Clinical trial NCT03151408
Conditions: Acute Myeloid Leukemia
Keywords: AML
Sponsor: Helsinn Healthcare SA
Start date: 2017-06-23; Completion date: 2020-08-20
Enrollment: 406 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, multicenter, double-blind, randomized study of pracinostat vs. placebo with azacitidine (AZA) as background therapy in patients ≥ 18 years of age with newly diagnosed acute myeloid leukemia (AML), excluding acute promyelocytic leukemia and cytogenetic low-risk AML, who are unfit to receive intensive remission induction chemotherapy due to age ≥ 75 years or comorbidities. Patients will be randomized in a 1:1 ratio to one of two groups: Group A (experimental group) to receive pracinostat plus AZA and Group B (control group) to receive placebo plus AZA. Randomization will be stratified by cytogenetic risk category (intermediate vs. unfavorable-risk, according to SWOG Cytogenetic Risk Category Definitions) and ECOG performance status (0-1 vs. 2). Treatments will be administered based on 28-day cycles, with pracinostat/placebo administered orally once every other day, 3 times a week for 3 weeks, followed by one week of no treatment and AZA administered for 7 days of each cycle. Study treatment should continue until there is documented disease progression, relapse from complete remission (CR), or non-manageable toxicity. A minimum of 6 cycles may be required to achieve a complete remission. Once permanently discontinued from study treatment, patients will enter the Long-term Follow-up phase of the study and will be followed for assessment of disease progression, if applicable, and survival every 3 months (±1 month) until death. The end of this study is defined when 390 events (deaths) have occurred and the study is unblinded for final overall survival analysis. Patients who are receiving study treatment at the end of the study may have the opportunity to continue to receive the study drugs to which they were randomized to (Post- Study Observation Period), until the Sponsor informs the Investigators of the appropriate course of action based on the study results. The Post-Study Observation Period is defined as the period starting from the end of the study for a maximum of 12 months.

Detailed description:

Arms: arm 1: 60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. arm 2: 1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle.
Interventions: intervention 1: Pracinostat intervention 2: Placebos intervention 3: Azacitidine
Intervention descriptions: intervention 1: 60 mg capsule intervention 2: capsule intervention 3: SC or IV injection

Protocol documents:
Prot_000.pdf: 
PRAN-16-52 
Final (v 5.0)/16 Dec 2019
Clinical Study Protocol
Confidential Information
The information contained in this document is confidential. Acceptance of this document constitutes agreement 
by the recipient that no information contained herein will be published or disclosed without prior written 
authorization from an official of Helsinn, except that this document may be disclosed to appropriate 
Institutional Review Boards and Ethics Committees or duly authorized representatives of a Regulatory 
Authority under the condition that they are requested to keep it confidential.
The clinical trial will be conducted, and essential study documentation archived, in compliance with this 
protocol, applicable SOPs and standards, which incorporate the requirements of the ICH Guideline for 
Good Clinical Practice.
Page 1 of 120
CONFIDENTIAL
A PHASE III, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER, RANDOMIZED STUDY OF 
PRACINOSTAT IN COMBINATION WITH AZACITIDINE 
IN PATIENTS ≥18 YEARS WITH NEWLY DIAGNOSED
ACUTE MYELOID LEUKEMIA UNFIT FOR STANDARD 
INDUCTION CHEMOTHERAPY
PROTOCOL NUMBER:
PRAN-16-52
PROTOCOL VERSION:
(Original Protocol Number: MEI-009)
Final (v 5.0)
EUDRACT NUMBER:
2016-004724-34
IND NUMBER:
79,597
TEST PRODUCT:
STUDY CHAIR:
STUDY CO-CHAIR:
PRACINOSTAT
Guillermo Garcia-Manero, MD
Lionel Adès, MD
MEDICAL ADVISOR:
Silvia Mappa, MD
SPONSOR:
CRO:
Helsinn Healthcare SA
Via Pian Scairolo 9, 6912 Lugano, Switzerland
CLINIPACE, INC.,
3800 Paramount Pkwy, Ste 100, Morrisville, NC 27560-USA
PROTOCOL DATE:
16 Dec 2019






