incurred by commercially purchasing the product or for charges related to an 
infusion.   
Per FDA regulations at 21 CFR 312.6, the immediate package of an investigational new drug 
intended for human use must bear a label with the statement “Caution: New Drug—Limited by 
Federal (or United States) law to investigational use.”  FDA recognizes that a commercially 
obtained product will not have this statement on its container.  In the setting of the COVID-19 
public health emergency, where alternative arrangements are being made to provide an 
investigational agent to a participant who is unable to come to the trial site, FDA intends to 
exercise flexibility without sponsors needing to seek a waiver under 21 CFR 312.10 of the 
investigational labeling requirements under 21 CFR 312.6.   
Q19.  Throughout the guidance, FDA recommends that sponsors consult with the review 
division for certain changes to ongoing clinical trials.  For drugs and biologics, is 
this a reference to scheduling a Type A meeting?  How should sponsors contact FDA 
regarding device clinical trials? 
As stated in our guidance for industry Best Practices for Communication Between IND Sponsors 
and FDA During Drug Development (December 2017),46 review division regulatory project 
managers (RPMs) are the primary point of contact for communications between a sponsor and 
FDA.  Both FDA and sponsors use various communication methods to focus discussions to 
exchange information and resolve issues efficiently.  For example, telephone communication 
between a sponsor and FDA RPM may be more effective for time-sensitive matters.  FDA staff 
try to respond to sponsor questions promptly, while balancing FDA public health priorities and 
other work obligations.  Note that to ensure participant safety, responses to safety-related 
inquiries will be prioritized over other inquiries.  More generally, FDA understands that many 
questions that will arise regarding changes in trial conduct due to COVID-19 will need to be 
addressed expeditiously.  RPMs will work with sponsors to determine the best path forward to 
answer their questions for certain changes in an expedited manner.   
To discuss urgent issues related to IDEs managed in CDRH, sponsors should contact the lead 
reviewer.  For IDEs managed in CBER, sponsors should contact the RPM.  For FDA feedback 
on a proposed future IDE study, or regarding modifications to ongoing studies that are not urgent 
(such as a statistical analysis plan to address missing data), a Pre-Submission is recommended.  
For additional information on Pre-Submissions, please refer to FDA’s guidance for industry 
Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission 
Program (May 2019).47  
For general questions regarding FDA policy on clinical trial conduct during the COVID-19 
public health emergency, sponsors should contact 
 
46 Available on the FDA guidance web page. 
47 Available on the FDA guidance web page. 


Contains Nonbinding Recommendations 
28 
Q20.  I am a sponsor and would like to use an alternate laboratory or imaging center48 for 
protocol assessments.  What should I consider regarding when this approach would 
be appropriate and the selection of alternate laboratories or imaging facilities? 
Given that trial participants may not be able to come to the investigational site for protocol-
specified visits at which laboratory tests or imaging would be conducted, sponsors should 
evaluate whether it is feasible to use alternative laboratories or imaging centers.  The suitability 
of such alternative arrangements may vary depending on whether the protocol-specified 
procedures are related to eligibility criteria, safety evaluations, or endpoint assessments.  
In general, if trial participants cannot access a clinical trial site, alternative sites may be used for 
laboratory tests or imaging assessments that focus on the safety of trial participants when such 
tests and assessments are routinely performed in those settings (e.g., routine chemistries, blood 
counts, chest radiographs).49   
However, if the results of laboratory tests or imaging assessments are the basis for formal 
hypothesis testing, including primary or secondary efficacy endpoints and some safety endpoints, 
sponsors should consult with the relevant FDA review division.  For example, disparities in 
laboratory measurements or imaging protocols will introduce increased variability and thus can 
affect type I and type II error rates.   
When baseline tests are necessary to characterize the eligible study population, potential 
variation in test performance or precision related to use of an alternative laboratory or imaging 
center may also warrant discussion with the FDA review division.  For example, an inclusion 
criterion based on a commonly available, routine test performed as a safety screen (e.g., renal 
function on a metabolic panel) might be amenable to alternative laboratory collection with 
minimal impact on study results.  Using an alternative laboratory for tests related to other 
eligibility factors could be more likely to affect study integrity (e.g., laboratory tests to identify a 
tumor biomarker required for inclusion, genetic test to identify a marker that is a critical 
inclusion criterion).  It may be important for such assessments to be standardized at a single site 
or at most a few sites.  Based on the nature of laboratory tests conducted for the purpose of 
protocol assessments, the alternative laboratory conducting such tests for investigational 
purposes will likely be subject to certification and other requirements under the Clinical 
Laboratory Improvement Amendments (CLIA).50  Alternative laboratory and imaging centers 
may also be subject to additional laws governing their operations. 
Q21.  We are instituting trial participant visits remotely through video conferencing.  Are 
there recommendations regarding best practices? 
48 For IND studies, this would be laboratories and imaging centers not listed on the Form FDA 1572. 
49 If a local laboratory or imaging center will be used for certain patients and will not replace the laboratory and 
imaging center specified in the Form FDA 1572 for all patients, these alternative facilities do not need to be listed on 
the Form FDA 1572; it is sufficient to retain documentation of when such facilities were used for protocol specified 
tests.  The sponsor can accumulate these changes and submit this information to the IND, in for example, an 
information amendment or a protocol amendment.   
50 For more information on CLIA, see https://www.cms.gov/Regulations-and-
Guidance/Legislation/CLIA/Downloads/Research-Testing-and-CLIA.pdf. 


Contains Nonbinding Recommendations 
29 
With the increasing use of telemedicine in clinical practice, a number of resources may be 
available to provide recommendations on best practices.  FDA does not endorse any particular 
telemedicine best practices.  However, from an FDA regulatory perspective, important 
considerations for trial visits through video conferencing include:   
•
The investigator or study personnel who will conduct remote visits should be
trained on how to conduct real-time video conferencing visits (e.g., training on the
use of telemedicine for remote clinical trial visits).
•
Procedures should be put in place to maintain a trial participant’s privacy, as
would be done for a clinical visit.
•
Both the investigator and the trial participant should confirm their respective
identities with one another before engaging in a real-time video conference visit
according to an identity verification plan developed by the sponsor.51
To provide the same information that would be documented during a face-to-face visit, the date 
of a real-time video conference visit should be documented in the trial records and, if specified in 
the protocol, the time of the visit.  Investigators should consider asking for the trial participant’s 
location during a video conference visit in case a medical emergency arises during the visit.   
FDA considers real-time video interactions, including telemedicine, as a live exchange of 
information between the trial personnel and trial participants.  These interactions are not 
considered electronic records and therefore are not subject to 21 CFR part 11.  
Q22.  How does the COVID-19 public health emergency affect drug and biological 
product clinical trials required as postmarketing requirements (PMRs)?  What 
about for required postmarket device studies? 
The information in this guidance applies to all clinical trials, including those postmarketing 
clinical trials that FDA requires an applicant52 to conduct53 for drugs and biological products.  
Many of the considerations outlined in this guidance may also be relevant to postmarket device 
studies.54   
51 FDA does not endorse any specific identification method.  Sponsors may consider the National Institute of 
Standards and Technology (NIST) Digital Identity Guidelines, Special Publication 800-63A—Enrollment and 
Identity Proofing Requirements When Developing an Identity Verification Plan, available at 
https://pages.nist.gov/800-63-3/sp800-63a html.  
52 After a company submits a marketing application (e.g., new drug application (NDA), biologics license application 
(BLA), premarket approval application (PMA), De Novo Classification Request, or premarket notification (510(k)) 
for review, the company is referred to as the applicant.  The person who initiates a clinical investigation is referred 
to as the sponsor (see 21 CFR 312.3 and 812.3(n)). 
53 Specifically, this response is intended to apply to studies or clinical trials required under 505(o)(3) of the FD&C 
Act (21 U.S.C. 355(o)(3)), confirmatory trials for drugs approved under the accelerated approval pathway (21 
U.S.C. 356(c)(2)(A)) and deferred pediatric studies (21 U.S.C. 355B). 
54 For devices subject to PMA, FDA may require post-approval studies as a condition of approval (21 CFR 
814.82(a)(2)). FDA may also require manufacturers to conduct postmarket surveillance studies of certain class II 
and class III devices under section 522 of the FD&C Act (21 U.S.C. 360l). 


Contains Nonbinding Recommendations 
 
30 
 
 
Applicants who are required to complete postmarketing clinical trials for drugs or biological 
products follow a timetable that includes due dates for completing certain milestones in the trial.  
FDA encourages applicants to inform FDA as soon as possible if they experience COVID-19-
related delays that may affect the applicant’s ability to meet the applicable interim,55 trial 
completion, and/or final report submission milestone(s).  These applicants should propose 
feasible revised milestones for interim, trial completion, and/or final report submission 
milestone(s).56 
  
For post-market device studies, the approved post-approval study protocol or post-market 
surveillance plan generally includes due dates for completing certain study milestones.  Due 
dates for certain milestones may also be listed expressly in the order requiring the postmarket 
study.  Applicants required to complete such studies should similarly inform FDA as soon as 
possible of COVID-19-related delays that may affect the applicant’s ability to meet those 
milestones and propose feasible revised milestones.   
 
Applicants with PMRs or required postmarket device studies should also provide an explanation 
to FDA of how COVID-19 impacts the ability to meet the original milestones.  FDA will 
evaluate the facts and circumstances of the explanation provided, as well as the conduct of the 
applicant, in determining whether the applicant is in compliance with the applicable authority 
requiring the postmarketing trial or postmarket device study after the milestone has been missed.   
 
Additional considerations for drug and biological product PMRs include: 
 
• PMRs Under Section 505(o)(3) of the FD&C Act.  FDA will continue to make 
“good cause” determinations on a case-by-case basis for all missed milestones, 
including those where the applicant asserts that its failure to meet a PMR interim, 
trial completion, and/or final report submission milestone(s) is related to the 
current public health emergency.  
 
• Deferred Pediatric Study PMRs Under the Pediatric Research Equity Act 
(PREA).57  If circumstances involving COVID-19 have affected an applicant’s 
ability to complete a PREA PMR, applicants may request a deferral extension for 
the final report submission milestone.  If an applicant has not obtained a deferral 
extension and fails to submit required PREA studies by the final report 
submission date listed in the PREA PMR, FDA is required to issue a non-
compliance letter to the applicant.58 
 
 
55 Interim milestones refer to those due dates scheduled to occur between the final protocol submission and trial 
completion milestones. 
56 Although a revised trial completion date may be acknowledged by FDA, for drugs and biological product PMRs, 
the original projected completion date will continue to be displayed on the FDA’s Postmarket Requirements and 
Commitments web page.  
57 Section 505B(a)(3)(B) of the FD&C Act governs the process and timelines required for requests for a deferral 
extension for deferred pediatric studies required under section 505B of the FD&C Act (21 U.S.C. 355c) (often 
referred to as PREA PMRs).   
58 See section 505B(d)(1) of the FD&C Act (21 U.S.C. 355c(d)(1)). 


Contains Nonbinding Recommendations 
31 
•
PMRs Under Accelerated Approval.  For confirmatory trials, if an applicant
misses an interim, trial completion, and/or final report submission milestone,
FDA will review the applicant’s explanation for the delay, as well as assess the
trial’s progress prior to the current public health emergency, before determining
whether or not the applicant has been compliant with its milestone obligations.
•
Annual Status Reports of PMRs.  Applicants must continue to follow the annual
reporting requirements for PMRs59 and should document in their annual status
report the COVID-19-related reason(s) for missing interim, trial completion,
and/or final report submission milestone(s), and any steps taken to address
COVID-19-related factors.
Q23.  My company is the NDA holder of an FDA-approved drug for a non-COVID-19 
indication and is also the sponsor of an IND for the same drug being investigated to 
treat COVID-19.  If I receive a spontaneous report of a serious adverse event that 
occurred with the approved drug being used in clinical practice for treatment of 
COVID-19, do I report that event to the IND for the COVID-19 investigational use? 
Reports of serious adverse events (SAE) that occur in clinical practice with the use of an 
approved drug or biological product, whether or not the use is included in the labeling for that 
product, must be reported in accordance with the applicable post-marketing reporting 
requirements under FDA regulations at 21 CFR 314.80 and 600.80.  Reports of SAEs for 
approved vaccines are submitted to the Vaccine Adverse Events Reporting System (VAERS), 
while reports of SAEs for other approved drugs and biological products are submitted to the 
FDA Adverse Event Reporting System (FAERS).60    
Serious adverse events that occur during a clinical trial under an IND for an approved drug or 
biological product being investigated for a new use to treat COVID-19 must be reported as an 
IND safety report per FDA regulations at 21 CFR 312.32 if they are unexpected and the sponsor 
determines that there is a reasonable possibly that the drug caused the SAE.  
Regardless of whether an SAE occurs in the course of clinical practice or during a clinical trial, 
and regardless of where it is first reported, an NDA or BLA holder who is also the sponsor of an 
IND investigating the same drug for COVID-19 is responsible for monitoring the safety of its 
drug and evaluating all accumulating safety data.61  If accumulating safety data, including use in 
clinical practice, indicates a new serious risk associated with the drug, an IND safety report will 
need to be filed to the IND, and updates will likely need to be made to the investigator brochure 
and/or the informed consent document.62  For more information, see FDA’s guidance for 
59 See section 506B of the FD&C Act (21 U.S.C. 356b), 21 CFR 314.81(b)(2)(vii), and 601.70(b). 
60 For more information, see the Vaccine Adverse Event Reporting System, available at 
https://vaers hhs.gov/reportevent html, and the FDA Adverse Event Reporting System (FAERS) Public 
Dashboard, available at https://www fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-
faers/fda-adverse-event-reporting-system-faers-public-dashboard. 
61 See 21 CFR 312.32(b). 
62 See 21 CFR 312.32(c).  


Contains Nonbinding Recommendations 
 
32 
 
industry and investigators Safety Reporting Requirements for INDs and BA/BE Studies 
(December 2012).63 
 
Q24.  For a clinical trial that is not investigating treatments for COVID-19, if a trial 
participant diagnosed with COVID-19 experiences a serious adverse event 
associated with COVID-19 during the trial, should that be reported as an IND 
safety report?  Should these events be reported to the IRB? 
 
Under FDA regulations at 21 CFR 312.32, a sponsor must report to FDA any serious adverse 
event (SAE) that is both unexpected and for which there is a reasonable possibility that the drug 
caused the serious adverse event, i.e., there is evidence to suggest a causal relationship between 
the drug and the adverse event.  
  
Given the community spread of infection during the COVID-19 public health emergency, trial 
participants in a clinical trial may be diagnosed with COVID-19 and experience SAEs associated 
with the disease that are not causally related to the investigational drug.  However, it also is 
possible that an investigational drug might be causally related to a SAE associated with COVID-
19 by making trial participants in the trial more susceptible to complications from COVID-19.  
Establishing this potential causal relationship likely requires more than a single or even a few 
cases.  To determine whether a reasonably possible causal relationship exists between an 
investigational drug and an SAE in a randomized controlled trial, FDA recommends a 
comparison between the rate of observed SAEs among COVID-19 infected trial participants in 
the investigational drug arm to COVID-19 infected trial participants in the control arm.  Given 
that such analyses entail examination of unblinded data, such assessments should be done only 
by a data monitoring committee that routinely reviews unblinded data or by a specially 
constituted safety committee that is appropriately “firewalled” and independent from those 
conducting the trial and performing other study analyses.  If the latter, such a committee should 
review safety data only, not efficacy data.  If the trial is not randomized, in some circumstances it 
may be warranted to determine whether there is an excess of SAEs in trial participants diagnosed 
with COVID-19 by comparing the rate of such events to an external similar population 
diagnosed with COVID-19, recognizing that the reported rates of SAEs and mortality in patients 
with COVID-19 have varied widely.  In comparing the rate in the trial to the published literature, 
sponsors should consider reports in patients with similar comorbidities and levels of care.  If the 
difference in SAEs across treatment arms or compared to an external population suggests a 
causal relationship between the investigational product and the SAEs in trial participants 
diagnosed with COVID-19, this finding must be submitted to FDA as an IND safety report in 
accordance with 21 CFR 312.32.   
 
FDA had provided additional information about aggregate safety assessment and reporting for 
INDs in the guidance for industry and investigators, Safety Reporting Requirements for INDs and 
BA/BE Studies (December 2012),64 and has proposed recommendations in the draft guidance for 
industry Safety Assessment for IND Safety Reporting (December 2015).65 
 
63 Available on the FDA guidance web page. 
64 Available on the FDA guidance web page.  
65 Available on the FDA guidance web page.  When finalized, this guidance will represent FDA’s current thinking 
on these issues. 


Contains Nonbinding Recommendations 
 
33 
 
 
Where an IND safety report is required to be submitted to FDA under 21 CFR 312.32, the 
investigator must also send that IND safety report to the IRB.66  The IRB may have additional 
reporting requirements regarding COVID-19 during the clinical trial. 
 
Q25.  Trial participants with COVID-19 may experience a number of  serious and 
unexpected adverse clinical events, which may increase the volume of corresponding 
IND safety reports.  If an investigator receives an IND safety report from a sponsor, 
is it acceptable to review only reports that the sponsor indicates will result in a 
change to the investigator brochure, informed consent, or protocol?  Which IND 
safety reports must an investigator send to the IRB?    
 
No, it is not acceptable for an investigator to review only certain IND safety reports.  Under 21 
CFR 312.60, investigators are responsible for protecting the safety of trial participants in a 
clinical investigation.  IND safety reports must be sent by the sponsor to FDA and all 
participating investigators67 when the sponsor determines that a serious adverse event is 
unexpected and there is a reasonable possibility that the drug caused the serious adverse event, 
i.e., there is evidence to suggest a causal relationship between the drug and the adverse event.68  
Reviewing IND safety reports is essential for protecting the safety of trial participants because a 
serious and unexpected adverse event represents a new potential risk associated with the 
investigational product.  FDA considers the review of all IND safety reports critical to fulfilling 
investigators’ responsibility to protect the safety of trial participants in a clinical investigation.69 
 
In addition, investigators are required under 21 CFR 312.66 to report all “unanticipated problems 
involving risk to human subjects or others” to the IRB.  FDA considers a serious and unexpected 
adverse event that meets the criteria for sponsor reporting to FDA and all investigators in an IND 
safety report under 21 CFR 312.32, and would generally consider a serious adverse event that 
meets the criteria for safety reporting for an IND-exempt bioavailability/bioequivalence study 
under 21 CFR 320.31(d)(3), to be an “unanticipated [problem] involving risk to human subjects 
or others” that therefore must be reported to the IRB by the investigator.70,71   
 
 
66 See 21 CFR 312.53(c)(1)(vii) and 312.66.  See also the guidance for clinical investigators, sponsors, and IRBs 
Adverse Event Reporting to IRBs—Improving Human Subject Protection (January 2009), available on the FDA 
guidance web page. 
67 See 21 CFR 312.32(c)(1). 
68 See 21 CFR 312.32.  IND safety reports must be submitted as soon as possible, but no later than 15 calendar days 
after the sponsor determines that the information qualifies for reporting.  Unexpected fatal or life-threatening 
suspected adverse reactions must be submitted no later than 7 calendar days after the sponsor’s initial receipt of the 
information (21 CFR 312.32(c)(2)).  
69 See 21 CFR 312.60. 
70 See 21 CFR 312.66. 
71 Many study protocols specify that the sponsor will submit IND safety reports to the IRB on the investigator’s 
behalf.  In these situations, where the investigator receives confirmation that the report has been sent to the IRB 
(e.g., the investigator is copied on the report sent to the IRB by the sponsor), FDA does not intend to object to the 
sponsor submitting the report to the IRB on the investigator’s behalf and would not expect an investigator to provide 
the IRB with a duplicate copy of the report. 