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CONFIDENTIAL
INVESTIGATOR ACCEPTANCE APPROVAL PAGE
TITLE:
A PHASE III, DOUBLE-BLIND,
PLACEBO-CONTROLLED, MULTICENTER, 
RANDOMIZED STUDY OF PRACINOSTAT IN 
COMBINATION WITH AZACITIDINE IN 
PATIENTS ≥ 18 YEARS WITH NEWLY 
DIAGNOSED ACUTE MYELOID LEUKEMIA 
UNFIT FOR STANDARD INDUCTION 
CHEMOTHERAPY
PROTOCOL NUMBER:
PRAN-16-52
EUDRACT NUMBER:
2016-004724-34
IND NUMBER:
79,597
TEST PRODUCT:
PRACINOSTAT
SPONSOR:
Helsinn Healthcare SA
I have read and understood the protocol and agree to implement the study in accordance 
with the procedures set forth in the protocol and in accordance with the Sponsor's 
guidelines and all applicable government regulations and the ICH-GCP.
I will provide adequate protocol training to my associates, colleagues, and employees 
assisting in the conduct of the study.
I will obtain Institutional Review Board (IRB)/Ethics Committee (EC) approval of the 
Protocol and Informed Consent Form (ICF) prior to enrollment of patients in the study. I 
understand that any modifications to the protocol made during the course of the study 
must first be approved by the IRB/EC except when such modification is made to remove 
an immediate hazard to the patient.
I will ensure that a fully executed ICF is obtained from each patient prior to initiation of 
any study procedures.
I will report any serious adverse event that occurs during the course of the study in 
accordance with the procedures described in this protocol and in accordance with local 
and ICH/GCP regulatory requirements.
I will allow the Sponsor, Helsinn Healthcare SA and its designees as well as the United 
States Food and Drug Administration and other Regulatory Agencies, to inspect study 
facilities and pertinent records, ensuring patient confidentiality. If I am notified that this 
study is to be inspected by a Regulatory Agency, I will notify Helsinn Healthcare SA 
/designee as soon as possible thereafter.
Principal Investigator’s Name (print)
Site Number
Principal Investigator’s Signature
Date (day/month/year)


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................9
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19
1
INTRODUCTION ................................................................................................24
1.1
Overview of Acute Myeloid Leukemia............................................................24
1.2
Histone deacetylase inhibitors and Hypomethylating agents.........................25
1.3
Background on Pracinostat .............................................................................25
1.4
Background on Azacitidine in AML ...............................................................27
1.5
Benefit-Risk Assessment ..................................................................................27
2
STUDY OBJECTIVES.........................................................................................28
2.1
Primary Objective............................................................................................28
2.2
Secondary Objectives.......................................................................................28
3
STUDY PLAN.......................................................................................................29
3.1
Study Design.....................................................................................................29
3.2
End of Study.....................................................................................................30
3.3
Study Rationale................................................................................................30
3.3.1
Rationale for Patient Population ...............................................................30
3.3.2
Rationale for Definition of Ineligibility for Intensive Induction 
Chemotherapy............................................................................................31
3.3.3
Clinical Rationale.......................................................................................32
3.3.4
Rationale for the Control Arm ..................................................................32
3.4
Eligibility and Enrollment ...............................................................................33
3.4.1
Inclusion Criteria .......................................................................................33
3.4.2
Exclusion Criteria ......................................................................................34
4
STUDY TREATMENTs.......................................................................................36
4.1
Study Treatment Groups.................................................................................36
4.2
Pracinostat and Placebo...................................................................................36
4.2.1
Pracinostat and Placebo Supply, Storage and administration .................36
4.2.2
Precautions and Risks Associated with Pracinostat..................................39
4.3
Azacitidine........................................................................................................41
4.3.1
Azacitidine Supply, Storage and Administration......................................41
4.3.2
Warnings and Precautions for Azacitidine ...............................................42
4.4
Duration of Therapy ........................................................................................43
4.5
Dose Modifications and/or Dose Interruptions...............................................44
4.5.1
Dose Modification or Interruption for Hematologic Toxicity ..................45
4.5.2
Dose Modification or Interruption for Non-Hematologic Toxicity ..........47
4.5.3
Dose Interruption in Patients with < 5% Bone Marrow Blasts 
(“Drug Holiday”)........................................................................................47
4.6
Management of Toxicity ..................................................................................48
4.6.1
Prophylactic Therapies ..............................................................................48
4.7
Prior and Concomitant Medications...............................................................48
4.7.1
Medications Affecting Metabolism of Pracinostat via Cytochrome 
P450 ............................................................................................................49


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4.7.2
Possible Effects of Pracinostat on Other Drugs via Cytochrome 
P450 ............................................................................................................49
4.7.3
Prohibited Concomitant Medications........................................................49
4.8
Treatment compliance .....................................................................................50
5
STUDY CONDUCT..............................................................................................51
5.1
Study Procedures .............................................................................................51
5.1.1
Informed Consent.......................................................................................51
5.1.2
Screening Assessments ...............................................................................51
5.1.3
Cycle 1 on Day 1.........................................................................................52
5.1.4
Cycle 1 on Day 2.........................................................................................54
5.1.5
Cycle 1 on Day 3.........................................................................................54
5.1.6
Cycle 1 on Days 4 to 7 (or 9) ......................................................................55
5.1.7
Cycle 1 on Day 15.......................................................................................55
5.1.8
Cycle 2 and All Subsequent Cycles on Day 1 ............................................55
5.1.9
Cycle 2 and All Subsequent Cycles on Days 2 to 7 (or 9)..........................56
5.1.10
Cycle 2 and All Subsequent Cycles from Day 21 to 26 .............................56
5.1.11
Cycle 2 and Subsequent Even Cycles from Day 21 to 26..........................57
5.1.12
Cycle 3 and Subsequent Odd Cycles on Day 1..........................................57
5.1.13
Study Treatment Interruption/ Drug Holiday Schedule...........................58
5.1.14
End of Treatment Visit ..............................................................................59
5.2
In-Study Long-term Follow-Up.......................................................................59
5.3
Post-Study Observation Period .......................................................................60
The Post-Study Observation Period is defined as the period starting from the 
end of the study (Section 3.2) for a maximum of 24 months. .........................60
5.3.1
Patients on treatment at the end of study..................................................60
5.3.2
After discontinuation of the treatment each patient enters in the 
post-study long-term follow-up as described below.Post-study 
long-term follow-up....................................................................................60
6
METHODS OF ASSESSMENT AND ENDPOINTS..........................................61
6.1
Efficacy Assessments........................................................................................61
6.1.1
Bone Marrow Aspirate/biopsy...................................................................61
6.1.2
RBC and platelet transfusions ...................................................................62
6.1.3
Quality of Life Questionnaire ....................................................................62
6.2
Safety Assessments...........................................................................................62
6.2.1
Physical Examination.................................................................................62
6.2.2
Vital Signs...................................................................................................62
6.2.3
12-lead ECG ...............................................................................................63
6.2.4
Laboratory Assessments ............................................................................64
6.3
PK Assessments................................................................................................65
6.3.1
Pracinostat Population PK Assessments ...................................................65
6.3.2
AZA/Pracinostat PK sub-study (IN SELECTED SITES ONLY): 
Assessment of the possible drug interaction of Pracinostat on the 
PK of Azacitidine........................................................................................65
6.4
Biomarker Analysis (Optional)........................................................................67
6.5
Efficacy Endpoints...........................................................................................67
6.5.1
Primary Endpoint ......................................................................................67


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6.5.2
Secondary Endpoints .................................................................................68
6.5.3
Exploratory Endpoints...............................................................................68
6.6
PK Endpoints ...................................................................................................69
7
DISCONTINUATION FROM STUDY TREATMENT PHASE OF THE 
STUDY..................................................................................................................70
7.1
Patient Treatment Discontinuation.................................................................70
7.2
Patient Withdrawal..........................................................................................70
7.3
Site Discontinuation.........................................................................................71
7.4
Study Termination...........................................................................................71
8
SAFETY................................................................................................................72
8.1
Safety Parameters and Definitions..................................................................72
8.1.1
Definition of Adverse Events......................................................................72
8.2
Adverse Event Reporting.................................................................................73
8.2.1
Serious Adverse Event (SAE) ....................................................................74
8.2.2
Pregnancies.................................................................................................75
8.2.3
Adverse Event Severity ..............................................................................75
8.2.4
Adverse Event Causal Relationship to study treatment ...........................76
8.2.5
Procedures for Recording of Adverse Events ...........................................76
8.2.6
Adverse Events of Special Interest ............................................................77
8.2.7
Patient Unblinding For Safety Reasons.....................................................78
8.3
Independent Data Monitoring Committee (IDMC)........................................78
9
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN........................80
9.1
Statistical Design..............................................................................................80
9.2
Randomization and Stratification ...................................................................80
9.3
Analysis Sets.....................................................................................................80
9.4
Procedures for Handling Missing, Unused and Spurious Data......................82
9.5
General Statistical Considerations ..................................................................82
9.6
Study Population Data.....................................................................................82
9.7
Efficacy Analyses .............................................................................................83
9.7.1
Primary Efficacy Analysis - Overall Survival...........................................83
9.7.2
Secondary Efficacy Endpoints...................................................................83
9.7.3
Exploratory Efficacy Outcome Measures .................................................85
9.7.4
Subgroup Analyses.....................................................................................87
9.7.5
Quality of Life ............................................................................................87
9.7.6
Compliance to study treatment..................................................................87
9.8
Safety Analyses.................................................................................................87
9.8.1
Analysis of Adverse Events........................................................................88
9.8.2
Clinical Laboratory Evaluation Analyses .................................................88
9.8.3
Vital Sign Analyses.....................................................................................88
9.8.4
Electrocardiogram Analyses......................................................................89
9.9
Pharmacokinetic Analyses...............................................................................89
9.10
Health Economics Analysis..............................................................................89
9.11
Power and Sample Size Determination ...........................................................89
9.12
Interim Analysis...............................................................................................90
10
ETHICAL AND REGULATORY CONSIDERATIONS ...................................91
10.1
Compliance with Laws and Regulations .........................................................91