Contains Nonbinding Recommendations 
 
34 
 
For more information about safety reporting, see FDA’s guidances Safety Reporting 
Requirements for INDs and BA/BE Studies (December 2012)72 and Adverse Event Reporting to 
IRBs—Improving Human Subject Protection (January 2009).73 
 
Q26.  What considerations apply to the electronic systems used to generate electronic 
signatures on clinical trial records, including informed consent documents, during 
the COVID-19 public health emergency? 
 
Electronic systems74 used to generate electronic signatures75 on clinical trial records, including 
informed consent documents, during the COVID-19 public health emergency must comply with 
the requirements outlined in FDA regulations at 21 CFR part 11 (Part 11) when applicable.76, 77  
 
FDA is aware that there are multiple commercial off-the-shelf (COTS) software systems 
providing electronic signature services for clinical trial records.  FDA does not certify individual 
electronic systems or methods to obtain Part 11 compliant electronic signatures, but COTS 
vendors may be able to provide sponsors and other regulated entities with information regarding 
whether their systems are Part 11 compliant.  When such information is unavailable from the 
vendor, and a Part 11 compliant electronic system is required, sponsors and other regulated 
entities must take other steps to ensure the  electronic system or software in use is Part 11 
compliant.  For further information regarding Part 11 compliance, see FDA’s guidance for 
industry Part 11, Electronic Records; Electronic Signatures—Scope and Application (August 
2003)78 and the additional recommendations proposed in the draft guidance for industry Use of 
Electronic Records and Electronic Signatures in Clinical Investigations under 21 CFR Part 11—
Questions and Answers (June 2017).79   
 
When an electronic system that is Part 11 compliant is not available, regulated entities must have 
an alternate means of obtaining required signatures (e.g., handwritten80 wet ink signatures 
executed on documents, handwritten stylus or finger-drawn signatures executed on electronic 
documents that are then printed or appropriately witnessed).  Alternative methods for obtaining 
signatures on informed consent documents during the COVID-19 public health emergency are 
described in Q11 and Q12 of this guidance.  When handwritten methods are used, the sponsor 
and other regulated entities should ensure that all records containing original handwritten 
signatures are (1) collected and archived, as either original paper copies or appropriately certified 
 
72 Available on the FDA guidance web page. 
73 Available on the FDA guidance web page.  
74 For the purposes of this guidance, the term electronic systems means systems, including hardware and software, 
that produce electronic records. 
75 For the purposes of this guidance, the term electronic signature means a computer data compilation of any symbol 
or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the 
individual’s handwritten signature (21 CFR 11.3(b)(7)). 
76 See 21 CFR 11.1(b).  See also the guidance for industry Part 11, Electronic Records; Electronic Signatures—
Scope and Application (August 2003), available on the FDA guidance web page. 
77 For records that are not subject to Part 11, sponsors and other regulated entities should rely on their internal 
business practices to determine acceptable electronic signature methods and controls.   
78 Available on the FDA guidance web page. 
79 Available on the FDA guidance web page.  When final, this guidance will represent FDA’s current thinking on 
this topic.   
80 See 21 CFR 11.3(b)(8) for the definition of a handwritten signature. 


Contains Nonbinding Recommendations 
 
35 
 
electronic copies (e.g., using a validated process for scanning paper copies), and (2) retained 
according to applicable FDA record retention requirements.81 
 
Q27.  Certain clinical trial protocols have an exclusion criterion for receipt of another 
“investigational medical product.”  If a participant receives a vaccine or other 
medical product for the prevention or treatment of COVID-19 authorized under an 
Emergency Use Authorization (EUA), would FDA consider this receipt of an 
investigational medical product? 
 
When a medical product is being used under an EUA, it is an authorized (though not an approved 
or cleared) medical product for use in clinical care that has met the statutory criteria under 
section 564 of the FD&C Act.  The product is not being studied under an IND or IDE when used 
pursuant to an EUA, and FDA therefore does not consider receipt under an EUA as receipt of an 
investigational product.82  In contrast, when the same product is used in a clinical investigation 
under an IND or IDE, the product’s safety and/or effectiveness is being studied for 
investigational uses, and FDA would consider receipt in this situation to be receipt of an 
investigational product.  
 
As always in the design of a clinical investigation, there may be valid scientific reasons to have 
an exclusion (and even a discontinuation) criterion for a medical product—a monoclonal 
antibody or vaccine, for example—whether that product was used under an EUA or not.  These 
scientific reasons may include risks to an individual if they enroll or continue to participate in a 
clinical trial after receiving (or having received) the excluded product, or the potential impact of 
the use of the excluded product on trial objectives, such as confounding the determination of 
effectiveness of the product under investigation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
81 See 21 CFR 312.57, 312.62, and 812.140. 
82 See guidance for industry Emergency Use Authorization of Medical Products and Related Authorities (January 
2017), available on the FDA guidance web page.  


Contains Nonbinding Recommendations 
 
36 
 
 
Q28. During the COVID-19 public health emergency some sponsors have used remote 
monitoring to oversee study conduct at clinical trial sites, including remote review of 
source data.  Should data that have been remotely monitored be re-monitored 
during an on-site monitoring visit once pandemic-related restrictions that prevented 
on-site monitoring visits have been lifted?   
 
FDA regulations require sponsors to monitor the conduct and progress of their clinical 
investigations.83  These regulations are not specific about how sponsors must conduct such 
monitoring and are therefore compatible with a range of approaches that may vary depending on 
multiple factors.  FDA’s guidance for industry Oversight of Clinical Investigations – A Risk-
Based Approach to Monitoring (August 2013) clarifies that sponsors can use a variety of 
approaches to fulfill their responsibilities for monitoring clinical investigations; the guidance 
also describes monitoring activities that reflect modern, risk-based approaches, including remote 
monitoring when appropriate.  
 
The decision as to whether remote monitoring conducted for a given site or clinical investigation 
was adequate or should be followed up with additional on-site monitoring visits should be based 
on the sponsor’s ongoing risk assessment.  The sponsor may determine that on-site follow-up of 
remote monitoring activities is appropriate based on a risk assessment (e.g., sites with certain 
data anomalies or a higher frequency of errors, important protocol violations, or dropouts relative 
to other sites).  As with on-site monitoring, remote monitoring should be focused on critical data 
and processes for human subject protection and trial integrity, such as the site’s conduct of key 
study procedures and documentation related to important efficacy endpoints and safety 
assessments. 
 
 
83 See 21 CFR 312.50, 312.53(d), 312.56(a), 812.40, 812.43(d), and 812.46.  


 
 
 
 
Commission européenne/Europese Commissie, 
 - Tel.
 
Office: 
 - Tel. direct line 
 
 
 
 
GUIDANCE ON THE MANAGEMENT OF CLINICAL TRIALS 
DURING THE COVID-19 (CORONAVIRUS) PANDEMIC   
Version 4  
04/02/2021 
 
Key changes from v3 (27-04-2020): remote source data verification  
 
 


 
2 
 
CONTENTS 
1. 
INTRODUCTION ........................................................................................... 3 
2. 
INITIATING NEW TRIALS .......................................................................... 4 
3. 
CHANGES TO ONGOING TRIALS ............................................................. 4 
4. 
SAFETY REPORTING .................................................................................. 6 
5. 
RISK ASSESSMENT ..................................................................................... 6 
6. 
COMMUNICATION WITH AUTHORITIES ............................................... 7 
7. 
AGREEMENT WITH AND COMMUNICATION BETWEEN SPONSORS, 
TRIAL SITES AND TRIAL PARTICIPANTS .............................................. 9 
8. 
CHANGES TO INFORMED CONSENT .................................................... 10 
9. 
CHANGES IN THE DISTRIBUTION OF THE INVESTIGATIONAL 
MEDICINAL PRODUCTS ........................................................................... 11 
10. CHANGES IN THE DISTRIBUTION OF IN VITRO DIAGNOSTIC AND 
MEDICAL DEVICES ................................................................................... 14 
11. CHANGES TO MONITORING ................................................................... 14 
12. CHANGES TO AUDITING ......................................................................... 17 
13. PROTOCOL DEVIATIONS ......................................................................... 17 
14. REIMBURSEMENT OF EXCEPTIONAL EXPENSES ............................. 17 
15. INITIATION OF NEW TRIALS AIMING TO TEST NEW TREATMENTS 
FOR COVID-19 ............................................................................................ 17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


3 
The European Medicines Agency (EMA), Good Clinical Practice (GCP) Inspectors 
Working Group (GCP IWG), the Clinical Trials Facilitation and Coordination Group 
(CTFG, a working group of the Heads of Medicines Agency (HMA), the Clinical Trials 
Expert Group (CTEG, a working group of the European Commission representing Ethics 
Committees and National Competent Authorities (NCA)) and the European Commission 
(EC) acknowledge the impact of COVID-19 on the health system and broader society, and 
the impact it may have on clinical trials and trial participants1. Extraordinary measures may 
need to be implemented and trials adjusted due, among others, to trial participants being in 
self-isolation/quarantine, limited access to public places (including hospitals) due to the 
risk of spreading infection, and health care professionals being committed to critical tasks. 
The COVID-19 pandemic is rapidly escalating putting national health care systems under 
continuously increasing pressure. In some Member States the capacity of the health-care 
system has already reached its limits. Against this background, pragmatic and harmonised 
actions are required to ensure the necessary flexibility and procedural simplifications 
needed to maintain the integrity of the trials, to ensure the rights, safety and wellbeing of 
trial participants and the safety of clinical trial staff during this global public health crisis. 
The points mentioned below are intended to provide guidance and clarity for all parties 
involved in clinical trials during this time. It should be noted that the simplification 
measures proposed in this document will only last during the current public health 
crisis until the revocation of this Guidance, when there is a consensus that the period 
of the COVID-19 outbreak in the EU/EEA, has passed.  
Sponsors2 and investigators should note that due to the rapidly evolving situation further 
updates to this guidance are possible and likely. 
Member States are encouraged to implement the harmonised guidance to the 
maximum possible extent to mitigate and slow down the disruption of clinical 
research in Europe during the public health crisis. At the same time, sponsors and 
investigators need to take into account that national legislation and derogations 
cannot be superseded. Member States shall complement this guidance to create 
additional clarity on specific national legal requirements and derogations to them3.  
This document sets out to include most of the current guidance across Member States with 
the aim of serving as a harmonised EU-level set of recommendations. Hence, this guidance 
was drafted and supported by the CTEG, EMA, the CTFG of the HMA and the GCP IWG 
coordinated by the EMA. Commissioner Kyriakides shared this guidance with the Health 
Ministers and no Member State has raised any concern with this guidance in the 
videoconference of Ministers of Health of 27 April 2020. 
1.
INTRODUCTION
Various challenges exist which result in restrictions of visits to healthcare facilities, 
increased demands on the health service and changes to trial staff availability. Trial 
1The word "trial participant" is used in this text as a synonym for the term “subject”, defined in Directive 2001/20/EC 
as “an individual who participates in a clinical trial as a recipient of the investigational medicinal product or a control”. 
2Sponsors should be read in this context as ”sponsor and/or CRO”. 
3Links to national guidance documents are collected here: 
https://www hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_03_CTFG_Link_to_National_guidance_on_CT_managmant_ 
during_the_COVID-19_pandemia.pdf  


4 
participants may also be required to self-isolate, which can make it difficult for 
investigators to maintain their medical oversight. These challenges could have an impact 
on the conduct of trials, such as the completion of trial assessments, completion of trial 
visits and the provision of Investigational Medicinal Products (IMPs).  
The impact of COVID-19 on ongoing trials, on opening new trial sites in an existing trial, 
on ongoing recruitment and continued involvement of participants in the trial, or on starting 
of new trials needs to be considered. This evaluation should take into account national 
recommendations and measures including travel restrictions and confinements of trial 
participants and trial staff and the availability of trial staff to perform visits, enter data in 
the Case Report Form (CRF), notify serious adverse events and, more generally, follow 
the protocol. The ability to confirm eligibility and to conduct key safety assessments and 
trial evaluations is of particular importance.  
Actions should be proportionate and based on benefit-risk considerations, on contingency 
provisions taken nationally and locally by the authorities, with priority given to the impact 
on the health and safety of the trial participant. Where a trial participant is unable to attend 
the site, other measures, such as home nursing, if possible given social distancing needs, 
or contact via phone or telemedicine, may be required to identify adverse events and ensure 
continuous medical care and oversight. However, the limitations and risks of such methods 
and the requirements for data protection should be taken into account and such alternative 
arrangements need to be adequately documented. 
The International Committee of Medical Journal Editors has made clear that in the event 
of public health emergencies, information with immediate public health implications 
should be disseminated without concern that this will preclude subsequent consideration 
for publication in a journal.4 
2.
INITIATING NEW TRIALS
The feasibility and immediate necessity of starting a new clinical trial should be critically 
assessed by sponsors, in close collaboration with other relevant parties, in particular the 
investigators. Additional risks to trial participants should be addressed in the benefit-risk 
section of the protocol along with risk mitigation measures (see chapter 5).    
3.
CHANGES TO ONGOING TRIALS
Sponsors should consider in their risk assessment whether the following measures could 
be the most appropriate during COVID-19. Measures should generally be agreed with 
investigators and could be: 

Conversion of physical visits into phone or video visits, postponement or
complete cancellation of visits to ensure that only strictly necessary visits are
performed at sites;

A temporary halt of the trial at some or all trial sites;
4 http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/overlapping-publications html 


 
5 
 
 Interruption or slowing down of recruitment of new trial participants – the 
feasibility of including new trial participants in an ongoing trial needs to be 
critically assessed; 
 
 Extension of the duration of the trial; 
 
 Postponement of trials or of activation of sites that have not yet been initiated; 
 
 Closing of sites. In case it is not feasible for a site to continue participation at all, 
the sponsor should consider if the trial site should be closed and how this can be 
done without compromising the rights, safety and well-being of trial participants 
and data validity; 
 
 If unavoidable (it should be justified that this is a truly exceptional situation based 
on the personal benefit-risk ratio for the individual trial participant), transfer of trial 
participants to investigational sites away from risk zones, or closer to their home, 
to sites already participating in the trial, or new ones, could occur. Initiation of new 
trial sites is generally not expected in the current situation unless no other solution 
exists for the trial participant. If there is an urgent need to open a new trial site for 
critical trial visits, for example outside the hospital, this may be implemented as an 
urgent safety measure (USM) first, followed later by a substantial amendment (SA) 
application (see below in chapter 6) for the approval and initiation of this additional 
site. In such cases, it is important that trial participants as well as investigators (both 
receiving and sending) are in agreement about the transfer, that the receiving site 
has the possibility to access previously collected information/collected data 
(including necessary medical records) for the trial participant and that any eCRF 
can be adjusted accordingly to allow the receiving site to enter new data. The 
impact on trial participants should be considered and arrangements made such as 
providing adequate transportation; 
 
 There may be a need for critical laboratory tests, imaging or other diagnostic tests 
to be performed, (e.g. blood cell count, liver function test, X-ray, CT, MRI, 
ultrasonography, ECG etc.), e.g. for trial participant safety or the integrity of the 
trial. In case the trial participant cannot reach the site to have these performed, it is 
acceptable that laboratory, imaging or other diagnostic tests are done at a local 
laboratory or relevant clinical facility authorised/certified (as legally required 
nationally) to perform such tests routinely, if this can be done within local 
restrictions on social distancing. The sites should inform the sponsor about such 
cases. Local analysis can be used for safety decisions.  
 
 
If this is a trial endpoint and biological samples cannot be shipped to the central 
laboratory, analysis should be performed locally and then explained with detailed 
justification, assessed and reported in the clinical study report following ICH E3. 
In these cases, it is important that the sponsor is given access to the normal ranges 
and certification information of any additional laboratory used in order to support 
the use and evaluation of results. 
 