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10.2
Institutional Review Boards and Ethics Committees .....................................91
10.3
Informed Consent ............................................................................................91
10.4
Source Data Documentation............................................................................91
10.5
Use of Computerized Systems..........................................................................91
10.6
Quality control .................................................................................................91
10.7
Retention of Records........................................................................................92
10.8
Confidentiality..................................................................................................92
10.9
Insurance..........................................................................................................93
11
PUBLICATION POLICY....................................................................................94
12
REFERENCES .....................................................................................................95
13
APPENDICES ......................................................................................................99
Appendix A: 
Schedule of Assessments.................................................................99
Appendix B: 
SWOG Cytogenetic Risk Category Definitions ...........................105
Appendix C: 
ECOG Performance Status ..........................................................106
Appendix D: 
Acute Myeloid Leukemia Classification - WHO 2016.................107
Appendix E: 
New York Heart Association (NYHA) Classification of  
Cardiac Disease..............................................................................................108
Appendix F: 
Response Criteria .........................................................................109
Appendix G: 
Examples of CYP450 1A2, 3A4 and 2C8 inducers, and 
CYP3A4 and CYP2C8 inhibitors of clinical relevance.................................112
Appendix H: 
Examples of CYP1A2, CYP2B6 and CYP3A4 substrates...........114
Appendix I: 
Drugs with A Risk of Prolonging the QT Interval and/or  
Torsades de Pointes........................................................................................115
Appendix J: 
Acceptable Contraception Methods for male and female 
patients of childbearing potential or female partners of male patients .......117
Appendix K:
Patient- Reported Outcomes Instrument....................................119
LIST OF IN TEXT TABLES 
Table 1: 
Pracinostat Dose Reduction .................................................................44
Table 2: 
AZA Dose Reductions...........................................................................44
Table 3:
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE..........................................................................75
Table 4:
Adverse Event Causal Attribution Guidance......................................76
LIST OF IN TEXT FIGURES
Figure 1:
Study Schema .......................................................................................30
Figure 2: 
Dose Adjustment...................................................................................46


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PROTOCOL SYNOPSIS
Title:
A Phase III, Double-Blind, Placebo-Controlled, Multicenter, Randomized 
Study of Pracinostat in Combination with Azacitidine in Patients ≥18 Years
with Newly Diagnosed Acute Myeloid Leukemia (AML) Unfit for Standard 
Induction Chemotherapy
Protocol 
Number:
PRAN-16-52 
(Original Protocol Number: MEI-009)
EudraCT 
Number:
2016-004724-34
Test Product: Pracinostat
Phase:
III
Indication:
Acute Myeloid Leukemia (AML)
Study Sites:
Approximately 130 worldwide
No. of 
Patients:
Up to 500
Study Design
This is a Phase III, multicenter, double-blind, randomized study of 
pracinostat vs. placebo with azacitidine (AZA) as background therapy in 
patients ≥18 years of age with newly diagnosed acute myeloid leukemia 
(AML), excluding acute promyelocytic leukemia and cytogenetic low-risk 
AML, who are unfit to receive intensive remission induction chemotherapy 
due to age ≥ 75 years or comorbidities.
Patients will be randomized in a 1:1 ratio to one of two groups: Group A 
(experimental group) to receive pracinostat plus AZA and Group B (control 
group) to receive placebo plus AZA. Randomization will be stratified by 
cytogenetic risk category (intermediate vs. unfavorable risk, according to 
SWOG Cytogenetic Risk Category Definitions, Appendix B) and ECOG 
performance status (0-1 vs. 2, Appendix C). 
Treatment 
will 
be 
administered 
based 
on 
28-day 
cycles, 
with 
pracinostat/placebo administered orally once every other day, 3 times a week 
for 3 weeks, followed by one week of no treatment and AZA administered 
for 7 days of each cycle. Study treatment should continue until there is 
documented disease progression, relapse from complete remission (CR), or
non-manageable toxicity. A minimum of 6 cycles may be required to achieve 
a complete remission. 
Once permanently discontinued from study treatment, patients will enter the
Long-term Follow-up phase of the study and will be followed for assessment 
of disease progression, if applicable, and survival every 3 months (±1 month) 
until death.
The end of this study is defined when 390 events (deaths) have occurred. 
Patients who are receiving study treatment at the end of the study may have 
the opportunity to continue to receive the study drug to which they were 