The changes above may also be initiated by the investigator sites contacting the sponsor. 
There might also be cases where the current principal investigator (PI) of a site is 




7 
All decisions to adjust clinical trial conduct should be based on a risk assessment by the 
sponsor (ICH GCP section 5.0). It is expected that the sponsor performs a risk assessment 
of each individual ongoing trial and the investigator of each individual trial participant and 
implement measures, which prioritise trial participant safety and data validity. In case 
these two conflict, trial participant safety always prevails.  
These risk assessments should be based on relevant parties’ input and should be 
documented on an ongoing basis. It is important that sponsors in their risk assessment 
consider prioritisation of critical tasks in the clinical trial and how these are best 
maintained. 
The sponsor should reassess risks as the situation develops. This reassessment should also 
be documented as part of the sponsor's trial master file. 
It is possible that, with the escalation of the pandemic, local circumstances lead to a local 
change in risk assessment, therefore the need to implement additional measures may arise, 
and an investigator-driven risk assessment might be necessary. This assessment should be 
documented in the investigator’s site master file and communicated to the sponsor.  
The potential impact of COVID-19 on trial participants who may be determined as being 
part of a-risk group for COVID-19 or who are in trials involving treatments, which may 
increase such risks, should be carefully considered when deciding to start or continue such 
clinical trials. 
6.
COMMUNICATION WITH AUTHORITIES
Priority is given to any (new) clinical trial application for the treatment or prevention of 
COVID-19 infection, and/or substantial amendment applications to existing clinical trials 
necessary as a result of COVID-19.  
For ongoing trials, the guidance given by EC CT-18 on substantial amendments remains 
applicable. A single submission by the same sponsor with the list of concerned trials and 
an aggregated list of changes is acceptable and encouraged in case of substantial 
amendments as well as of urgent safety measures. 
Two important aspects need to be taken into account: 
1) It is up to the sponsor to assess whether an amendment is to be regarded as
‘substantial’. A change is substantial when it has a potential impact on the safety
or physical or mental integrity of the clinical trial participant, or on the scientific
value of the trial (CT-1 section 3.3, CT-2 section 59). Substantial amendments
relate to amendments of documents/information that are part of the clinical trial
application dossier.
2) Submission of information is only obligatory if the amendment is a substantial
amendment. Directive 2001/20/EC does not require notification, or immediate
submission of information on non-substantial amendments. In other words, the
8Communication 
from 
the 
Commission 
- 
('CT-1') 
(2010/C 
82/01) 
https://eur-lex.europa.eu/legal-
content/EN/TXT/?uri=CELEX:52010XC0330(01) 
9Detailed 
guidance 
from 
the 
Commission 
(’CT-2’) 
(2006) 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/12_ec_guideline_20060216_en.pdf 


 
8 
only communication mechanism of substantial changes to information in the 
protocol or clinical trial dossier is through the submission of a substantial 
amendment. Non-substantial amendments, or changes that do not relate to 
information submitted in the clinical trial application dossier should be recorded in 
the documentation when it is subsequently submitted, for example in the 
subsequent submission of a substantial amendment (CT-1 section 3.1).    
In case the risk assessment leads to actions that affect the trial as described below in a), b), 
and c), the relevant NCA and/or Ethics Committees must be informed in accordance with 
Directive 2001/20/EC and national laws: 
a) It is possible that urgent actions are required by the sponsor and investigator to 
protect the trial participants against immediate hazard. These urgent safety 
measures do not need prior notification. Due to specific local or national 
circumstances related to the COVID-19 Pandemic, submission to the relevant 
authorities could take longer than usual, but the information needs to be provided 
to the NCA and the Ethics Committee as soon as possible (CT-1, Art 3.9). The 
sponsor needs to document the justification for this delay in the trial master file. In 
communication with authorities, the sponsor is expected to provide adequate 
information on the cause, measures taken and the plan for further actions. 
b) If changes, which are substantial amendments, do not require immediate action 
from the sponsor or investigator, these should be submitted as substantial 
amendment applications. Sponsors are encouraged to take into account the limited 
capacity of regulatory authority assessors and Ethics Committees, and submit only 
high quality, complete applications containing only the necessary changes. Over-
reporting should be avoided (Art. 11b of Directive 2001/20/EC; CT-1 article 3.9). 
c) Certain procedural or other changes might become necessary to address global 
or local consequences of the pandemic (e.g. related to social distancing or to avoid 
unnecessary strain on health care professionals). If these changes are justifiable, 
COVID-19 related changes, not related to trial participants’ safety and do not have 
a serious effect on the benefit-risk balance for the trial participants and the scientific 
value of the trial, they can be notified as soon as possible taking into account 
national and local circumstances. In these cases, sponsors are expected to submit 
to the relevant NCA and Ethics Committee the list of all changes with appropriate 
risk assessment and justification as well as follow-up actions when necessary. 
Cumulative changes must not have a negative impact on trial participants’ safety 
and/or on the integrity of the trial. Relevant protocol deviations are sufficient to be 
recorded according to chapter 13. 
The sponsor is expected to maintain appropriate records, in a timely manner, of all changes 
described in the chapter above in the trial master file. 
Communication should be clearly marked with ’COVID-19’ in the subject field.  
The following table provides a non-exhaustive list of examples for the classification of 
different mitigating measures – more information on specific approaches can be found in 
the chapters 3, 9 and 11 below, and/or in the national recommendations, where applicable.  
 
 




 
10 
by the latter to the competent authorities and ethics committees, in line with the principles 
described in chapter 6. 
In addition, trial participants should be informed by the investigator, in a timely manner, 
about changes in the conduct of the clinical trial relevant to them (e.g. cancellation of visits, 
change in laboratory testing, delivery of IMP). 
 
8. 
CHANGES TO INFORMED CONSENT 
Unless linked to the implementation of urgent safety measures, changes in informed 
consent procedures will need to be reviewed and approved by the relevant ethics committee 
in advance. 
The informed consent procedure in all trials needs to remain compliant with the trial 
protocol as well as with EU and national legal framework. It is acknowledged that national 
provisions and approaches differ.   
Sponsors should be mindful of the current pressure on the medical profession and should 
carefully assess the pertinence of enrolling new trial participants in ongoing clinical trials. 
Absolute priority should be given to clinical trials for the prevention or treatment of 
COVID-19 and COVID-19-related illnesses, or trials on serious diseases with no 
satisfactory treatment option. In case a sponsor plans to initiate a trial aiming to test new 
treatments for COVID-19, advice should be sought on alternative procedures to obtain 
informed consent, in case the physical consent cannot leave the isolation room, and 
therefore is not appropriate as trial documentation. 
However, the following specific aspects should be taken into account with trials involving 
COVID-19 patients: 
 If written consent by the trial participant is not possible (for example because of 
physical isolation due to COVID-19 infection), consent could be given orally by 
the trial participant (Art 2(j) of Directive 2001/20/EC) in the presence of an 
impartial witness. In such cases, the witness is required to sign and date the 
informed consent form and the investigator is expected to record how the impartial 
witness was selected.  
 
 In addition, it could be considered that the trial participant and the person obtaining 
consent sign and date separate informed consent forms.  
 
In either case, all relevant records should be archived in the investigator's site 
master file. A correctly signed and dated informed consent form should be obtained 
from the trial participant later, as soon as possible. 
 Where potential COVID-19 trial participants are incapacitated adults not able to 
give informed legal consent due to the severity of their medical condition, or when 
minors are included, consent has to be obtained from the legal representative(s) 
according to Articles 4 and 5 of Directive 2001/20/EC or according to national 
rules.  
 
 In case of acute life-threatening situations, where it is not possible within the 
therapeutic window to obtain prior informed consent from the trial participant (or 


 
11 
her/his legal representatives(s)), informed consent will need to be acquired later, 
when this is allowed by national legislation. In these cases, the investigator is 
expected to record why it was not possible to obtain consent from the trial 
participant prior to enrolment.  
 
There may be a need to re-consent already included trial participants. However, it should 
be avoided that trial participants visit trial sites for the sole purpose of obtaining re-consent. 
If re-consent is necessary for the implementation of new urgent changes in trial conduct 
(mainly expected for reasons related to COVID-19 or important safety issues for other 
trials), alternative ways of obtaining such re-consent should be considered during the 
pandemic. These could comprise contacting the trial participants via phone or video-calls 
and obtaining oral consents, to be documented in the trial participants' medical records, 
supplemented with e-mail confirmation. Approved updated patient information sheet and 
consent form should be provided to trial participants by the investigator by e-mail, mail or 
courier before re-consent is obtained. Any consent obtained this way should be 
documented and confirmed by way of normal consent procedures at the earliest 
opportunity when the trial participants are back at the regular sites. 
Any validated and secure electronic system already used in the trial in the particular 
member state for obtaining informed consent can be used as per usual practice and if in 
compliance with national legislation. 
 
9. 
CHANGES IN THE DISTRIBUTION OF THE INVESTIGATIONAL MEDICINAL PRODUCTS 
The recommendations in this section of the guidance also apply to "non-investigational 
medicinal products" (NIMP) and other products or devices normally provided to the trial 
participants during on-site trial visits, as defined in the protocol.  
Changes in the distribution of the investigational medicinal products (IMP) may be 
necessary to prevent avoidable visits to sites and to provide the trial participants with 
needed treatments. Sponsors must assess the risks relating to the product and consider any 
alternative shipping and storage arrangements.  
Such measures raise various practical considerations, including whether the IMP is 
appropriate for administration and general storage at the trial participant’s home, how the 
stability of the product will be maintained during transit (especially for a cold chain 
product), how safe custody of products will be ensured and how IMP accountability and 
the evaluation of compliance to treatment (as defined in the protocol) will be managed. 
The overriding objective of all changes in distribution is to provide trial participants with 
the IMP as needed according to the trial protocol and to avoid treatment interruptions, in 
order to maintain a positive benefit-risk balance and to protect the rights, safety and well-
being of trial participants as well as the integrity of the data collected during the clinical 
trial. The continuation of treatment should be under adequate supervision of the 
responsible investigator. 
Changes in distribution of IMP may include the following: 
 Provided that such measures do not create shortages of marketed medicinal 
products: 


 
12 
o Larger amounts of IMP than normally foreseen can be provided to the trial 
participant. This is to sustain the trial participant for a longer period and 
thereby avoid non-critical visits by the trial participant to the investigator 
site. 
o It is recommended for all IMPs and non-IMPs in clinical trials that 
appropriate stock is maintained to ensure treatment in case of distribution 
failure. 
 
 In case of urgent shortage of IMP at some sites or transfer of trial participants from 
one clinical trial site to another site, there might be a need to potentially re-
distribute the IMP between sites in accordance with GMP annex 13 (section 47). 
This should only be considered in cases where a direct distribution of the IMP to a 
trial site by the usual distributor is not possible or in the exceptional circumstance 
where a trial participant is transferred from one site to another. Sponsors should 
assess whether sites can handle and control such a re-distribution process, 
especially in case of restricted conditions for storage such as the need for specific 
conditions other than room temperature (e.g. -20°C, +2-8°C).  
 Re-distribution should follow a written procedure established in cooperation with 
the Qualified Person or the person responsible for distribution of the IMP, and sites 
should be provided with enough information to ensure that the process can be 
performed securely. Appropriate associated records should be included in the 
transfer and retained. Adequate documentation of the transfer needs to be included 
in the investigators’ and the sponsor’s trial master file.  
 In line with the reduction of physical site visits, we foresee that there will be a need 
for delivery of the IMP directly to trial participants’ homes during the COVID-19 
pandemic to avoid that the trial participant has to reach the site with the consequent 
risk of spreading/acquiring infection. The following should be considered for the 
direct shipment of IMP to trial participants: 
o 
It should also be determined whether further education or training of the trial 
participants will be necessary for IMP receipt, handling and self-
administration. Written information on the dose regimen needs to be provided 
to trial participants along with contact information to site for any questions 
they may have. The same contact should be used for trial participant to inform 
the investigator if there is any damage to the IMP packaging, containers or the 
IMP itself. 
o 
The delivery should be done from trial sites (hospital pharmacies as applicable) 
to trial participants. The sponsor should bear the cost of the shipment and 
should provide logistical assistance to the trial site if needed, for instance for 
the selection of an appropriate courier or transporter.  
o If, due to the COVID-19 pandemic, a trial site is not able to handle the 
additional burden of IMP shipment to trial participants, the IMP may as an 
exception be shipped to the trial participants by a distributor10 independent from 
                                                 
10A  distributor is a third party located in the EU/EEA contracted by the sponsor to store the IMP and distribute it to the 
trial sites and, in the current exceptional circumstances, to the home of the trial participant. 


 
13 
and acting on behalf of the sponsor in line with national law or temporary 
national emergency measures11. The following then applies: 
 IMP shipment to the trial participants should be described in a contract 
between the sponsor and the distributor. The contract should identify all 
involved investigators/ trial sites. The contract should set out what 
documents or other materials are permitted to be supplied to the site. 
The contract and procedures involved should be documented in the 
sponsor trial master file.  
 The IMP may only be dispatched to trial participants after agreement 
with the investigator and on the basis of the investigator’s prescription. 
The agreement and the procedure should be recorded in the investigator 
site file; 
 The investigator should explain the process to the trial participant or 
carer orally and should obtain her/his oral consent before agreeing with 
the sponsor, including for the investigator to provide the trial 
participant’s name, address and contact details (phone and or e-mail) to 
the distributor. When possible, consent should be confirmed in writing 
by e-mail, mail or letter sent via a courier. The oral or written consent 
should be documented in the trial participant's medical records; 
 The distributor should not store the personal data of the trial participant 
for a longer period than is required for the purpose of dispatching the 
IMP (should be destroyed as soon as no longer needed and in no case 
longer that the duration of the public health crisis) and should only use 
this information for the purpose of making the IMP deliveries 
during the period of the pandemic. It should not be used for any other 
purpose or disclosed to a third party for another purpose, other than 
monitors, auditors or inspectors verifying the conduct of the trial. This 
should be set out in the contract between the sponsor and distributor. 
 The trial participants' names, address and contact details should never 
be provided to the sponsor, and the distributor should not have access 
to the trial participants' health information. 
o The organisational measures agreed between the sponsor and the contracted 
distributor should protect blinding and ensure compliance with the 
randomisation. 
o Dedicated couriers should be contracted for IMP shipment with procedures in 
place. These procedures should ensure timely delivery directly to the trial 
participant or her/his designated caregiver to avoid that e.g. the IMP is handed 
over to the neighbour etc. The investigator should receive confirmation of all 
deliveries by the courier and confirm the receipt with the trial 
participant/caregiver by e.g. phone-call or e-mail. The investigator is 
responsible for proper IMP administration.  
o The shipment should be done under conditions that safeguard the integrity of 
the IMP, whether physically or with regards to temperature. Temperature 
                                                 
11The provision of IMP directly from an independent distributor to participants under specific conditions was shared with 
the health ministers and no concern was raised in the videoconference of Ministers of Health of 27 April 2020. 


 
14 
records should be maintained during shipment for temperature-sensitive 
products. The investigator should be immediately informed in case the 
temperature departs from the specified conditions and should advise the trial 
participant at the earliest on the possibility to use or not the IMP, after 
consultation with the sponsor. 
o The courier should be informed of, and commit to, the shipment conditions (in 
particular regarding temperature) and maximum duration. 
o Procedures for the accountability of the IMP must be in place (among others 
for compliance monitoring). Accountability of the IMP should be maintained. 
Clear records of shipment from the trial site or from the distributor should be 
kept in the investigator site file, itemising the medication being delivered and 
the quantity involved. Documentation of receipt by the trial participant should 
be kept. Participants should retain unused IMP and containers and return them 
to the investigator when they next have a visit to the investigator site 
 
Changes in IMP distribution are often associated with additional changes (e.g. in the visits 
schedule per protocol or replacement of physical visits with virtual ones). Such changes 
need to be communicated to regulatory bodies as described in section 6. 
10. CHANGES IN THE DISTRIBUTION OF IN VITRO DIAGNOSTIC AND MEDICAL DEVICES  
It is important to ensure the availability of those in vitro diagnostic devices and medical 
devices, which are essential for the conduct of the clinical trial (e.g. to allow enrolment, 
monitoring trial participants’ safety and treatment efficacy, providing data for trial 
endpoints). Therefore, it is recommended that appropriate stock of these devices is 
maintained in case of distribution failure, if this can be done without posing any risk to the 
treatment of patients outside of the clinical trial under standard medical care. In addition, 
changes in the distribution of these devices between trial sites may be necessary. 
11. CHANGES TO MONITORING  
Certain sponsor oversight responsibilities, such as monitoring and quality assurance 
activities need to be re-assessed and temporarily, alternative proportionate mechanisms of 
oversight may be required.  
The first priority when considering any change is to protect the rights, safety and well-
being of trial participants. 
As part of the risk assessment outlined in chapter 5, a risk-based approach to monitoring 
should be taken, focusing on certain sites, certain data points and certain processes that are 
critical to ensure the rights, safety and well-being of trial participants and the integrity of 
the trial (and trial data). The sponsor should consider the extent and nature of monitoring 
that would be eligible in each specific trial under this exceptional situation, and weigh this 
against the extra burden that introduction of any alternative measures would put on site 
staff and facilities. The monitoring plan should then be revised in accordance with these 
considerations, in order to strike an acceptable balance between appropriate oversight and 
the capacity of the trial site.  


 
15 
Results of adjusted monitoring/review measures and their impact should be reported to the 
sponsor in monitoring reports and in the clinical study report, where applicable.  
It is essential that robust follow-up measures are planned and ready to be implemented 
when the situation is normalised. This should include increased on-site monitoring for a 
period that is sufficient to ensure that the impact of the reduced monitoring can be rectified, 
and problems resolved or properly documented. Data subject to remote source data 
verification are likely to require re-monitoring, in particular if it was based on 
pseudonymised documents, which cannot be considered as source documents, and 
considering that remote monitoring is expected to only have focused on the most critical 
information. 
Adjusting monitoring activities may include a combination of the following: 
a) On-site monitoring 
Cancelling or postponing of on-site monitoring visits and extending of the period between 
monitoring visits are likely to be necessary. 
To the extent on-site monitoring remains feasible, it should take into account national, 
local and/or organisational social distancing restrictions, the urgency (e.g. source data 
verification can often be postponed) and the availability of site staff and should only be 
performed as agreed with trial sites.  
Additional measures regarding on-site monitoring may include limited, targeted on-site 
monitoring identifying higher risk clinical sites, if not already applicable for the trials of 
concern. 
The on-site monitoring plan will need to be adapted and alternative measures (like those 
outlined in b), c) and d) below) put in place, or relied on to a greater extent if already 
present. 
b) Centralised monitoring and central review of data collected 
Centralised monitoring is an established method under ICH GCP E6. 5.18.3 (Addendum). 
In the context of the pandemic, the role of centralised monitoring has an increasing 
importance. Centralised monitoring of data acquired by electronic data capture systems 
(e.g. eCRFs, central laboratory or ECG / imaging data, ePROs etc.) that are in place or 
could be put in place provides additional monitoring capabilities that can supplement and 
temporarily replace on-site monitoring through a remote evaluation of ongoing and/or 
cumulative data collected from trial sites, in a timely manner. Centralised monitoring 
should not be confused with remote source data verification (see 11.d. below).  
c) Off-site monitoring 
Additional off-site monitoring activities could include phone calls, video visits, e-mails or 
other online tools in order to discuss the trial with the investigator and site staff. These 
activities could be used to get information on the clinical trial progress, to exchange 
information on the resolution of problems, review of procedures, trial participant status as 
well as to facilitate remote site selection and investigator training for critical trials. 
d) Remote source data verification  
In addition to the above mentioned, established methods (11.a-c), and taking into account 
the continuing nature of the COVID-19 pandemic and the need to ensure the quality of 


 
16 
clinical trial data and to protect the rights, safety and well-being of the participants in the 
EU/EEA, remote source data verification (rSDV) can be justified in clinical trials. Remote 
SDV can be considered only during the COVID-19 pandemic related public health crisis 
and when in line with EU and national law (or temporary national emergency measures)12. 
Remote SDV may be considered for trials: 
 involving COVID-19 treatment or prevention; 
 investigating serious or life-threatening conditions;  
 where the absence of SDV for critical data may likely pose unacceptable risks to 
participants’ safety or the reliability/integrity of trial results; 
 involving particularly vulnerable participants such as children or those 
temporarily (e.g. trials in emergency situations) or permanently (e.g. trials in 
patients with advanced dementia) incapable of giving their informed consent or 
 in pivotal trials.  
Remote SDV should focus on the quality control of critical data such as primary efficacy 
data, important safety data. Important secondary efficacy data may be monitored 
simultaneously, provided this does not result in a need to access additional documents and 
therefore in an increased burden for trial site staff. The sponsor should determine the extent 
and nature of remote SDV that they consider needed for each trial under this exceptional 
situation and should carefully weigh it against the extra burden that introduction of any 
alternative measures would put on site staff and facilities. 
In the case of these trials, principal investigators should make their own determination as 
to whether or not the situation at their clinical site allows any of the following options for 
remote SDV:  
 Sharing pseudonymised copies of trial related source documents with the monitor; this 
may be done electronically where manageable by the site staff;  
 Direct, suitably controlled remote access to trial participants’ electronic medical 
records; 
 Video review of medical records with clinical site team support, without sending any 
copy to the monitor and without the monitor recording images during the review. 
For COVID-19 trials starting now, when remote SDV is foreseen, it should be described 
in the initial protocol application (and informed consent form). In case of ongoing trials 
introduction of remote source data verification should be submitted, in line with national 
law or temporary national emergency measures, via a substantial amendment. These 
provisions should be in line with the principles of necessity and proportionality and in a 
way that protects trial participants’ rights and should not place any disproportionate burden 
on site staff as determined by the investigator and trial site staff.  
Remote SDV can be carried out only in agreement with the investigators who should not 
be put under undue pressure to accept remote SDV and should always give priority to the 
care to be given to trial participants and other patients.  
                                                 
12 The initial provision for source data verification to take place remotely in the case of trials with (1) COVID-19 
treatments and (2) medicines for treatment of serious or life-threatening conditions with no satisfactory treatment option, 
provided that certain conditions are met to protect trial participants’ rights was shared with the health ministers and no 
concern was raised in the videoconference of Ministers of Health of 27 April 2020. The scope for rSDV was further 
extended in February, 2021 (v4) due to the prolonged nature of the pandemic. 


17 
Remote SDV should not be carried out if adequate data protection, including data security 
and protection of personal data even if pseudonymised, is not ensured. Refer to Annex 1 
for controls that, where applicable, can protect trial participants’ rights while permitting 
remote SDV. 
12. CHANGES TO AUDITING
In the current situation, on-site audits should, in general, be avoided or postponed. Audits 
should only be conducted if permitted under national, local and/or organisational social 
distancing restrictions. For critical trials, on-site audits as well as remote audits can be 
considered, after agreement with the investigator and if the audits are assessed as essential, 
e.g. triggered audits with the purpose of investigating serious deviations from  the trial 
protocol or  from the applicable legislation.  
13. PROTOCOL DEVIATIONS
The COVID-19 situation is likely to introduce more protocol deviations than normal. It is 
expected that the sponsor manages such protocol deviations in accordance with their 
standard procedures. The sponsor should perform an analysis of the number and type of 
deviations periodically to assess whether a protocol amendment or other modifications are 
needed. A proportionate approach will be taken by the GCP inspectors when such 
deviations are reviewed, recognising that the best interest of the trial participants is 
maintained, and the trial participants are not put at risk. 
An increase in protocol deviations in relation to the COVID-19 situation will not, of itself, 
trigger the actions required by ICH GCP section 5.20. Such deviations will need to be 
assessed and reported in the clinical study report, following ICH E3. 
Please also refer to the guidance on the implications of Coronavirus disease (COVID-19) 
on methodological aspects of ongoing clinical trials5 by the CHMP Biostatistics Working 
Party, published on 25 March 2020. 
14. REIMBURSEMENT OF EXCEPTIONAL EXPENSES
Taking into account this exceptional situation, the implementation of urgent safety 
measures may create unplanned expenses. These expenses should be borne by the sponsor, 
preferably directly. If expenses nevertheless arise which have to be borne initially by the 
trial participants, these should typically be compensated subsequently by the sponsor via 
the investigator. If additional financial compensation is provided to sites/investigators (e.g. 
to cover the cost of using couriers for IMP delivery), this needs to be documented and 
performed according to national legislation. Handling of reimbursement of such expenses 
should follow national legislation and/or guidance. 
15. INITIATION OF NEW TRIALS AIMING TO TEST NEW TREATMENTS FOR COVID-19
The Member States support the submission of large, multinational trial protocols for the 
investigation of new treatments for COVID-1913.  
13https://www.ema.europa.eu/en/news/call-pool-research-resources-large-multi-centre-multi-arm-clinical-trials-
generate-sound-evidence 






 
20 
 Monitors should sign a written confidentiality agreement committing to securely 
destroy any copy of redacted documents, whether paper or electronic, as soon as 
they have been used for source data verification and committing not to make any 
copy (or recording in the case of video access) of any non-pseudonymised 
document.  
 
 If the agreed remote SDV process involves redaction by the site staff 
(pseudonymisation) of source records:  
o The monitor should provide a written request to the site for the specific 
participant’s specific trial records required for SDV. 
o Site staff should create copies of the requested trial participant’s records, 
redact (i.e. pseudonymise and mask any unnecessary private information 
unrelated to the trial) the copies, identify them with the trial participant 
identification code in the trial, have a second person perform and document 
a quality control to ensure that all identifying information has been redacted 
and is no longer readable, and make the pseudonymised copies available to 
the monitor using a secure mechanism. The redacted copies should be kept 
in the investigator's site master file with records of their communication to 
the monitor. 
o The monitor should access the records securely, complete the monitoring 
task, securely destroy any copy made locally and provide a certificate of 
destruction to the trial site. 
o Once on-site monitoring visits are again feasible, the monitor should verify 
at the earliest opportunity that the provided pseudonymised (coded) data 
are indeed data related to the trial participant with the provided code.  
 
 If the agreed remote SDV process involves a video review of records: 
o The quality of the video should be adequate to enable reading, without risk 
of confusion between similar characters, and to avoid a negative impact on 
the visual health of the monitors. 
o The video review of documents may include site staff sharing the screen of 
their computer with the monitor using a secure video conference application 
hosted on their computer. Videoconferencing solutions where data may be 
captured on third country servers may not be acceptable. 
o The video review of documents is likely to necessitate the presence of a 
member of the trial site staff at all times in order to change the document 
being viewed or to scroll the document on a computer screen. Sponsors and 
investigators should be aware of the importance of the burden that such 
SDV methods may represent for trial sites and hence the review should be 
restricted to a minimum of critical data in critical trials. 
o The transmission of the data should be adequately protected against 
unauthorised third party access. 
 
 If the agreed remote SDV process involves the site providing the monitor remote 
access to the site electronic medical record (EMR) system:  
o The monitor should be provided with a secure, read-only access to the EMR 
system, including all modules relevant for review. This access should be 
restricted to the records of only those patients who participate in the trial 
and who did not object against remote access to their medical records as 
outlined above. 


 
21 
o A list of the monitors to whom remote access has been granted should be 
maintained. In order to prevent unauthorised access, access rights should be 
revoked once remote SDV tasks have been completed for the trial. 
o The EMR system should have an audit trail and be able to log information 
on who accessed data and when. 
o Remote access to the EMR should only be possible using a two-factor 
authentication. 
 
 It should not be possible to make local copies of trial participants' health records. 
Users should be aware of the automatic creation of temporary files on their 
computer when reviewing trial participant data, and should securely delete such 
files immediately after each source data verification session.  
 
 


Page 1 of 4 
Supplementary recommendations of BfArM and PEI to the European Guidance on the Management 
of Clinical Trials during the COVID-19 (Coronavirus) pandemic, version 4 
In view of the impact of the pandemic on European healthcare systems, the European authorities 
published a guidance document on 20 March 2020 that provides sponsors with recommendations 
regarding clinical trials and the persons involved in them.  
This guidance document was revised again, adopted on 4 February 2021 and published as version 4 
both in the collection of laws of the European Commission (Eudralex, Volume 10) 1 and on the 
homepage of the European Medicines Agency (EMA)2.  
The guideline is a harmonised package of recommendations at EU level, which was co-developed and 
co-adopted by Germany. Some recommendations require closer consideration and interpretation, also 
with regard to the German legal area. These include, in particular, temporarily applicable measures for 
source data verification, if on-site monitoring at the trial sites is not indicated due to the coronavirus 
pandemic.  
Additional notes and recommendations for the implementation of Remote Source Data 
Verification (rSDV)  
This document does not repeat the recommendations of the European guideline in a comprehensive 
manner. Instead, only those recommendations that require interpretation and supplementation or for 
which the sponsor is expected to provide detailed information in an initial application in accordance 
with § 7ff GCP-V (Ordinance on the implementation of GCP in the conduct of clinical trials on medicinal 
products for use in humans) or an application for a subsequent amendment in accordance with § 10 
GCP-V ('substantial amendment'), which prove that the planned procedure corresponds to the state 
of science and technology, are taken up in the following.  
Regardless of the method chosen for rSDV, the sponsor shall first obtain the written agreement of the 
investigator and, if applicable, of the institution where the trial site is located.  
As described in detail in the European guideline, remote access to source documents/source data for 
monitoring purposes should only take place in justified exceptional cases and only to the extent 
strictly necessary. For details, see the European guideline. Remote SDV should also only take place if 
suitable data protection - including data security and the protection of personal data – is ensured. This 
is also to be borne in mind with regard to pseudonymised data. 
In justified exceptional cases, the guideline provides the following three options for source data 
reconciliation without the monitor being physically present at the trial site:  
•
The trial site provides the monitor, under the responsibility of the investigator, with copies of
the source documents/source data in which personal identifying information of the trial
subjects and information pertaining to their privacy has been obscured or redacted
(hereinafter referred to simply as "redacted copies").
•
Under the responsibility of the investigator, the trial site grants the monitor direct, controlled
remote access to the systems with which the source documents/source data are managed.
1 https://ec.europa.eu/health/documents/eudralex/vol-10_en  
2 https://www.ema.europa.eu/en/human-regulatory/research-
development/compliance/goodclinical-practice#guidance-on-clinical-trial-management-during-
the-covid-19-pandemic-section  


Page 2 of 4  
• 
The trial site grants the monitor, under the responsibility of the investigator, passive access to 
the source documents/source data via live image transmission (e.g. sharing of the screen or 
image/sound transmission).  
Implementation requires the authorisation of the responsible higher federal authority as well as the 
favourable opinion of the responsible ethics committee. For this purpose, an application according to 
§ 7ff GCP-V or for subsequent amendment according to § 10 GCP-V ('substantial amendment') shall be 
submitted. In this application, the planned procedure should be described in sufficient detail, 
beginning with a summary of the underlying, study specific risk assessment. This can be done either in 
the Quality Control and Quality Assurance section of the protocol (ICH-GCP, Section 6) or as an 
appendix to the protocol. In the latter case, the appendix to the trial protocol must be submitted with 
the application.  
Irrespective of this, the standard operating procedures and study specific documents (including those 
on risk-based quality management [ICH-GCP, Section 5.0] and monitoring [ICH-GCP, Section 5.18]) 
used in the clinical trial should be adapted accordingly.  
The method chosen for the rSDV depends very much on the infrastructure of the trial site. In the 
application for approval according to § 7ff or § 10 GCP-V, the sponsor shall list all methods that may 
be used for rSDV, as only the alternatives described therein are considered approved.  
For each method applied for, at least the following information should be provided:  
• 
Identification of the source documents/source data to be made available under the rSDV (e.g.  
those related to the primary endpoint, serious adverse events, important medical events, or 
the reasons for exclusion of a subject from the trial);  
• 
Presentation of the precautions taken for data security to ensure the confidentiality of data 
and the privacy of the trial subjects.  
Depending on the method applied for, the following additional information is required:  
a.  Passing on of redacted copies of original documents and documents with original data  
The sponsor shall provide the following details in the protocol or in an annex to the protocol:  
• 
Minimum copy quality requirements to be met by investigator/institution (e.g. format, 
resolution, colour);  
• 
Method for ensuring that the copies are complete;  
• 
Method for ensuring that all information that could reveal the identity of subjects is obscured 
or redacted, and a description of actions to be taken by the monitor and the 
investigator/institution if this has failed;  
• 
Requirements to prevent loss of or unauthorized access to source documents/data during 
the document/data sharing process;  
• 
Documentation requirements for the traceability of documents forwarded by the 
investigator/institution as well as received and processed by the monitor.  
 
b.  Direct, controlled remote access to the systems used by the trial site to manage the source 
documents/source data  
The sponsor shall clarify the following in the application for approval:  


Page 3 of 4  
• 
Name of the document management system(s) to be accessed (name of the software, 
version);  
• 
Name of the system used for remote access (name of the software, version, end-to-end 
encryption requirement);  
• 
Monitor access rights (two-factor identification, access limited to the trial subjects and the 
parts of the documentation provided for under the rSDV, right to navigate, read-only access);  
• 
Measures to prevent permanent storage of file contents by the monitor or to ensure short 
term, permanent deletion of automatically generated, temporary contents;  
The sponsor shall provide a written statement in the application for approval:  
• 
Confirmation that the rSDV is conducted exclusively by the authorized person(s) (i.e. monitor) 
in accordance with the written informed consent of the trial subjects.  
• 
Confirmation that remote access is provided via secured systems/environments and 
systems/servers within the EEA/EU and/or confirmation that the conditions set out in the 
European guideline for data transferred or processed outside the EEA/EU, are applied. 
Note:  
When establishing remote access or adding such access to an existing system, it should be ensured 
that the establishment or modification of such an access is validated according to the risk. Changes 
in running systems without sufficient validation (e.g. quick-fix engineering updates (QFE)) should 
be avoided.  
 
c. Passive access to original documents/original data via live image transmission  
The sponsor shall clarify the following in the application for approval:  
• 
Brief description of the method used and the parties involved in the process;  
• 
Identification of the devices and/or software used for live image transmission;  
• 
Security measures applied (e.g. for authentication, prevention of unauthorised recordings or 
transmission security).  
The sponsor shall make a written statement in the application for approval:  
• 
Confirmation that the rSDV will be conducted exclusively by the authorised person(s) (i.e. 
monitor(s)) in accordance with the written informed consent of the trial subjects;  
• 
Confirmation that live image transmission takes place via secured systems/environments and 
systems/servers within the EEA/EU and/or confirmation that the conditions set out in the 
European guideline for data transferred or processed outside the EEA/EU, are applied; 
• 
Confirmation that there is a written statement from the monitor and the sponsor that   
a) the rSDV takes place in a protected environment (i.e. providing protection from 
unauthorised access in any form, including the use of privacy screens to prevent 
unauthorised viewing of source documents/source data);   
b) the viewed source documents/source data are not permanently stored and   
c) if necessary, temporarily saved files (including ones automatically generated by the 
system) are permanently deleted at short notice;  


Page 4 of 4 
•
Confirmation that appropriate corrective measures will be implemented in the event of
technical difficulties or if the security of the transmission is no longer guaranteed.
Note: 
The information and communication technology used by the sponsor and the trial site for rSDV 
shall be designed in such a way that secure and GDPR-compliant transmission is guaranteed. As a 
rule, the known messenger services are not suitable for this purpose. In this context, we refer to 
the "Whitepaper Technical Data Protection Requirements for Messenger Services in the Hospital 
Sector" published by the Conference of Independent Data Protection Supervisors of the Federal 
and State Governments on November 7, 20193.   
Service providers for telemedicine who have the certificates, expert opinions and quality seals 
required according to § 5 para. 2 of Annex 31b to the Federal Master Treaty for Medical 
Practitioners 4  could be suitable for this purpose, provided that GCP-relevant aspects are 
guaranteed by the sponsor through the qualification and monitoring of these service providers.  
In accordance with their legal mandate, the ethics committee and the responsible competent 
higher federal authority examine the information provided in the context of the evaluation or 
approval of an application, respectively, in accordance with § 7ff or § 10 GCP-V only cursory in 
relation to compliance with data protection regulations (see also “Coming into effect of the GDPR 
— Handbook for Ethics Committees for the Consultation or Evaluation of Studies”). The activities 
undertaken should be included by all parties involved in rSDV in their list of data-processing 
activities, which is anchored in data protection law, and might be subject to an independent 
assessment by the responsible data protection supervisory authorities.5  
3 https://www.datenschutzkonferenz- 
online.de/media/oh/20191106_whitepaper_messenger_krankenhaus_dsk.pdf  
4 https://www.gkv-spitzenverband.de/krankenversicherung/
digitalisierung_und_innovation/ videosprechstunde/kv_videosprechstunde.jsp  
5 https://www.ak-med-ethik-komm.de/docs/intern-2018/DSGVO_Empfehlungen.pdf   


CONFIDENTIAL 
Protocol KB-ENTO-3001 v4.0 
(Amendment 3.0) 
 
85 
 
10.10 
Appendix 10: List of Abbreviations and Terms 
Abbreviation/Term 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B antibody 
anti-HCV 
hepatitis C antibody 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration time curve 
AUCss 
area under the concentration time curve at steady state 
AZA 
5-azacytidine 
BID 
twice a day 
C1D1 
Cycle 1 Day 1 
CBC 
complete blood count 
CBF 
core binding factor 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximal plasma concentration 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRh 
complete response with hematologic improvement 
CRi 
complete response with incomplete blood count recovery  
CT 
computed tomography 
CYP 
cytochrome P450 
DAC 
5-aza-2-deoxycytidine 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 


CONFIDENTIAL 
Protocol KB-ENTO-3001 v4.0 
(Amendment 3.0) 
 
86 
 
Abbreviation/Term 
Definition 
ECHO 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EFS 
Event free survival 
ELN 
The European Leukemia Network 
ENTO 
entospletinib 
EORTC-QLQ 30 
European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire-Core 30  
EQ-5D-5L 
European Quality of Life 5 Dimensions Questionnaire 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FSH 
follicle stimulating hormone 
FLT3 
FMS-like tyrosine kinase 3 
GCP 
Good Clinical Practice 
GO 
gemtuzumab-ozogamycin 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HMA 
hypomethylating agents 
HOX49 
homeobox protein  
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITD 
internal tandem duplication  
ITF 
induction treatment failure 
IV 
intravenous  
IWG 
International Working Group 


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87 
 
Abbreviation/Term 
Definition 
IxRS 
Interactive Voice/Web Response System 
MDS 
myelodysplastic syndromes 
MRD 
measurable residual disease 
mRNA 
messenger RNA 
MUGA 
Multi-gated acquisition 
N/A 
Not applicable 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NCCN 
National Comprehensive Cancer Network 
NPM1 
nucleophosmin-1 
NPM1-m 
nucleophosmin-1 mutated 
OS 
overall survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PD 
progressive disease 
pSYK 
phosphorylated spleen tyrosine kinase 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS CoV-2 
severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) 
SD 
stable disease 
SUSAR 
suspected, unexpected serious adverse reaction 
SYK 
spleen tyrosine kinase  
TEAE 
treatment-emergent adverse event 
TKD 
tyrosine kinase domain 
UGT1A1 
UDP-glucuronosyltransferase 1A1 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WHO 
World Health Organization 


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Abbreviation/Term 
Definition 
WOCBP 
woman of child-bearing potential 
 


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11.0 References 
Angenendt L, Röllig C, Montesinos P, et al. Chromosomal abnormalities and prognosis in NPM1-
mutated acute myeloid leukemia: A pooled analysis of individual patient data from nine 
international cohorts. J Clin Oncol. 2019;37(29):2632-2642.  
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization 
classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. 
Braselmann S, Taylor V, Zhao H, et al. R406, an orally available spleen tyrosine kinase inhibitor 
blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol 
Exp Ther 2006; 319:998–1008. 
Brunetti L, Gundry MC, Sorcini D, et al. Mutant NPM1 maintains the leukemic state through HOX 
Expression. Cancer Cell. 2018;34(3):499-512.e9. 
Burke JM, Shustov A, Essell J, et  al. An open label, phase II trial of entospletinib (GS-9973), a 
selective spleen tyrosine kinase inhibitor, in diffuse large B-cell lymphoma. Clin Lymphoma 
Myeloma Leuk 2018;18:e327–31. 
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International 
Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia [published correction 
appears in J Clin Oncol. 2004 Feb 1;22(3):576. LoCocco, Francesco [corrected to Lo-Coco, 
Francesco]]. J Clin Oncol. 2003;21(24):4642-4649.  
Collins CT, Hess JL. Deregulation of the HOXA9/MEIS1 axis in acute leukemia. Curr Opin 
Hematol. 2016;23(4):354-361. 
Daurismo 
prescribing 
information. 
label 
(fda.gov) 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf.  
DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in previously 
untreatedacute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. 
Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood. 2017;129(4):424-44. 
Falini B, Brunetti L, Sportoletti P, Martelli MP. NPM1-mutated acute myeloid leukemia: from 
bench to bedside. Blood. 2020;136(15):1707-1721. 
Gao L, Sun J, Liu F, Zhang H, Ma Y. Higher expression levels of the HOXA9 gene, closely 
associated with MLL-PTD and EZH2 mutations, predict inferior outcome in acute myeloid 
leukemia. Onco Targets Ther. 2016;9:711–22.  
Gu X, Ebrahem Q, Mahfouz RZ, et al. Leukemogenic nucleophosmin mutation disrupts the 
transcription factor hub that regulates granulomonocytic fates. J Clin Invest. 2018;128(10):4260-
4279. 
Gupta S, Meng A, Sharma S, et al. Exposure-response of Entospletinib (ENTO) for the treatment 
of relapsed or refractory chronic lymphocytic leukemia. Blood. 2017;130(S1):1735. 