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randomized to (Post-Study Observation Period), until the Sponsor informs the 
Investigators of the appropriate course of action, based on the study results.
The Post-Study Observation Period is defined as the period starting from the 
end of the study for a maximum of 24 months.
Background
and Study 
Rationale
Approximately about 21,380 new cases and 10,590 deaths from AML are 
expected to occur in the United States (US) in 2017, with the disease most 
commonly diagnosed in older people [American Cancer Society, 2017]. The 
average age of patients with AML is 67 years [American Cancer Society, 
2017]. According to the Surveillance of Rare Cancers in Europe 
(RARECARE) project, the incidence of AML in Europe is 3.7 per 100,000 
[Visser, 2012], similar to an incidence of 4.1 per 100,000 in the US [SEER, 
2016]. 
Population-based studies have reported 3-year survival rates of 9-10% in 
patients 60 years of age, compared with 5-year survival rates of up to 50% 
for patients < 60 years [Luger, 2010]. Poor overall survival (OS) in elderly 
patients with AML is due to two main factors: 1) high-risk disease 
characteristics (e.g., secondary AML, poor cytogenetic features) that respond 
poorly to standard induction chemotherapy, and 2) co-morbidities that 
preclude the use of intensive (curative) chemotherapy regimens. In addition, 
a much smaller but not trivial proportion of younger patients with AML are 
not able to receive standard induction chemotherapy due to comorbidities. 
Common approaches for patients with AML unfit to receive standard 
induction therapy regimens consist of low intensity therapies such as 
hypomethylating agents (HMA), low dose cytarabine, cloforabine, or
supportive care measures, but their benefit is limited. New treatment 
approaches are needed. 
Pracinostat, a potent, oral, pan-Histone DeACetylase (HDAC) (including 
Class I, II, and IV isoforms) inhibitor with favorable pharmacokinetic (PK) 
properties, has been administered to more than 400 patients with solid tumors 
or hematologic cancers in multiple Phase I and Phase II clinical studies, and 
has shown efficacy in myeloid malignancies. 
A Phase II, open-label, single-arm, multicenter study evaluated pracinostat in 
combination with AZA in 50 patients aged ≥ 65 years with newly diagnosed 
AML not eligible for induction chemotherapy (Study MEI-004). The primary 
objective was to estimate the composite complete remission (cCR) rate, 
composed of morphologic complete remission (CR) + morphologic complete 
remission with incomplete blood count recovery (CRi) + morphologic 
leukemia free state (MLFS). The CR rate was 42%, the CRi rate was 4% and 
the MLFS rate was 6%, for a cCR rate of 52%. The median OS was 
estimated at 19.1 months (95% confidence interval (CI): 10.0 - 26.5 months). 
These results indicate that pracinostat plus AZA may be an effective regimen 
in patients with AML unfit for induction therapy.
Azacitidine is approved in the EU [Vidaza®, SmPC 2017] and in other 
countries for the subset of patients with AML with 20-30% of blasts 


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[Fenaux, 2009] and in patients ≥ 65 years of age with AML and > 30% blasts 
who are not eligible for hematopoietic stem cell transplantation [Dombret, 
2015]. Based on data generated from these and other AZA studies in older 
patients with newly diagnosed AML [reviewed in Cruijsen, 2014], AZA is to 
be considered an acceptable agent for the background therapy in this Phase 3 
study. 
Based on the favorable Phase II data in older patients with AML (Study 
MEI-004), pracinostat in combination with azacitidine was selected as the 
experimental treatment group in this Phase III study PRAN-16-52. In order 
to optimize the interpretation of the final results and to avoid bias in both 
safety and efficacy reporting, the control group treatment consists of placebo 
in combination with azacitidine. 
Objectives
Primary Objective:
To show superiority in terms of overall survival (OS) of treatment with 
pracinostat (Group A – experimental group) versus placebo (Group B –
control group) in patients treated with AZA as background therapy.
Secondary Objectives:

To describe the efficacy of pracinostat  evaluating additional efficacy 
variables 

To assess the safety and tolerability

To evaluate the pharmacokinetics of pracinostat and its main metabolites

To assess the possible drug interaction of Pracinostat on the PK of 
Azacitidine

To perform a health-economic evaluation of treatment and control group
Study 
Treatments

Group A (experimental): pracinostat + background therapy
Pracinostat: one 60 mg capsule orally, once a day, 3 times a week (e.g., 
Monday, Wednesday, and Friday) for 3 weeks, followed by 1 week of 
rest during each 28-day cycle. 