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Protocol KB-ENTO-3001 v4.0 
(Amendment 3.0) 
 
90 
 
Hahn CK, Berchuck JE, Ross KN,  et al. Proteomic and genetic approaches identify SYK as an 
AML target. Cancer Cell. 2009;16:281–94. 
Herold T, Rothenberg-Thurley M, Grunwald VV, et al. Validation and refinement of the revised 
2017 European Leukemia Net genetic risk stratification of acute myeloid leukemia. Leukemia. 
https://doi.org/10.1038/s41375-020-0806-0. Published on line 30 April 2020. 
Ivey A, Hills RK, Simpson MA, et al. Assessment of Minimal Residual Disease in Standard-Risk 
AML. N Engl J Med. 2016;374(5):422-433. 
Löwenberg B, Downing JR, Burnett A. Acute myeloid leukemia [published correction appears in 
N Engl J Med 1999 Nov 4;341(19):1484]. N Engl J Med. 1999;341(14):1051-1062. 
Mims AS, Kohlschmidt J, Borate U, et al. A precision medicine classification for treatment of 
acute myeloid leukemia in older patients. J Hematol Oncol. 2021;14(1):96. 
Mohr S, Doebele C, Comoglio F, et al. HOXA9 and MEIS1 Cooperatively Induce Addiction to 
SYK signaling by suppressing miR-146a in acute myeloid leukemia. Cancer Cell. 2017;31(4):549-
562.e11.  
National Comprehensive Cancer Guidelines in Oncology (NCCN Guidelines)—Acute Myeloid 
Leukemia. V 3.2020, Dec. 23, 2019. 
Othus M, Appelbaum FR, Petersdorf SH, et al. Fate of patients with newly diagnosed acute 
myeloid leukemia who fail primary induction therapy. Biol Blood Marrow Transplant. 
2015;21(3):559-564. 
Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in 
acute myeloid leukemia. N Engl J Med 2012; 366:1079-1089. 
Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or Chemotherapy for relapsed or refractory 
FLT-3-mutated AML. N Engl J Med. 2019;381(18):1728-1740. 
Ruzza P, Biondi B, Calderan A. Therapeutic prospect of SYK inhibitors. Expert Opin Ther Pat. 
2009;19:1361–76. 
Sharman J, Hawkins M, Kolibaba K, et al. An open-label phase 2 trial of entospletinib (GS-9973), 
a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood. 
2015;125(15):2336-2343. 
Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for acute myeloid 
leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnoses of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & 
Co;1994:253-256. 
Tyner JW, Tognon CE, Bottomly D, et al. Functional genomic landscape of acute myeloid 
leukaemia. Nature. 2018;562(7728):526-531. 
Walker AR, Byrd JC, Blachly JS, et al. Entospletinib in Combination with Induction 
Chemotherapy in Previously Untreated Acute Myeloid Leukemia: Response and Predictive 
Significance of HOXA9 and MEIS1 Expression. Clin Cancer Res. 2020; 26(22):5852-5859. 


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(Amendment 3.0) 
 
91 
 
Walter RB, Estey EH. Management of older or unfit patients with acute myeloid leukemia. 
Leukemia. 2015;29(4):770-775. 
Zangenberg M, Grubach L, Aggerholm A et al. The combined expression of HOXA4 and MEIS1 
is an independent prognostic factor in patients with AML. Eur J Haematol. 2009;83:439–48. 

SAP_001.pdf: 
Protocol Number: KB-ENTO-3001
Official Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Assess the 
Efficacy and Safety of Entospletinib in Combination with Intensive Induction and Consolidation
Chemotherapy in Adults with Newly Diagnosed Nucleophosmin 1-mutated Acute Myeloid 
Leukemia
NCT Number: NCT05020665
Document Date:  4 May 2023


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STATISTICAL ANALYSIS PLAN 
 
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and 
Safety of Entospletinib in Combination with Intensive Induction and Consolidation 
Chemotherapy in Adults with Newly Diagnosed Nucleophosmin 1-mutated Acute Myeloid 
Leukemia  
 
 
Compound: 
Entospletinib (ENTO, formerly known as GS-9973) 
 
 
Trial Phase: 
3 
 
 
Protocol Number: 
KB-ENTO-3001 
 
 
Protocol Version and Date: 
Original Version: 09 April 2021  
Version 2: 06 July 2021 
Version 2.1: 24 November 2021 (Germany Only) 
Version 3: 27 January 2022 
Version 4: 10 February 2022 
 
 
Analysis Plan Version and 
Date: 
Final Version: 4 May 2023 
 
 
Prepared By: 
 
PharPoint Research, Inc. (PharPoint) 
1001 Military Cutoff, Suite 301 
Wilmington, NC 28405 
 
 
 
 
Prepared For: 
Kronos Bio 
1300 So. El Camino Real 
Suite 400 
San Mateo, CA 94402 


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STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL 
This Statistical Analysis Plan has been prepared in accordance with team reviewers’ specifications.  
 
Prepared by: 
 
 
Biostatistician II 
PharPoint 
 
 
Review:  
 
 
Chief Scientific Officer 
PharPoint 
 
 
 
Chief Medical Officer 
Kronos Bio 


Kronos Bio  
Entospletinib                                                                              
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ................................. 2 
1. 
GLOSSARY OF ABBREVIATIONS ......................................................................... 5 
2. 
INTRODUCTION ........................................................................................................ 8 
2.1. 
Study Overview .................................................................................................................................. 8 
2.2. 
Schedule of Assessments.................................................................................................................. 12 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 17 
4. 
GENERAL STATISTICAL CONSIDERATIONS ................................................. 20 
4.1. 
Statistical Hypothesis ...................................................................................................................... 20 
4.2. 
Sample Size ....................................................................................................................................... 20 
4.3. 
Measures to Minimize Bias: Randomization and Masking ......................................................... 20 
4.4. 
Handling of Data .............................................................................................................................. 21 
4.4.1. 
Strata and Covariates .................................................................................................................... 21 
4.4.2. 
Examination of Subject Subsets .................................................................................................... 21 
4.4.3. 
Multiple Testing and Comparisons ............................................................................................... 21 
4.4.4. 
Definitions and Data Derivations .................................................................................................. 21 
4.4.5. 
Presentations by Study Visit ......................................................................................................... 26 
4.4.6. 
Missing Data ................................................................................................................................. 26 
4.4.6.1. 
Imputation for Alphanumeric Data ..................................................................................... 26 
4.4.6.2. 
Incomplete or Missing Dates ............................................................................................... 26 
4.5. 
Timing of Analyses .......................................................................................................................... 27 
5. 
ANALYSIS SETS ....................................................................................................... 28 
5.1. 
Intent-To-Treat Analysis Set .......................................................................................................... 28 
5.2. 
Safety Analysis Set ........................................................................................................................... 28 
6. 
STATISTICAL METHODS ...................................................................................... 29 
6.1. 
Demographics and Baseline Characteristics ................................................................................. 29 


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6.2. 
Medical History................................................................................................................................ 29 
6.3. 
Exposure to Treatment ................................................................................................................... 29 
6.4. 
Efficacy ............................................................................................................................................. 29 
6.5. 
Safety Analysis ................................................................................................................................. 30 
6.5.1. 
Adverse Events ............................................................................................................................. 30 
6.5.2. 
Clinical Laboratory Assessments .................................................................................................. 30 
6.5.3. 
Prior and Concomitant Medications ............................................................................................. 31 
6.5.4. 
Vital Signs and Pulse Oximetry .................................................................................................... 31 
6.5.5. 
Electrocardiograms ....................................................................................................................... 31 
6.5.6. 
Echocardiograms/Multigated Acquisition Scan ............................................................................ 31 
6.5.7. 
Physical Examinations .................................................................................................................. 31 
6.5.8. 
ECOG Performance Status ........................................................................................................... 31 
7. 
PROTOCOL DEVIATIONS ..................................................................................... 32 
8. 
CHANGES IN THE PLANNED ANALYSES ......................................................... 33 
9. 
REFERENCES ........................................................................................................... 34 
10. PROPOSED TABLES, LISTINGS, AND FIGURES ............................................. 35 
APPENDIX A: PROGRAMMING CONVENTIONS .................................................... 36 
APPENDIX B: PROGRAMMING MODIFIED NCI-CTCAE GRADING FOR 
LABORATORY ABNORMALITIES .............................................................................. 38 


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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation/Term 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia  
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
β-HCG 
beta human chorionic gonadotropin 
BID 
twice daily 
BUN 
blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
CBC 
complete blood count 
CMML 
chronic myelomonocytic leukemia 
CPK 
creatine phosphokinase 
CR 
complete response 
CRh 
complete response with hematologic improvement 
CRi 
complete response with incomplete blood count recovery  
CRF 
case report form 
CSR 
clinical study report 
DIC 
disseminated intravascular coagulation 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EFS 
event free survival 
ELN 
European LeukemiaNet 


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Abbreviation/Term 
Definition 
ENTO 
Entospletinib 
EORTC-QLQ 30 
European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire-Core 30 
EQ-5D-5L 
European Quality of Life 5 Dimensions Questionnaire 
FISH 
fluorescense in situ hybridization 
FLT-3 
FMS-like tyrosine kinase 3 
FSH 
follicle stimulating hormone 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HOXA9 
homeobox protein 
HSCT 
hematopoietic stem cell transplant 
IDH 
isocitrate dehydrogenase 
ITD 
internal tandem duplication 
ITT 
intent to treat 
IV 
intravenous 
IWG 
International Working Group 
IxRS  
interactive voice/web response system  
LDH 
lactate dehydrogenase 
LFT 
liver function studies 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEIS1 
homeobox protein 
MFLS 
morphologic-free leukemia state 
mg 
milligrams 
mg/m2 
milligrams per meter squared 
MRD 
measurable residual disease 
MUGA 
multiple gated acquisition 


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Abbreviation/Term 
Definition 
n 
number of subjects 
N/A 
not available 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse 
Events 
NPM1 
Nucleophosmin-1 
OS 
overall survival 
pSYK 
phosphorylated spleen tyrosine kinase 
PD 
progressive disease 
PK 
pharmacokinetics 
PR 
partial response 
PT 
preferred term 
QLQ 
Quality of Life Questionnaire 
SD 
stable disease 
SOC 
system organ class 
STD 
standard deviation 
SUSAR 
suspected, unexpected, serious adverse event 
SYK 
spleen tyrosine kinase 
TEAE 
treatment-emergent adverse event 
TELT 
treatment-emergent laboratory toxicity 
TESAE 
treatment-emergent serious adverse event 
TKD 
tyrosine kinase domain 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO 
World Health Organization 


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Entospletinib                                                                              
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2. 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the summary 
of planned analyses of efficacy and safety data from Protocol KB-ENTO-3001. Background 
information is provided for the overall study design and objectives based on the current version of 
the protocol.  In November 2022, the sponsor terminated this study prior to full enrollment for 
business reasons.  This SAP is intended to describe the study design of the planned study and the 
analytic methods necessary to generate the safety analyses for the abbreviated Clinical Study 
Report (CSR). The reader is referred to the study protocol and case report forms (CRFs) for details 
of study conduct and data collection, the pharmacokinetics (PK) and pharmacodynamics (PD) 
analysis plan for the description of exploratory PK/PD analyses, and to the Data Monitoring 
Committee (DMC) charter for the roles and the responsibilities for that committee. 
2.1. 
Study Overview 
This is a Phase 3, multi-center, international, double-blind, placebo-controlled study in previously 
untreated subjects with Acute Myeloid Leukemia (AML) harboring nucleophosmin-1 (NPM1) 
mutations. Subjects will be randomized 1:1 to receive intensive induction chemotherapy in 
combination with either the spleen tyrosine kinase (SYK) inhibitor, entospletinib (ENTO), or 
placebo. Randomization will be stratified by age (<60 or ≥60 years) and anthracycline administered 
during induction (daunorubicin vs idarubicin). The study will consist of Screening, Induction, 
Consolidation, End-of-Treatment, and Long-term Follow-up phases.  
ENTO (400 mg) or placebo will be administered continuously twice daily (BID) approximately 
every 12 hours beginning on Cycle 1 Day 1 of induction chemotherapy (Table 1) through 
completion of consolidation (Table 2), including while awaiting blood count recovery.  
Subjects will undergo bone marrow examination no later than Day 42 of Induction Cycle 1 for 
assessment of response. Subjects with ≥5% residual leukemic blasts in bone marrow will receive 
Induction Cycle 2 as outlined in Table 1, which may be administered prior to blood count recovery. 
Subjects with <5% residual blasts will receive Consolidation Cycle 1 as outlined in Table 2 upon 
recovery of peripheral blood counts (absolute neutrophil count [ANC] > 1.0 x 109/L; platelet count 
> 100 x 109/L). 
After completion of Induction Cycle 2 or Consolidation Cycle 1 (hereafter referred to collectively 
as Chemotherapy Cycle 2), subjects will undergo bone marrow aspiration for assessment of 
remission status at the investigative site. Bone marrow examination should await recovery of ANC 
to at least 1.0 x 109/L and platelet count to at least 100 x 109/L on or before but no later than Day 
42 of Chemotherapy Cycle 2 unless leukemic progression is suspected. Subjects who achieve or 
remain in morphologic complete response (CR) after Chemotherapy Cycle 2 will undergo 
measurable residual disease (MRD) assessment in peripheral blood and bone marrow aspirate. 
Subjects who have not achieved morphologic CR last cycle of induction chemotherapy (no later 
than Day 42 of the last cycle of induction) will be considered treatment failures. *For subjects with < 
5% residual blasts post-Induction Cycle 1, Consolidation Cycle 1 will consist of Chemotherapy Cycle 2. For 
patients with ≥5% residual blasts post-Induction Cycle 1, Induction Cycle 2 (Table 1) will consist of 


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Entospletinib                                                                              
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Chemotherapy Cycle 2 with consolidation beginning thereafter. All subjects are eligible to receive up to 3 
cycles of high dose cytarabine after Chemotherapy Cycle 2. 
Figure 1 provides a schematic representation of the study treatment plan from Cycle 1 Day 1 
through completion of Chemotherapy Cycle 2 
Table 1: Induction Chemotherapy 
 
Age < 60 years 
Age ≥ 60 years 
Cycle 1: 
Cytarabinea 
100 mg/m2 by continuous 
infusion, Days 1-7 
100 mg/m2 by continuous 
infusion, Days 1-7 
Anthracycline 
Daunorubicin, 60 mg/m2 slow 
IV push, Days 1-3  
OR 
Idarubicin, 12 mg/m2 slow IV 
push, Days 1-3 
Daunorubicin, 60 mg/m2 by 
slow IV push, Days 1-3  
OR 
Idarubicin, 12 mg/m2 slow IV 
push, Days 1-3 
Cycle 2: 
Cytarabine 
1.0 g/m2, BID Days 1-6  
1.0 g/m2, BID Days 1-6  
Anthracycline 
Daunorubicin, 60 mg/m2 slow 
IV push, Days 1-3  
OR 
Idarubicin, 12 mg/m2 slow IV 
push, Days 1-3 
N/A 
Abbreviations: BID, twice daily; IV, intravenous; N/A, not administered. 
a Subjects who are candidates for continuous infusion of cytarabine in Cycle 1 at doses higher than 100 
mg/m2/day are ineligible. 
Subjects who achieve MRD negative CR status post-induction will undergo retrospective MRD 
assessments in peripheral blood every 3 months until morphologic relapse. 
All subjects who achieve morphologic CR, complete response with hematologic improvement 
(CRh), or complete response with incomplete blood count recovery (CRi) upon completion of 
Chemotherapy Cycle 2 may initiate or continue consolidation therapy in combination with ENTO 
or placebo as outlined in Table 2 at the investigator’s discretion either instead of or as a bridge to 
hematopoietic stem cell transplant (HSCT). 


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Table 2: Treatment Phase - Consolidation 
 
Age < 60 years 
Age ≥ 60 years 
Cytarabine 
3.0 g/m2, BID over 3 hours on 
Days 1, 3 and 5 every 28-35 
days for up to 3 cycles* 
1.5 g/m2, BID over 3 hours on 
Days 1, 3 and 5 every 28-35 
days for up to 3 cycles* 
*For subjects with < 5% residual blasts post-Induction Cycle 1, Consolidation Cycle 1 will consist of 
Chemotherapy Cycle 2. For patients with ≥5% residual blasts post-Induction Cycle 1, Induction Cycle 2 
(Table 1) will consist of Chemotherapy Cycle 2 with consolidation beginning thereafter. All subjects are 
eligible to receive up to 3 cycles of high dose cytarabine after Chemotherapy Cycle 2. 
Figure 1: Treatment Phase- Cycle 1, Day 1 through Completion of Chemotherapy Cycle 2: 
 
Following completion of consolidation chemotherapy, all subjects will undergo an End-of-Study 
Treatment Visit 30 ± 7 days after the last study treatment (either ENTO/placebo or cytarabine, 
whichever is later) or prior to initiation of follow-on therapy (e.g., maintenance therapy, HSCT) if 
sooner than 30 ± 7 days after last study treatment.  
All subjects regardless of their post-remission status will be followed monthly for 3 months after 
the End-of-Treatment Visit and thereafter at least once every 3 months for progression/relapse, first 
salvage therapy, and survival until study termination. Unscheduled study visits at other time points 


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are permitted in the setting of suspected leukemic recurrence or for evaluation and management of 
post-treatment sequelae.