Group B (control): placebo + background therapy 
Placebo: 1 capsule orally, once a day, 3 times a week (e.g., Monday, 
Wednesday, and Friday) for 3 weeks, followed by 1 week of rest during
each 28-day cycle.
As background therapy azacitidine (AZA) will be administered to both 
treatment groups at a dose of 75 mg/m2 by SC or IV injection daily for 7 days 
of each 28-day cycle.
Pracinostat/placebo oral administration is to be taken before injection of 
azacitidine.
Dose reduction of pracinostat/placebo, AZA, or both, are allowed in patients 
who develop drug-related toxicities.


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Study 
Population
Inclusion Criteria:
Patients must meet the following criteria for study entry:
1. Male or female patient ≥ 18 years of age with newly diagnosed, 
histologically or cytologically confirmed, AML including de novo, 
secondary to antecedent hematologic disorders, or treatment-related 
disease with intermediate or unfavorable risk cytogenetics (Appendix B)
2. Unable to receive intensive chemotherapy regimens at enrollment, based 
on one of the following:
I.
Age ≥ 75 years, or
II.
Age < 75 years with at least 1 of the following co-morbidities:
a.
An ECOG performance status of 2
b. Clinically significant cardiovascular disease defined as:
i.
Left ventricular ejection fraction (LVEF) ≤ 50%, 
measured within 3 months prior to Day 1 confirmed by 
ECHO/MUGA
ii.
Congestive heart failure requiring medical therapy
iii.
Chronic stable angina requiring medical therapy
iv.
Prior cerebrovascular accident with sequelae
c.
Clinically significant pulmonary disease defined as:
i.
Forced expiratory volume in 1 second (FEV1) ≤ 65% of 
expected
ii.
Lung diffusing capacity for carbon monoxide (DLCO) ≤ 
65% of expected
Confirmed by pulmonary tests within 3 months prior to 
Day 1.
d. Diabetes mellitus with symptomatic end-organ damage (e.g., 
retinopathy, nephropathy, neuropathy, vasculopathy)
e.
Autoimmune inflammatory conditions (e.g., rheumatoid 
arthritis, systemic lupus erythematous, inflammatory bowel 
disease, or similar) requiring chronic disease modifying 
therapy (e.g., etanercept, adalimumab, infliximab, rituximab, 
methotrexate, or similar)
f.
Class III obesity defined as a Body Mass Index (BMI) > 40 
kg/m2
g. Renal impairment defined as serum creatinine > 1.3 mg/dL (> 
115 µmol/L) or creatinine clearance <70 ml/min, but still 
fulfilling criterion #7
3.
20% blasts in bone marrow
4.
Peripheral white blood cell (WBC) count 30,000/µL
For cyto-reduction, hydroxyurea is allowed during screening and 
up to Cycle 1, Days 1-14, to reduce WBC count to < 30,000 µL


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prior to Day 1. After Cycle 1, Day 14, hydroxyurea is prohibited.
5. ECOG performance status ≤ 2
6.
Adequate organ function as evidenced by the following laboratory 
findings:
a.
Total bilirubin ≤ 2 × upper limit of normal (ULN) or < 3 x 
ULN for patients with Gilbert-Meulengracht Syndrome
b. Aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase (ALT) ≤ 2.5 × ULN
7.
Serum creatinine ≤ 1.5 × ULN according to institutional standards or 
creatinine clearance ≥ 50 mL/min 
8.
QT-interval corrected according to Fridericia’s formula (QTcF) ≤450 ms 
on electrocardiogram (ECG) at Screening
9. Male patient who is surgically sterile, or male patient who is willing to 
agree with the true abstinence (refrain from heterosexual intercourse) or 
who uses barrier contraceptive measures during the entire study treatment 
period and for 3 months after the last administration of study drug, and 
agree to refrain from donating sperm during the entire study treatment 
period and for 3 months after the last administration of study drug
(Appendix J)
10. Female patient who is of childbearing potential willing to use a highly 
effective contraceptive measure while participating on study, OR willing 
to agree with the true abstinence from heterosexual intercourse during the 
entire study treatment period and for 3 months after the last 
administration of study drug (Appendix J) 
11. Female patient who is of childbearing potential must have a negative 
serum pregnancy test result within 1 week prior to starting study drug. 
12. Willing to provide voluntary written informed consent before 
performance of any study related procedure not part of normal medical 
care 
13. Willing and able to understand the nature of this study and to comply 
with the study and follow-up procedures.
Exclusion Criteria:
Patients who meet any of the following criteria will be excluded from study 
entry:
1. Able to receive intensive induction chemotherapy 
2. AML-associated inv(16)/t(16;16)/del(16q), t(15;17) (i.e., promyelocytic 
leukemia) with/without secondary aberrations; t(8;21) lacking del (9q) or 
lacking complex karyotypes
3. Presence of an active malignant disease within the last 12 months, with 
the exception of adequately treated cervical cancer in-situ, non-melanoma 
skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis 