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2.2. 
Schedule of Assessments 
 
Study Phase 
Screening 
Induction (up to 2 Cycles)*  
At Recovery of Blood 
Counts/Assessment of 
Remission Status (Post-
Induction Cycle 1,  
Post-Chemotherapy 
Cycle 2)/ 
At Relapse 
Consolidation 
(up to 3 Cycles)*  
End-of-
Study 
Treatment 
Long-Term 
Follow-up x 
Study Visit Day a 
-14 to 0 
1 
3  7  14  
15  
until 
blood 
count 
recovery 
 
1 
3 
5 
28 
to 
35 
30 ± 7 
days after 
last study 
treatment 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IxRS registration/ 
randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/smoking history/ 
prior medications/AML 
baseline characteristics b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Safety assessments 
Vital signs c 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Physical examination d 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
X 
 
Height/weight e 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
ECG f 
X 
 
ECHO/MUGA g 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
ECOG PS 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
AEs/concomitant 
medications h 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Hematology i 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Clinical chemistries/ 
LFTs j 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
 


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Entospletinib                                                                              
 
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Study Phase 
Screening 
Induction (up to 2 Cycles)*  
At Recovery of Blood 
Counts/Assessment of 
Remission Status (Post-
Induction Cycle 1,  
Post-Chemotherapy 
Cycle 2)/ 
At Relapse 
Consolidation 
(up to 3 Cycles)*  
End-of-
Study 
Treatment 
Long-Term 
Follow-up x 
Study Visit Day a 
-14 to 0 
1 
3  7  14  
15  
until 
blood 
count 
recovery 
 
1 
3 
5 
28 
to 
35 
30 ± 7 
days after 
last study 
treatment 
 
Coagulation k 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Urinalysis l 
X 
 
ß-HCG/FSH m  
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
HBV/HCV/HIV 
serologies n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Induction therapy 
Study medication 
(ENTO/Placebo) o 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Cytarabine  
 
 
 
 
 
 
 
 
 
 
 
 
 
Daunorubicin or 
Idarubicin 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consolidation therapy 
Study medication 
(ENTO/Placebo) p 
 
 
 
 
 
 
 
 
 
 
 
 
 
Age-adjusted high dose 
cytarabine  
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow evaluations 
Aspirate q 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
NPM1-m MRD 
assessments r 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X  
Pharmacokinetics s 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 


Kronos Bio  
Entospletinib                                                                              
 
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Final Version 
 
 
 
 
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Study Phase 
Screening 
Induction (up to 2 Cycles)*  
At Recovery of Blood 
Counts/Assessment of 
Remission Status (Post-
Induction Cycle 1,  
Post-Chemotherapy 
Cycle 2)/ 
At Relapse 
Consolidation 
(up to 3 Cycles)*  
End-of-
Study 
Treatment 
Long-Term 
Follow-up x 
Study Visit Day a 
-14 to 0 
1 
3  7  14  
15  
until 
blood 
count 
recovery 
 
1 
3 
5 
28 
to 
35 
30 ± 7 
days after 
last study 
treatment 
 
Peripheral blood  
biomarker assessments t 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
 Bone marrow aspirate 
biomarker assessments u 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Pharmacogenomics (whole 
blood) v 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient reported outcomes w 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Follow-up for relapse, first 
salvage therapy, OS x 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: AEs, adverse events; AML, acute myeloid leukemia; β-HCG, beta human chorionic gonadotropin; ECG, electrocardiogram; ECHO, echocardiogram; ECOG PS, 
Eastern Cooperative Oncology Group Performance Status; FSH, follicle stimulating hormone; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; 
LFTs, liver function studies; MUGA, multi-gated acquisition; NPM1-m, Nucleophosmin 1-mutated; MRD, measurable residual disease; OS, overall survival. 
* Subjects with ≥5% residual leukemic blasts in bone marrow aspirate performed no later than Day 42 of Induction Cycle 1 will receive Induction Cycle 2 as outlined in Table 1, 
which may be administered prior to blood count recovery. Subjects with <5% leukemic blasts will proceed to Consolidation Cycle 1 (Table 2) upon recovery of peripheral blood 
counts (ANC ≥ 1.0 x 109/L; platelet count ≥ 50 x 109/L). After completion of Induction Cycle 2 or Consolidation Cycle 1 (i.e., Chemotherapy Cycle 2), subjects will undergo bone 
marrow examination for assessment of remission status at the investigative site. Patients in morphologic CR post-Chemotherapy Cycle 2 will undergo MRD assessment (see footnote 
“r” below). 
a Acceptable windows for study visits/assessments after Cycle 1 Day 1 (C1D1) are ± 1 day; however, study treatment must be administered on the days indicated (e.g., Days 1-7 for 
cytarabine, and Days 1-3 for daunorubicin or idarubicin in Induction Cycle 1).  


Kronos Bio  
Entospletinib                                                                              
 
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b The following details minimally, regarding the diagnosis of AML will be collected and recorded on the electronic case report form (eCRF): age and date of diagnosis (month, day, 
year); AML subtype (de novo; AML with myelodysplasia-related changes; therapy associated AML); history of myelodysplastic or myeloproliferative (e.g., chronic myelomonocytic 
leukemia [CMML] syndrome; history of prior exposure to leukemogenic agents (e.g. alkylating agents, topoisomerase II inhibitors); cytogenetic abnormalities identified by 
conventional cytogenetic testing and/or fluorescence in situ hybridization (FISH); complete blood count (CBC) with differential; percent blasts (peripheral blood and bone marrow); 
NPM1 mutation subtype (A, B, D, other); FMS-like tyrosine kinase 3 (FLT-3) mutational status (wild-type; internal tandem duplication [ITD] mutation, tyrosine kinase domain 
[TKD] mutation, or both).  
c Vital signs include measurement of blood pressure, respiratory rate, pulse, temperature, and oxygen saturation level by pulse oximetry. After discharge from hospital, assess vital 
signs at each of the designated time points.  
d Perform a complete physical examination including neurological exam at Screening. After discharge from the hospital, a targeted physical exam may be performed at each of the 
designated time points. Subjects ≥60 years old receiving intermediate dose cytarabine or those with impaired renal function are at risk for cerebellar toxicity. Monitor for the 
occurrence of nystagmus, slurred speech, or dysmetria on each day of cytarabine dosing during Induction Cycle 2 and consolidation. Follow dose modification guidelines outlined 
in Section 6.5.2 of the protocol or in accordance with institutional care standards in the setting of neurotoxicity. 
e Height and weight will be measured at Screening. Only weight will be measured thereafter at designated time points.  
f ECG is required at Screening and thereafter as clinically indicated during treatment. 
g An echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan must be performed at Screening and at the End-of-Treatment Visit. Consider repeating ECHO or MUGA 
within 48 hours prior to Induction Cycle 2 for subjects receiving anthracycline in Cycle 2 and at increased risk for cardiac toxicity.  
h Record all adverse events and concomitant medications through 30 ± 7 days after treatment completion. Thereafter, record only serious adverse events assessed as study medication 
related. 
i Includes hemoglobin, hematocrit, white blood cell (WBC) and platelet counts, and WBC differential (neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, blasts). 
At times not designated in Table 7, monitor CBC and WBC differential in accordance with institutional care standards until ANC is ≥1.0 x 109/L or persistent leukemia is documented. 
Monitor platelet counts at times designated in Table 7 and at other times, per institutional care standards until the platelet count is ≥100 x 109/L or persistent leukemia is documented. 
Monitor CBC and platelet count twice weekly during consolidation and at other times, as clinically indicated. 
j Includes electrolytes (sodium, potassium, chloride, total CO2 and/or bicarbonate, calcium, phosphate), liver function studies (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], total and direct bilirubin), lactate dehydrogenase (LDH), alkaline phosphatase, blood urea nitrogen [BUN] or serum urea, creatinine, uric acid, glucose, 
amylase, and lipase. Include total creatine phosphokinase (CPK) at Screening, Day 14 of each induction cycle, and End of Study Treatment. At times not designated in Table 7, 
monitor electrolytes, LFTs, BUN, creatinine, uric acid, and phosphate in accordance with institutional care standards until the risk of tumor lysis syndrome has abated. For subjects 
receiving nephrotoxic antimicrobial agents, closer monitoring of renal function throughout the period of hospitalization is recommended, consistent with institutional standards of 
care.  
k Includes prothrombin time, activated partial thromboplastin time and international normalized ratio. Perform coagulation panel twice per week during Induction. For subjects with 
evidence of disseminated intravascular coagulation (DIC), coagulation parameters including fibrinogen should be monitored in accordance with institutional care standards until 
resolution. 
l Includes dipstick evaluation for pH, glucose, protein, blood, leukocyte esterase and microscopic evaluation for red and white blood cells. After Screening, perform urinalysis as 
clinically indicated. 
m A negative serum pregnancy test is required for female subjects (unless surgically sterile or postmenopausal) at Screening. Female subjects with medically documented ovarian 
failure must also have serum follicle stimulating hormone (FSH) levels within the institutional postmenopausal range at Screening. A urine pregnancy test will be performed for all 
females (unless surgically sterile or postmenopausal) on Day 1 of each cycle of induction and consolidation and at the End-of-Treatment Evaluation. 


Kronos Bio  
Entospletinib                                                                              
 
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CONFIDENTIAL  
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n HBV/HCV/HIV serology tests include hepatitis B surface antigen (HBsAg), anti-HBs, anti-HBc, anti-HCV, and anti-HIV.o Study medication will be administered orally every 12 
hours during Induction Cycles 1 and Induction Cycle 2, if administered (see Table 1) 
). Subjects are to continue receiving study medication while awaiting blood count recovery and response assessment results. 
p Subjects who achieve CR, CRh or CRi post-Chemotherapy Cycle 2 may receive consolidation chemotherapy in combination with study medication (see Table 2). Subjects are to 
continue receiving study medication while awaiting blood count recovery. The number of cycles of consolidation (up to 3) will be at the investigator’s discretion.  
q A bone marrow aspirate will be performed at Screening (within 14 days before the first administration of study treatment) for confirmation of diagnosis, morphology (spicule 
prep), cytogenetics/FISH and NPM1 and FLT-3 mutational status. In cases in which an adequate bone marrow aspirate cannot be obtained at Screening (eg, due to dry tap, 
hypocellularity or hemodilution), a trephine bone marrow biopsy is mandated. Bone marrow aspirates are required in Induction Cycle 1 (up to but no later than Day 42) and 
again post-Chemotherapy Cycle 2 (no later than Day 42) to assess remission status. Thereafter, perform bone marrow examination for confirmation of suspected leukemic relapse. 
r NPM1-m allelic frequency will be assessed in peripheral blood and bone marrow aspirate in a central laboratory at the following time points:  Screening; post-Chemotherapy Cycle 
2 for subjects in CR (no later than Day 42, for MRD assessment); and at the End of Study Treatment visit (peripheral blood only). MRD will be assessed retrospectively on 
peripheral blood in subjects who achieve MRD negative CR post-Chemotherapy Cycle 2, every 3 months during long term follow-up until morphologic relapse. 
s Blood sampling for pharmacokinetic assessments will be performed at the following time points: Cycle 1 (Induction): Day 1 between 2- and 4-hours post-study medication dose, 
Day 7 predose only, Day 14 predose and between 2- and 4-hours post-study medication dose; Cycle 3 (Consolidation): Day 1 predose and between 2- and 4-hours post-study 
medication dose, Day 28-35 predose and between 2- and 4-hours post-study medication dose. All predose samples must be obtained within 60 minutes before the first daily dose of 
study medication (Protocol Section 8.7). 
t Blood samples for biomarker assessments including (but not limited to) other somatic mutations will be obtained at Screening; Cycle 1 (Induction), Day 1 (predose and 2 hours 
post-dose), Day 7 and Day 14 (predose only) prior to the first daily dose of study medication; Cycle 3 (Consolidation) Day 1 (predose) and Day 28-35 (predose); at time of post-
Chemotherapy Cycle 2; relapse; and End of Study Treatment. See Protocol Section 8.9 for a description of planned biomarker assessments. 
u Bone marrow aspirate samples for biomarker assessments including (but not limited to) other somatic mutations will be obtained at Screening; post-Chemotherapy Cycle 2; and at 
relapse. 
v Whole blood will be collected during Screening for evaluation of CYP2C9 and cytidine deaminase polymorphisms. Examinations of other germline genes implicated in 
leukemogenesis may be conducted for comparison with corresponding genes in the leukemic clone. See Protocol Section 8.9 for additional details. 
w Includes the European Quality of Life 5 Dimensions Questionnaire (EQ-5D-5L) and the European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC-QLQ 30). 
x All subjects regardless of post-remission status will be followed monthly for 3 months after the End-of-Treatment Visit and thereafter at least once every 3 months for 
progression/relapse, first salvage therapy, and overall survival until study termination.


Kronos Bio  
Entospletinib                                                                              
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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
 
 
To evaluate the efficacy of ENTO compared 
to placebo when added to chemotherapy in 
previously untreated NPM1-m AML, as 
defined by the rate of molecularly defined 
MRD.  
 
 
 
MRD negative CR rates after completion of 
2 cycles of chemotherapy plus either ENTO 
or placebo.  
 
Note: MRD negative CR requires CR as defined 
by the European Leukemia Network (ELN) 
2017 criteria (with minor modification for 
neutrophil and platelet count thresholds as 
defined by International Working Group 
[IWG]) as assessed by study site 
investigators, and MRD negativity 
(<0.01%) in bone marrow as measured by a 
molecular NPM1-m assay (e.g., by next 
generation sequencing) in a central 
laboratory upon recovery of peripheral 
blood counts following completion of 2 
cycles of chemotherapy (i.e., no later than 
Day 42 of Cycle 2).  
Secondary 
 
 
 
To evaluate the efficacy of ENTO compared 
to placebo when added to chemotherapy in 
previously untreated NPM1-m AML, as 
defined by relapse-free, event-free, and 
overall survival. 
 
 
Event-free survival, defined as the time 
from randomization to the earliest 
occurrence of induction treatment failure, 
relapse from CR, or death from any cause.  
 
Note: Induction treatment failure is failure 
to achieve morphological CR after 
completion of the last cycle of induction 
chemotherapy (no later than Day 42 of the 
last cycle of induction). 
 
 
Relapse-free survival, defined as the time 
from CR until relapse or death from any 
cause as assessed by study site 
investigators. 


Kronos Bio  
Entospletinib                                                                              
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 
Overall survival defined as the time from 
enrollment until death from any cause. 
 
To evaluate the efficacy of ENTO compared 
to placebo when added to chemotherapy in 
previously untreated NPM1-m as defined by 
CR rate.  
 
 
CR rates after 2 cycles of chemotherapy, as 
defined by ELN 2017 criteria (with minor 
modification for neutrophil and platelet 
count thresholds as defined by IWG) as 
assessed by study site investigators. 
 
To evaluate the safety of ENTO compared 
to placebo when added to intensive 
chemotherapy. 
 
Type, incidence, severity, and outcome of 
adverse events; changes from baseline in 
safety laboratory assessments, ECGs, 
ECHO/MUGA scans, ECOG PS. 
Exploratory 
 
 
To explore the predictive value of potential 
biomarkers that correlate with differential 
outcomes (CR, MRD negativity, event-free 
and overall survival) among ENTO- vs 
placebo-treated subjects. 
 
Baseline expression levels of homeobox 
protein (HOXA9/MEIS1) and other relevant 
genes in leukemic cells from peripheral 
blood and bone marrow aspirate using 
standard expression profiling platforms 
(e.g., Nanostring® or next-generation 
sequencing) for correlations with response 
and progression. 
 
Mutational profiling in leukemic cells using 
standard platforms like next generation 
sequencing for correlations with response 
and progression. 
 
Targeted protein/phosphoprotein profiling 
(e.g., phosphorylated spleen tyrosine kinase 
(pSYK) expression) in leukemic cells at 
baseline for correlations with response and 
progression. 
 
Extent of ENTO target engagement as 
measured by pSYK expression/expression 
of other relevant genes for correlation with 
response and progression. 
 
Level of concordance for MRD for NPM1-
m in leukemic cells derived from bone 
marrow aspirate and peripheral blood. 
 
Log reduction in NPM1-m alleles in bone 
marrow post-induction compared with 
baseline for correlation with response and 
progression. 
 
To assess the value of MRD detection as a 
prognosticator of relapse. 
 
Longitudinal assessment of peripheral blood 
for detection of NPM1-m alleles among 
subjects who achieve MRD-negative CR 
post-Chemotherapy Cycle 2 using standard 


Kronos Bio  
Entospletinib                                                                              
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molecular platforms (eg, next-generation 
sequencing) for correlation with 
morphologic relapse. 
 
To further assess the PK of ENTO in 
combination with intensive induction 
therapy for population PK modeling. 
 
To explore the relationship between 
CYP2C9 genetic polymorphisms and 
ENTO exposure. 
 
To assess the relationship (if any) between 
cytidine deaminase polymorphisms and 
safety and efficacy outcomes. 
 
Population-based PK parameter assessment. 
 
Identification of CYP2C9 polymorphism 
and population-based PK analysis. 
 
Correlation between cytidine deaminase 
polymorphisms and selected safety metrics 
and efficacy outcomes, described above. 
 
To compare changes in quality-of-life 
measures over time among subjects treated 
with ENTO compared to placebo when 
added to intensive induction therapy in 
previously untreated NPM1-m AML. 
 
EQ-5D-5L and EORTC-QLQ 30 over time. 
Abbreviations: AML, acute myeloid leukemia; CR, complete remission; ECG, electrocardiogram; ECHO, 
echocardiogram; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ELN, The European 
Leukemia Network; EORTC-QLQ 30, European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30; EQ-5D-5L, European Quality of Life 5 Dimensions Questionnaire; MRD, measurable residual 
disease; MUGA, multigated acquisition; NPM1-m, nucleophosmin-1 mutated; PK, pharmacokinetics; pSYK, 
phosphorylated spleen tyrosine kinase. 
 
The study was terminated early at the request of the sponsor. Therefore, the endpoints described above 
could not be conducted. See Section 8 for details. 