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[carcinoma in situ] and T1 [tumor invades lamina propria]). Other 
malignancies may be considered after consultation with the Medical 
Monitor
4. Life-threatening illnesses other than AML, uncontrolled medical 
conditions or organ system dysfunction that, in the Investigator’s opinion, 
could compromise the patient’s safety or put the study outcomes at risk
5. Uncontrolled arrhythmias; any Class 3-4 cardiac diseases as defined by 
the New York Heart Association (NYHA) functional classification 
(Appendix E)
6. Evidence of AML central nervous system (CNS) involvement
7. Previous therapy for AML except for the following, which are allowed:
a.
Hydroxyurea for cytoreduction
b. One course of hypomethylating agent therapy (i.e.; up to 7 doses 
of azacitidine or 3-5 days of decitabine) within 30 days prior to 
enrollment (Day 1)
8. Use of experimental drugs ≤ 30 days prior to screening
9. Received any prior HDAC inhibitor therapy
10. Received prior treatment with a hypomethylating agent, except as allowed 
in Exclusion Criterion 7.b
11. Known hypersensitivity to any components of pracinostat, azacitidine, or 
mannitol
12. Human immunodeficiency virus (HIV) infection or an active and 
uncontrolled infection with hepatitis C virus (HCV) or hepatitis B virus 
(HBV)
13. Gastrointestinal (GI) tract disease that causes an inability to take oral 
medication, malabsorption syndrome, or a requirement for IV 
alimentation; prior surgical procedures affecting absorption; or 
uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative 
colitis)
14. Any disease(s), psychiatric condition, metabolic dysfunction, or findings 
from a physical examination or clinical laboratory test result that would 
cause reasonable suspicion of a disease or condition, that contraindicates 
the use of pracinostat and/or AZA, that may increase the risk associated 
with study participation, that may affect the interpretation of the results, or 
that would make the patient inappropriate for this study
15. Breast-feeding woman
16. Current smokers (use of patches, chewing gums or vaping nicotine 
containing fluids is permitted). Patients who stopped smoking at least 8 
days prior to first pracinostat dosing can be enrolled, provided they refrain 
from smoking during the whole study.
17. Prohibited concomitant medications
18. Uncontrolled infections


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19. Received more than 1 prior cycle of HMA or bone marrow transplant for 
any prior hematological disorder antecedent to AML.
Length of 
Study
The study duration is dependent on reaching 390 events (deaths) for final 
survival analysis. It is assumed that recruitment will occur over a 30-months 
period with 18 additional months to reach 390 events.
Patients still on treatment or in follow up at the time of 390 events will enter 
the Post-Study Observation Period of 24 months.
Assessments 
and 
Endpoints
Efficacy assessments:

Bone Marrow Aspirate/biopsy
Bone marrow aspirate/biopsy sample will be collected for:
o
morphologic diagnosis of AML and evaluation of morphologic 
response to therapy
o
Classical cytogenetic analysis (karyotyping) to assess cytogenetic 
risk category and allow stratification by cytogenetic risk factor 
(intermediate vs. unfavorable) at randomization and to evaluate 
cytogenetic response to therapy in patients with abnormal 
cytogenetics at baseline
o
MRD evaluation by MFC
o
Biobanking for mutational analysis
Bone marrow aspirate/biopsy samples are to be collected at screening and 
then at the end of every even cycle, in order to evaluate the disease response 
to therapy at the beginning of each odd cycle. Response evaluation 
assessment is required until a morphologic complete response is achieved and 
confirmed after 2 further cycles of treatment. At subsequent cycles, bone 
marrow response evaluation is no longer required, unless there is a suspicion 
of disease progression or relapse.
MRD evaluation will be performed on bone marrow blood only at screening 
and after 2 cycles from first CR.
A small quantity of bone marrow blood will be collected and stored in all 
patients for potential analysis of mutations of six genes known to have a 
prognostic impact in patients affected by AML: NPM1, FLT3, CEBPA, 
RUNX1, ASXL1, TP53.

RBC and platelet transfusions
Information regarding red blood cell and platelet transfusions is to be 
collected on a regular basis.