Kronos Bio  
Entospletinib                                                                              
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4. 
GENERAL STATISTICAL CONSIDERATIONS 
4.1. 
Statistical Hypothesis 
Due to the study termination, no formal statistical testing will be performed. 
4.2. 
Sample Size  
Based on a completed study of newly diagnosed AML subjects treated with ENTO, it is anticipated that 
87% of NPM1-m subjects will achieve CR (Walker et al, 2020). Based on analysis of a historical dataset 
from the Cancer and Leukemia Group B Alliance (Mims et al, 2021) showing a 68% CR rate in 107 
NPM1-mutated/FLT3-ITD negative patients ≥ 60 years of age treated with 7+3 induction, a conservative 
estimate of 70% CR rate for placebo is assumed for sample size determination. The MRD negative rate 
among placebo subjects achieving CR is assumed to be 60% (Ivey et al, 2016). Alternatively, it is 
hypothesized that 80% of subjects with CR receiving ENTO will be MRD negative. 
 
Approximately 180 subjects will be randomized with a randomization ratio of 1:1. A sample size of 90 
subjects per group will provide > 97% power to detect a difference in the MRD negative CR rate of 28% 
(87% x 80% = 70% for ENTO vs 70% x 60% = 42% for placebo) with a 2-sided alpha level of 0.05 
(PASS 2008: Two sample test of Proportion Module). Up to 10% over enrollment is allowed in order to 
account for technical or logistical barriers (e.g., inadequate bone marrow aspirate or poor sample quality) 
related to the ascertainment of MRD status in patients who achieve CR post-Chemotherapy Cycle 2. 
Assuming the two-year event free survival (EFS) rate for the control group is 63% (hazard rate of 0.231), 
a total of 124 events (70 in the placebo arm, 54 in the ENTO arm) would be sufficient to provide 80% 
power to detect a hazard ratio of 0.6 for EFS (PASS 2008: log rank tests (Lakatos) [Hazard Rate] module) 
assuming 2-sided alpha = 0.05 and a total study duration of 60 months.  
The study was terminated early with a final sample size of 15 randomized subjects.  
4.3. 
Measures to Minimize Bias: Randomization and Masking 
Subjects will be randomized 1:1 to study medication (ENTO or placebo) using an Interactive Voice/Web 
Response System (IxRS) and randomization schedule prepared by a non-study statistician using 
PharPoint standard operating procedure BIO002. The randomization will be stratified by age (<60 years 
vs ≥60 years) and anthracycline administered during induction (daunorubicin or idarubicin). All subjects, 
study site personnel, and the Sponsor’s clinical trial management staff and their designees will be blinded 
to treatment assignment.  
 
Under certain circumstances, members of the DMC may be unblinded to treatment assignment for 
individual subjects or treatment arm, in order to better assess safety and efficacy trends that could 
potentially underlie the basis for specific recommendations to modify the study. The criteria and 
procedures for unblinding at the DMC are outlined in the DMC Charter. Investigators will also have the 
ability to unblind the study medication assignment for individual patients in circumstances where this 


Kronos Bio  
Entospletinib                                                                              
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information is critical for the assessment and management of specific adverse events, including suspected, 
unexpected, serious adverse events (SUSARs) and Grade 5 AEs assessed as at least possibly related to 
study medication. The investigator will have the capability to unblind the study medication assignment 
for individual patients without prior authorization from the study medical monitor or Sponsor and will 
access this information via the IxRS.  Upon unblinding the medication assignment for a specific patient, 
the investigator must notify the study’s medical monitor as soon as possible thereafter. 
4.4. 
Handling of Data 
4.4.1. Strata and Covariates 
No adjustments for strata and covariates will be implemented.  
4.4.2. Examination of Subject Subsets 
No planned analysis of subject subsets will be conducted. 
4.4.3. Multiple Testing and Comparisons 
No statistical inference is planned.  
4.4.4. Definitions and Data Derivations  
Age 
Age is defined as the age in years at time of informed consent recorded on the Demographics page of the 
CRF.  
 
Study Medication 
Study medication refers to ENTO/placebo. 
 
Study Treatment 
Study treatment refers to ENTO/placebo and/or chemotherapy. 
 
Time since AML Diagnosis 
Time since AML diagnosis, expressed in weeks, will be calculated as (date of randomization – date of 
AML diagnosis +1)/7. 
 
Cycle 1 Day 1 (Baseline) 
Cycle 1 Day 1 (C1D1) is defined as the earliest day that the first dose of any component of study 
treatment is administered.  
 
Baseline Value 
Baseline value is defined as the last observation of an assessment prior to the first dose of study treatment. 
 


Kronos Bio  
Entospletinib                                                                              
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Study Day 
Study Day is defined relative to C1D1. For events prior to C1D1, Study Day is calculated as: 
 
 
 
 
Study Day = event date – date of C1D1 
 
For events occurring on or after C1D1, Study Day is calculated as: 
 
 
 
 
 
Study Day = event date – date of C1D1 + 1 
 
Post-Baseline Value 
Any assessment occurring after the initiation of study treatment will be considered a post-baseline value. 
For assessments occurring on C1D1 where no time of assessment is captured, the value will be considered 
as post-baseline if the assessment was not planned as part of the set of screening assessments (e.g., an 
assessment taken on C1D1 where no time was recorded but not designated as a screening assessment will 
be considered a post-baseline assessment whereas a laboratory assessment on C1D1 without a time but 
designated as a screening assessment will be considered as such). 
  
Change from Baseline 
Change from baseline will be determined for post-baseline assessments (where applicable) as:  
 
Post-baseline value – baseline value 
Days on Study Medication 
Days on study medication is the number of days from C1D1 (or the first day of study medication, if later) 
to the date of the last dose of study medication as recorded on the Study treatment- Oral administration 
page of the CRF. 
 
Days on Study Treatment  
Days on study treatment is the number of days from the start of study treatment (either study medication 
or chemotherapy) to the date of the last dose of study treatment as recorded on the Study treatment- Oral 
administration or Study treatment- IV administration pages of the CRF. 
 
Days on Study 
Days on Study is the number of days from C1D1 to the date of completion or study discontinuation on the 
End of Study page of the CRF. 
 
Cumulative Dose of ENTO 
Cumulative dose of ENTO is defined as the sum of the doses administered to a patient measured in 
milligrams (mg). For subjects receiving placebo, this is set to 0 mg. 
 
Cumulative Dose of Chemotherapy 
The cumulative dose of each chemotherapy agent is defined as the sum of the doses administered to a 
patient measured in milligrams per meter squared (mg/m2). Cumulative chemotherapy administration will 
be calculated separately for Induction and Consolidation. 
 


Kronos Bio  
Entospletinib                                                                              
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Actual Dose Intensity (mg/m2) 
The actual dose intensity will be defined separately for each chemotherapy component by phase 
(Induction, Consolidation) and treatment cycle (as the cumulative dose / duration). 
 
Relative Dose Intensity 
Relative dose is set to 100*(Actual Dose Intensity/ (Expected Cumulative Dose / 28)). 
 
Completed Chemotherapy Cycle 
A chemotherapy cycle is considered completed if at least one of the assigned chemotherapy agents in the 
regimen has been completed per protocol. Information regarding premature discontinuation of 
chemotherapy will be as recorded on the Study treatment – IV administration pages of the CRF. 
 
Response Criteria 
Criteria for responses as outlined below and assessed by the investigator are based on the ELN 2017 
definitions (Döhner et al 2017) with minor modification for neutrophil and platelet count thresholds as 
defined by the IWG and as applicable to the current study:  
 
CR* 
CR requires all the following: 
 
 
Bone marrow blasts < 5% 
 
Absence of circulating blasts and blasts with Auer rods 
 
Absence of extramedullary disease (i.e., leukemia outside of bone marrow confirmed by biopsy) 
 
Absolute neutrophil count > 1.0 x 109/L (1000/μL) 
 
Platelet count > 100 x 109/L (100,000/μL) 
Note: *MRD positive or unknown 
 
Complete Response with Hematologic Improvement (CRh)** 
CRh requires all the CR criteria, except for residual thrombocytopenia and/or neutropenia and is defined 
as: 
 
Bone marrow blasts < 5% 
 
Absence of circulating blasts and blasts with Auer rods 
 
Absence of extramedullary disease 
 
Absolute neutrophil count > 0.5 x 109/L (500/μL) 
 
Platelet count > 50 x 109/L (50,000/μL) 
 
Complete Response with Incomplete Blood Count Recovery (CRi)** 
CRi requires all the CR criteria, except for residual neutropenia or thrombocytopenia and is defined as: 
 
Bone marrow blasts < 5% 
 
Absence of circulating blasts and blasts with Auer rod 
 
Absence of extramedullary disease 


Kronos Bio  
Entospletinib                                                                              
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 
Absolute neutrophil count ≤ 1.0 x 109/L (1000/μL) or platelet count ≤ 100 x 109/L (100,000/μL) 
Note: **If subjects meet criteria for both CRh and CRi, they should be classified as CRh 
 
Morphologic-free Leukemia State (MLFS)*** 
 
Bone marrow blasts < 5% 
 
Absence of blasts with Auer rods 
 
Absence of extramedullary disease 
 
No hematologic recovery required 
Note: *** Marrow should not be merely “aplastic”; at least 200 cells should be enumerated or 
cellularity on bone marrow biopsy should be at least 10% of normal. 
 
Partial Response (PR) 
PR meets all hematologic criteria of CR: 
 
Absolute neutrophil count > 1.0 x 109/L (1000/μL) 
 
Platelet count > 100 x 109/L (100,000/μL), and 
 
Residual bone marrow blast percentage of 5% to 25% 
 
Reduction of bone marrow blast percentage by ≥ 50% compared with pretreatment 
 
Stable Disease (SD) 
Absence of MRD negative CR, CR, CRh, CRi, PR, MLFS and criteria for PD not met. 
 
Progressive Disease (PD) 
Evidence for an increase in bone marrow blast percentage and/or circulating blast counts as defined by at 
least one of the following: 
 
50% increase in bone marrow blasts over baseline (a minimal absolute 15% increase is required 
in cases with < 30% blasts at baseline), or 
 
Persistent bone marrow blast percentage > 70% over ≥ 3 months without at least a 100% 
improvement in ANC to an absolute level > 0.5 x 109/L (500/μL) and/or platelet count to > 50 x 
109/L (50,000/μL) without transfusion, or 
 
50% increase in circulating blasts to > 25 x 109/L (>25,000/μL) in the absence of Differentiation 
Syndrome,**** or 
 
New extramedullary disease 
**** Certain targeted therapies, for example, those inhibiting mutant isocitrate dehydrogenase (IDH) 
proteins, other kinase or targets may cause a transient increase in the percentage of bone marrow blasts 
accompanied by an increase in circulating blasts (differentiation syndrome). In the setting of therapy with 
such compounds, an increase in blasts may not necessarily indicate progressive disease. Such instances 
should be discussed with the study medical monitor on a case-by-case basis. 
 
Recurrence 
Recurrence for subjects with prior MRD-CR, morphological CR, CRh, CRi, or MLFS is defined as one of 
the following: 


Kronos Bio  
Entospletinib                                                                              
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 
Morphologic relapse as defined by the reappearance of circulating blasts or ≥ 5% blasts in the 
bone marrow not attributable to any other cause. Note: In the setting of recent treatment, if there 
are no circulating blasts and the bone marrow contains 5 to 20% blasts, a bone marrow 
aspirate/biopsy should be repeated within 1 week to distinguish relapse from bone marrow 
regeneration.  
 
Reappearance of cytologically or biopsy documented extramedullary disease, including new CNS 
disease or other new sites of extramedullary involvement. Note: The reappearance of a 
cytogenetic or molecular abnormality would be considered a cytogenetic or molecular relapse. In 
the absence of morphologic relapse, this would not be considered a recurrence. 
 
Evaluation of response is recorded on the Response Assessment eCRF, and documentation of recurrence 
(relapse) is recorded on the Relapse Assessment eCRF. 
 
Adverse Event  
An AE is defined as any untoward medical occurrence in a clinical study subject, temporally associated 
with the use of study treatment, whether or not considered related to the study treatment. 
Treatment-emergent Adverse Event (TEAE)  
A TEAE is any adverse event beginning or worsening from C1D1 through 30 days following study 
treatment completion.  
 
Treatment-emergent Laboratory Toxicity (TELT) 
A TELT is a laboratory abnormality as defined in the National Cancer Institute - Common Toxicity 
Criteria for Adverse Events (NCI-CTCAE) v5.0 (NCI 2017, which occurs on or after the start of study 
treatment and up to 30 days following discontinuation of all study treatment and is at least 1 grade shift 
from the baseline value. TELTs are determined programmatically from laboratory assessments recorded 
in the relevant CRF pages. 
 
Concomitant Medications 
Concomitant medications are those medications taken on or after the initiation of study treatment. This 
includes medications started prior to the initiation of ENTO/placebo and continued after the initiation of 
ENTO/placebo. These medications will be recorded in the Prior and Concomitant Medications page of the 
CRF.  
 
Prior Medications 
Prior medications are those medications taken and discontinued prior to the initiation of study treatment. 
These medications will be recorded in the Prior and Concomitant Medications page of the CRF.  
 


Kronos Bio  
Entospletinib                                                                              
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4 May 2023 
 
 
4.4.5. Presentations by Study Visit 
All study visits should be scheduled relative to C1D1 regardless of any treatment interruptions. Visits will 
be presented according to the visit designation as recorded in the CRF. Unscheduled and Early 
Termination Visits will be excluded from by visit presentations. All data will be presented in data listings. 
4.4.6. Missing Data 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects who have 
been randomized. In situations where it is not possible to obtain all data, it may be necessary to impute 
missing data. AEs with missing causal relationship will be assessed as related to study treatment. AEs 
with missing severity will be included in the denominator for all grade events of the same preferred term 
(PT) but will not be included in the numerator for any severity when reporting the frequency of events by 
severity. See Section 4.4.4.4 for details of imputing missing dates. See Section 6.4 for details of imputing 
missing efficacy endpoints. 
 
Unless otherwise specified, all other missing data will not be imputed. 
4.4.6.1. Imputation for Alphanumeric Data 
Should there be instances where a clinical laboratory parameter is reported with imbedded non-numeric 
characters, such as, for example, “<0.1” or “>10”, the data will be imputed for quantitative summaries. The 
actual values as reported in the database will be presented in data listings.  
For incorporation in quantitative summaries, the following imputation rules will be employed: 
The limit of quantitation will be increased by one level of precision in the direction of the symbol that 
precedes the value. For example, “< 0.1” will be imputed to “0.09”, while “>0.1” will be imputed to “0.11”, 
and “>10” will be imputed to “10.1”. 
4.4.6.2. Incomplete or Missing Dates 
An incomplete date occurs when the exact date an event started or ended cannot be obtained. The 
database contains data fields for month, day, and year. A date is incomplete if at least one of these three 
fields is not known.  
For many of the planned analyses, a complete date is necessary to determine if the event should be 
included in the analysis (i.e., if the event is treatment-emergent) or to establish the duration of an event. In 
such cases, incomplete or missing dates will be imputed. 
For the purposes of handling partially reported start and stop dates for an event the following algorithm 
will be applied: 
 
Missing start day, but month and year present: 


Kronos Bio  
Entospletinib                                                                              
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Final Version 
 
 
 
 
CONFIDENTIAL  
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4 May 2023 
 
 
If the event occurs in the same month and year as the initiation of study treatment, then the 
start day of the event will be assigned to C1D1. For example, if an AE occurred in December 
2021, and C1D1 study treatment administration was on 8 December 2021 then the date of AE 
onset would be set to 8 December 2021. 
Otherwise, the start day will be set to the first day of the month. 
 
Missing start day and month, but year present: 
If an event occurs in the same year as the initiation of study treatment, then the start date of 
the event will be assigned to C1D1. For example, in the event a subject started study 
treatment on 20 January 2022 and had an AE starting in 2022 with no Month and Day 
indicated, the AE date would be set to 20 January 2022. 
Otherwise, the start day and month will be set to 01 January. Thus, for AEs with a start date 
of 2022 and initiation of study treatment in 2021, the AE start date would be 01 January 
2022. 
 
Missing start day, month, and year will be set to C1D1. 
 
Missing end day, but month and year present: 
The day will be set to the last day of the month. 
 
Missing end day and month, but year present: 
The end day and month will be set to 31 December of that year or the study treatment 
completion date, if earlier. 
If any imputed date causes the end date to occur prior to the start date of the event, the start date of the 
event will be used for the imputation of the end date. In subject data listings, start and stop dates of events 
will be displayed as reported on the CRF (i.e., imputed values will not be listed). 
4.5. 
Timing of Analyses 
A single DMC analysis occurred in September 2022.   
A final analysis will be conducted once the  database is cleaned and locked.  
 


Kronos Bio  
Entospletinib                                                                              
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5. 
ANALYSIS SETS 
The following analysis populations will be defined for this study: Intent-to-Treat Analysis Set and Safety 
Analysis Set. 
5.1. 
Intent-To-Treat Analysis Set 
The Intent-to-Treat (ITT) Analysis Set consists of all subjects who are randomized. The ITT analysis set 
will be the primary population for efficacy analyses.  
5.2. 
Safety Analysis Set 
The Safety Analysis Set consists of all subjects who receive at least one dose of study medication. 
Subjects in this population will be analyzed according to the treatment they received, regardless of the 
treatment to which they were randomized. The Safety Analysis Set will be used for all summaries of 
safety data. 
 


Kronos Bio  
Entospletinib                                                                              
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KB-ENTO-3001 
 
Final Version 
 
 
 
 
CONFIDENTIAL  
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4 May 2023 
 
 
6. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study. Unless stated 
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median, standard 
deviation , interquartile range, minimum, and maximum for continuous data and frequency and 
percentage for categorical data. The term “treatment group” refers to the randomized assignment: ENTO 
or placebo. Unless otherwise specified, data summaries and analyses described below will be reported by 
treatment group. All data collected during the study will be included in data listings. Unless otherwise 
noted, the data will be sorted first by treatment, patient number, and then by assessment date for each 
patient number. The number of subjects screened, enrolled, treated, and discontinued from study drug will 
be summarized along with the primary reason for study treatment discontinuation. The number of subjects 
in each analysis population will be presented by treatment group.  
6.1. 
Demographics and Baseline Characteristics 
Demographic data including age (years), sex, race, ethnicity, geographic region (North America, South 
America, European Union, Asia Pacific), (height (cm), weight (kg), and body surface area (m
2) will be 
summarized for the ITT Analysis Set.  
All information pertaining to AML diagnosis as collected on the eCRF will be listed. 
6.2. 
Medical History 
All clinically relevant prior or concurrent medical conditions will be mapped to system organ class (SOC) 
and PT using the version of Medical Dictionary for Regulatory Activities (MedDRA) in effect at the time 
of database lock. The number and percent of subjects in the ITT Analysis Set reporting each medical 
condition will be summarized according to SOC and PT. 
All medical history will be listed. 
6.3. 
Exposure to Treatment  
The number of days on oral study drug and cumulative dose will be summarized by treatment group for 
the Safety Analysis Set. Additionally, the number of chemotherapy cycles completed and the relative dose 
intensities for each chemotherapy agent will be presented by treatment group, separately for Induction 
and Consolidation and presented by cycle and overall. Drug administration details will be listed. 
6.4. 
Efficacy  
No analysis of protocol defined primary or secondary efficacy endpoints will be generated.  A summary 
of the investigator assessment of response after two cycles of chemotherapy will be summarized by 
treatment group for the Safety Analysis Set as this analysis was previously generated for the DMC.   


Kronos Bio  
Entospletinib                                                                              
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6.5. 
SAFETY ANALYSIS 
Descriptive summaries will be generated for safety data including TEAEs as well as changes from 
baseline in laboratory assessments (figure only), and graded laboratory toxicities. All adverse events will 
be graded for severity using NCI-CTCAE as follows: 
 
Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observation only; 
intervention not indicated 
 
Grade 2 (Moderate): minimal, local, or non-invasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL) 
 
Grade 3 (Severe): Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL 
 
Grade 4 (Life-threatening): Urgent intervention indicated required to remove or abrogate risk of death 
 
Grade 5: Death related to AE 
6.5.1. Adverse Events 
Adverse events will be mapped to the MedDRA version in effect at the time of database lock. TEAEs will 
be summarized by treatment group using system organ class and preferred term. 
If a subject experiences multiple events that map to a single preferred term, the event of greatest severity 
will be assigned to the preferred term for the appropriate summaries. Subjects with events mapping to 
multiple preferred terms within the same system organ class will be counted once at the system organ 
class level.  
Separate summaries for treatment-emergent serious adverse events (TESAEs), TEAEs by severity, 
TEAEs related to study medication, TEAEs leading to ENTO/placebo dose reduction, interruption, 
discontinuation, and TEAEs with an outcome of death will be generated.  
Missing onset dates will be imputed as previously outlined in Section 4.4.4.4.  
6.5.2. Clinical Laboratory Assessments 
Laboratory toxicities will be graded for severity using NCI-CTCAE Version 5.0 (see section Appendix B 
for more details about laboratory grading). The frequency and percentage of subjects experiencing 
treatment-emergent toxicities will be summarized by treatment group. Shifts from baseline toxicity grades 
to worst post-treatment toxicity grades will be presented by treatment group. 
Figures of observed values by study visit will be produced for the following hematology and clinical 
chemistry parameters of interest: hemoglobin, white blood cells, lymphocytes, ANC, platelets, alanine 
aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, 
indirect bilirubin, creatinine, urea nitrogen, percent leukemic blasts, and lactate dehydrogenase.  
.   


Kronos Bio  
Entospletinib                                                                              
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6.5.3. Prior and Concomitant Medications 
Prior and concomitant medications will be classified using World Health Organization (WHO) Drug 
Dictionary codes and Anatomical Therapeutic Chemical (ATC) Classification for therapeutic indication. 
ATC Level 4 will be utilized as the drug classification. Prior and concomitant medications will be listed.  
6.5.4. Vital Signs and Pulse Oximetry 
Vital signs include systolic and diastolic blood pressures, respiratory rate, pulse, temperature. Vital signs 
and pulse oximetry will be listed.  
6.5.5. Electrocardiograms 
Triplicate 12-lead ECGs will be obtained at Screening.  
ECG data will be listed.  
6.5.6. Echocardiograms/Multigated Acquisition Scan 
An ECHO or MUGA scan will be performed at screening and at the end-of-treatment visit. For subjects 
receiving anthracycline in Induction Cycle 2, the ECHO or MUGA scan may be repeated within 48 hours 
prior to Cycle 2, Day 1 in subjects at increased risk for cardiotoxicity. ECHO data will be listed. 
6.5.7. Physical Examinations 
Physical examination will include body weight, height (at screening only) and a full neurological 
examination. These data will be presented in listing format. 
6.5.8. ECOG Performance Status 
ECOG PS score at each visit will be presented in a data listing. 
 


Kronos Bio  
Entospletinib                                                                              
Statistical Analysis Plan 
KB-ENTO-3001 
 
Final Version 
 
 
 
 
CONFIDENTIAL  
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4 May 2023 
 
 
7. 
PROTOCOL DEVIATIONS 
All protocol deviations will be reviewed by the project team prior to unblinding to identify subjects with 
important protocol deviations.  
All deviations from the study protocol will be available from the clinical team. 
 


Kronos Bio  
Entospletinib                                                                              
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KB-ENTO-3001 
 
Final Version 
 
 
 
 
CONFIDENTIAL  
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8. 
CHANGES IN THE PLANNED ANALYSES 
As the study was terminated prior to the enrollment of 180 subjects, analyses of the efficacy and 
exploratory endpoints described in the protocol will not be conducted. These deviations will be 
documented in the final CSR. 


Kronos Bio  
Entospletinib                                                                              
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4 May 2023 
 
 
9. 
REFERENCES 
DHHS (2009). "Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation." 
 
Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood. 2017;129(4):424-44. 
 
Ivey A, Hills RK, Simpson MA, et al. Assessment of Minimal Residual Disease in Standard-Risk AML. 
N Engl J Med. 2016;374(5):422-433. 
 
Mims AS, Kohlschmidt J, Borate U, et al. A precision medicine classification for treatment of acute 
myeloid leukemia in older patients. J Hematol Oncol. 2021;14(1):96.  
  
 
Walker AR, Byrd JC, Blachly JS, et al. Entospletinib in Combination with Induction Chemotherapy in 
Previously Untreated Acute Myeloid Leukemia: Response and Predictive Significance of HOXA9 and 
MEIS1 Expression. Clin Cancer Res. 2020; 26(22):5852-5859.


Kronos Bio  
Entospletinib                                                                              
Statistical Analysis Plan 
KB-ENTO-3001 
 
Final Version 
 
 
 
 
CONFIDENTIAL  
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4 May 2023 
 
 
10. 
PROPOSED TABLES, LISTINGS, AND FIGURES 
 
Summary Tables 
1 
Subject Disposition 
2 
Demographics and Baseline Disease Characteristics 
3 
Exposure to Study Medication and Chemotherapy 
4 
Summary of Responses after Two Cycles of Chemotherapy 
5 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Greatest Severity 
6 
Summary of Treatment-Related Adverse Events by System Organ Class and 
Preferred Term 
7 
Summary of Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
8 
Summary of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
9 
Summary of Treatment-Emergent Severity Graded Laboratory Abnormalities 
 
Figures 
1 
Chemistry Parameters Over Time 
2 
Hematology Parameters Over Time 
 
Data Listings 
1 
Subject Disposition 
2 
Treatment-Emergent Adverse Events 
3 
Treatment-Emergent Severity Graded Laboratory Abnormalities 
4.1 
Demographics 
4.2 
AML Diagnosis 
5.1 
Study Treatment - IV/Infusion Administration Details 
5.2 
Study Treatment - Oral Administration Details 
6 
Response Assessment after Two Cycles of Chemotherapy 
7 
Vital Signs, Height, and Weight 
8 
Electrocardiogram 
9 
Physical Examinations 
10 
ECOG Performance Status 
11 
Echocardiogram/MUGA for LVEF Assessment 
12 
General Medical History 
13 
Prior and Concomitant Medications 
14 
Prior Leukemogenic Agent Exposure 


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Appendix A: Programming Conventions 
 
Statistical software: The statistical analyses will be conducted with the SAS® software package 
version 9.4 or higher.  
 
Verification procedures: All analyses will be subject to formal verification procedures. 
Specifically, results will be verified utilizing independent programming prior to issuance of the 
draft statistical report. All documents will be verified by the lead statistician to ensure accuracy 
and consistency of analyses. 
 
Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in 
landscape orientation. There should be a minimum of a 1” boundary on the upper (bound) 
edge, and a minimum of a 1.0” boundary on the remaining three edges. Output should be 
printed in Courier New with a point size of 8. Titles may be printed using a larger font (e.g., 
Arial point size 10). 
 
Identification of analysis population: Every summary table and figure should clearly specify 
the analysis population being summarized. Listings will be prepared for all subjects enrolled. 
 
Group headers: In the summary tables, the group headers will identify the treatment group and 
the within-group sample size for the indicated analysis population. Of note, the header’s 
sample size does not necessarily equal the number of subjects actually summarized within any 
given summary module; some subjects in the analysis population may have missing values and 
thus may not be summarized. 
 
Suppression of percentages corresponding to null categories: When count data are presented as 
category frequencies and corresponding percentages, the percent should be suppressed when 
the count is zero in order to draw attention to the non-zero counts. 
 
Presentation of sample sizes: Summary modules should indicate, in one way or another, the 
number of subjects actually contributing to the summary statistics presented in any given 
summary module. As mentioned above, this may be less than the number of subjects in the 
analysis population. 
 In the quantitative modules describing continuous variables (and thus presenting sample 
size, means, and standard deviations), the sample size should be the number of non-
missing observations. 
 For categorical variables that are presented in frequency tables, the module should present 
the total count in addition to the count in each category. Percentages should be calculated 
using this total as the denominator, and the percentage corresponding to the sum itself (that 
is, 100%) should be presented so as to indicate clearly to a reviewer the method of 
calculation. 
 
Sorting: Listings will be sorted by treatment group, patient number, and date, if applicable. If a 
listing is sorted in a different manner, a footnote will indicate as such.  
 
 


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 
General formatting rules: Rounding for all variables will occur only as the last step, 
immediately prior to presentation in listings, tables, and figures. No intermediate rounding will 
be performed on derived variables. The standard rounding practice of rounding numbers 
ending in 0-4 down and numbers ending in 5-9 up will be employed.  
 
The presentation of numerical values will adhere to the following guidelines:  
 Raw measurements will be reported to the number of significant digits as captured 
electronically or on the CRFs.  
 Standard deviations will be reported to two decimal places beyond the number of decimal 
places the original parameter is presented. 
 Means, medians, first and third quartiles will be reported to one decimal place beyond the 
number of decimal places the original parameter is presented.  
 Calculated percentages will be reported with no decimals. 
 
Dates will be formatted as DDMMMYYYY. Partial dates will be presented on data listings as 
recorded on CRFs. 
 
Time will be presented according to the 24-hour clock (HHMM). 
 


Kronos Bio  
Entospletinib                                                                              
Statistical Analysis Plan 
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Final Version 
 
CONFIDENTIAL  
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Appendix B: Programming Modified NCI-CTCAE Grading for Laboratory Abnormalities 
Category 
Analyte Name 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Chemistry 
Albumin 
Hypoalbuminemia 
<LLN - 3 g/dL 
<3 - 2 g/dL 
<2 g/dL 
- 
Chemistry 
Amylase 
Serum amylase 
increased 
>ULN - 1.5 x ULN >1.5 - 5.0 x ULN  
>5.0 x ULN 
- 
Chemistry 
Alanine 
Aminotransferase  
Alanine 
aminotransferase 
increased 
>ULN - 3.0 x ULN if 
baseline was normal; 
1.5 - 3.0 x baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline 
if baseline was 
abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x 
baseline if baseline 
was abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal 
Chemistry 
Alkaline 
Phosphatase 
Alkaline phosphatase 
increased 
>ULN - 2.5 x ULN if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was 
abnormal 
>2.5 - 5.0 x ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline 
if baseline was 
abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x 
baseline if baseline 
was abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal 
Chemistry 
Aspartate 
Aminotransferase  
Aspartate 
aminotransferase 
increased 
>ULN - 3.0 x ULN if 
baseline was normal; 
1.5 - 3.0 x baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline 
if baseline was 
abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x 
baseline if baseline 
was abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal 


Kronos Bio  
Entospletinib                                                                              
Statistical Analysis Plan 
KB-ENTO-3001 
 
Final Version 
 
CONFIDENTIAL  
Page 39 of 42 
4 May 2023 
 
 
Category 
Analyte Name 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Chemistry 
Bilirubin (Total or 
Direct) 
Blood bilirubin 
increased 
>ULN - 1.5 x ULN if 
baseline was normal; 
> 1.0 - 1.5 x baseline 
if baseline was 
abnormal 
>1.5 - 3.0 x ULN if 
baseline was normal; 
>1.5 - 3.0 x baseline 
if baseline was 
abnormal 
>3.0 - 10.0 x ULN if 
baseline was normal; 
>3.0 - 10.0 x 
baseline if baseline 
was abnormal 
>10.0 x ULN  
Chemistry 
Calcium 
Corrected for 
Albumin 
Hypocalcemia 
<LLN - 8.0 mg/dL  <8.0 - 7.0 mg/dL  
<7.0 - 6.0 mg/dL  
<6.0 mg/dL 
Hypercalcemia 
>ULN - 11.5 mg/dL >11.5 - 12.5 mg/dL >12.5 - 13.5 mg/dL >13.5 mg/dL  
Chemistry/
Lipid 
Profile 
Cholesterol  
Cholesterol high 
>ULN - 300 mg/dL >300 - 400 mg/dL 
>400 - 500 mg/dL; >500 mg/dL 
Chemistry 
Creatine Kinase 
CPK increased 
>ULN - 2.5 x ULN 
>2.5 x ULN - 5 x 
ULN 
>5 x ULN - 10 x 
ULN 
>10 x ULN 
Chemistry 
Creatinine 
Creatinine increased >ULN - 1.5 x ULN 
>1.5 - 3.0 x baseline 
or >1.5 - 3.0 x ULN 
>3.0 x baseline or 
>3.0 - 6.0 x ULN 
>6.0 x ULN 
Chemistry 
GGT 
GGT increased 
>ULN - 2.5 x ULN if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was 
abnormal 
>2.5 - 5.0 x ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline 
if baseline was 
abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x 
baseline if baseline 
was abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal 


Kronos Bio  
Entospletinib                                                                              
Statistical Analysis Plan 
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Final Version 
 
CONFIDENTIAL  
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4 May 2023 
 
 
Category 
Analyte Name 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Chemistry 
eGFR or CrCL 
eGFR 
decreased/CrCL 
decreased 
<LLN – 60 
ml/min/1.73 m2 
<60 – 30 
ml/min/1.73 m2 
<30 - 15 
ml/min/1.73 m2 
<15 
ml/min/1.73 m2 
Chemistry 
Glucose 
Hypoglycemia 
<LLN - 55 mg/dL 
<55 - 40 mg/dL 
<40 - 30 mg/dL 
<30 mg/dL 
Chemistry 
Lipase 
Serum lipase 
increased 
>ULN - 1.5 x ULN >1.5 - 5.0 x ULN  
>5.0 x ULN  
- 
Chemistry 
Magnesium 
Hypermagnesemia 
>ULN - 3.0 mg/dL  
- 
>3.0 - 8.0 mg/dL 
mmol/L 
>8.0 mg/dL 
Hypomagnesemia 
<LLN - 1.2 mg/dL 
<1.2 - 0.9 mg/dL 
<0.9 - 0.7 mg/dL 
<0.7 mg/dL  
Chemistry 
Potassium 
Hyperkalemia 
>ULN - 5.5 mmol/L >5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L 
>7.0 mmol/L 
Hypokalemia 
<LLN - 3.0 mmol/L - 
<3.0 - 2.5 mmol/L 
<2.5 mmol/L 
Chemistry 
Sodium 
Hypernatremia 
>ULN - 150 mmol/L >150 - 155 mmol/L; >155 - 160 mmol/L >160 mmol/L  
Hyponatremia 
<LLN - 130 mmol/L 125-129 mmol/L  
120-124 mmol/L  
<120 mmol/L  
Chemistry/
Lipid 
Profile 
Triglycerides  
Hypertriglyceridemia 
150 mg/dL - 300 
mg/dL 
>300 mg/dL - 500 
mg/dL 
>500 mg/dL - 1000 
mg/dL 
>1000 mg/dL 
Chemistry 
Uric Acid  
Hyperuricemia 
>ULN 
- 
- 
- 


Kronos Bio  
Entospletinib                                                                              
Statistical Analysis Plan 
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Final Version 
 
CONFIDENTIAL  
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Category 
Analyte Name 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Chemistry 
Bicarbonate or 
CO2  
Blood bicarbonate 
decreased 
<LLN 
- 
- 
- 
Hematology 
Eosinophils 
Eosinophilia 
>ULN and > 
Baseline 
Hematology 
Hemoglobin 
Anemia 
<LLN – 100 g/L 
<100 – 80 g/L 
<80 g/L 
- 
Hematology 
Lymphocytes  
Lymphocyte count 
decreased 
<LLN - 800/mm3 
<800 - 500/mm3 
<500 - 200/mm3 
<200/mm3 
Lymphocyte count 
increased 
- 
>4000/mm3 - 
20,000/mm3 
>20,000/mm3 
- 
Hematology 
Neutrophils 
Neutrophil count 
decreased 
<LLN - 1500/mm3 <1500 - 1000/mm3  <1000 - 500/mm3 
<500/mm3 
Hematology 
Platelets  
Platelet count 
decreased 
<LLN - 75,000/mm3 
<75,000 - 
50,000/mm3 
<50,000 - 
25,000/mm3 
<25,000/mm3 
Hematology 
Leukocytes/ 
White Blood Cells 
Leukocytosis 
- 
- 
>100,000/mm3 
- 
White blood cell 
decreased 
<LLN - 3000/mm3 <3000 - 2000/mm3 <2000 - 1000/mm3 <1000/mm3 


Kronos Bio  
Entospletinib                                                                              
Statistical Analysis Plan 
KB-ENTO-3001 
 
Final Version 
 
CONFIDENTIAL  
Page 42 of 42 
4 May 2023 
 
 
Category 
Analyte Name 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Coagulation 
Activated partial 
thromboplastin 
time 
Activated partial 
thromboplastin time 
prolonged 
>ULN - 1.5 x ULN >1.5 - 2.5 x ULN 
>2.5 x ULN 
- 
Coagulation 
Fibrinogen 
Fibrinogen decreased 
<1.0 - 0.75 x LLN; if 
abnormal, <25% 
decrease from 
baseline 
<0.75 - 0.5 x LLN; 
if abnormal, 25 - 
<50% decrease from 
baseline 
<0.5 - 0.25 x LLN; if 
abnormal, 50 - <75% 
decrease from 
baseline 
<0.25 x LLN; if 
abnormal, 75% 
decrease from 
baseline; absolute 
value <50 mg/dL 
Coagulation 
International 
Normalized Ratio 
INR increased 
>1.2 - 1.5 
>1.5 - 2.5 
>2.5 
- 
Note: Values noted as ‘abnormal’ at baseline should be outside the normal range in the direction of the toxicity grade. 
Note: In cases where the lower limit of normal (LLN) or upper limit of normal (ULN) of a given laboratory value falls in the Grade 2 or 
higher range of the scale, the toxicity will be graded at the higher value (i.e., a lymphocyte test has a LLN of 600/mm3, any value of 
600/mm3 will be considered as a Grade 2 abnormality).