Quality of Life using the EORTC QLQ-C30 questionnaire
The questionnaire is to be administered to the patients during the first visit of 
each odd cycle. 
Safety assessments:
The following safety assessments will be obtained: physical examination, 


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vital signs, 12-lead electrocardiogram (ECG), laboratory test (hematology 
and blood chemistry), and adverse events (AEs) assessments.
During the conduct of the study, an Independent Data Monitoring Committee
will periodically review safety data.
Pracinostat Population PK assessments:
PK samples are collected in all patients (except for patients participating in 
AZA/Pracinostat PK sub-study) to characterize the pracinostat population PK 
and assess the effect of drug exposure on safety and efficacy.
The following PK samples are to be collected post pracinostat/placebo 
administration:

30 minutes ± 15 minutes

3 hours ± 30 minutes

6 hours ± 30 minutes

24 hours ± 1 hour  (before azacitidine)

48 hours ± 2 hours (before next pracinostat dose)

Day 15 (any time within 24 h after pracinostat dosing for the day)
AZA/Pracinostat PK sub-study (IN SELECTED SITES ONLY):
Assessment of the possible drug interaction of pracinostat on the PK of 
azacitidine.
The azacitidine PK in individual patients with/without the concomitant 
administration of pracinostat will be studied in two groups of at least 12 
patients each.
Blood samples will be collected at the following time points on Cycle 1 Day 1 
after start of AZA administration:

15 minutes ± 2 minutes

30 minutes ± 2 minutes

1 hour ± 5 minutes

2 hours ± 5 minutes

3 hours ± 5 minutes

4 hours ± 5 minutes

6 hours ± 30 minutes  

8 hours ± 30 minutes (optional sampling)
On Cycle 1 Day 2 before start of AZA administration:

24 hours ± 1 hour
Two additional blood samples will be collected at the following time points 
on Cycle 1 Day 3 and Day 15:

48 hours ± 2 hours (before next pracinostat dose intake)


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
Day 15 (any time within 24 h after pracinostat dosing for the day)
Efficacy Endpoints:

Primary Endpoint
The primary efficacy endpoint is the overall survival (OS), as measured from 
the time of randomization until death from any cause.

Secondary Endpoints
Morphologic Complete Remission (CR) rate
Transfusion independence
Complete Remission without minimal residual disease (CRMRD-) rate
Cytogenetic Complete Remission (CRc) rate

Exploratory Endpoints
Composite Complete Remission (cCR) rate
Relapse Free Survival (RFS) 
Progression free survival
Duration of Morphologic Complete Remission
Duration of Composite Complete Remission
Time to CR
CR within 6 cycles
Quality of Life
PK Endpoints:

To characterize the pharmacokinetics (PK) of pracinostat and its main 
metabolites in AML patients by a population pharmacokinetic approach

To characterize demographic, physiopathological and therapeutic 
covariates that may influence pracinostat PK parameters and their 
interindividual variability

To characterize the pracinostat exposure-response relationship for safety 
and efficacy endpoints (PK/PD)

To assess the possible drug interaction of pracinostat on the PK of AZA in 
AML patients by comparing the descriptive statistics of PK parameters of 
azacitidine in the two groups
Statistical 
Analyses
Sample Size: 
This is an event-driven study. Sample size was computed for a group-
sequential design with stopping rules for both futility and superiority (study-
wise one-sided alpha level=0.025, power 0.90) with one interim analysis at 
67% (2/3) of information and a final analysis. The error spending function is 
from the Gamma Family using γ=-3.6 (similar to O’Brien Fleming) for 
superiority and γ=-5.5 (more conservative than O’Brien Fleming) for futility 


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(non-binding). Proportionality of hazards is assumed. Assuming that median 
OS is 10.0 months in the Group B (placebo + AZA) the aim is to detect, by 
means of the log-rank test or equivalent, an increase to 14.0 months in Group 
A (pracinostat + AZA), i.e., a HR of 0.714. A total of 390 events (deaths) 
allows to meet a power requirement of at least 90% (actually 90.78%) at a 
study-wise one-sided significance level of 0.025. 
Interim Analysis:
An interim analysis at 67% (2/3) of information (260 over 390 events 
(deaths), being the study event-driven) will be performed for both futility and 
superiority.
Statistical Evaluation: 
Summary statistics for continuous variables will include the mean, standard 
deviation, median and range (minimum/maximum). Categorical variables 
will be presented as frequency counts and percentages, and time-to-event 
variables will be summarized using Kaplan-Meier estimates including 
median with 95% CI, number of events, number censored. Data listings will 
be created to support each table and to present all data.
The primary efficacy endpoint of overall survival will be analyzed using the 
intent-to-treat (ITT) set. Inferential statistical analysis for treatment group 
differences will be based on the stratified log-rank test at the alpha = 0.025 
level of significance (one-sided) including the stratification factors used for 
randomization. The unadjusted analysis will be performed as sensitivity 
analysis.
Secondary endpoints will be tested according to a fixed sequence method. If 
the primary endpoint is statistically significant, then the first secondary 
endpoint will be tested, and so on for the other three secondary endpoints. A 
group-sequential procedure will be applied also to the secondary endpoints.
Safety analyses will be performed on the Safety Set. Safety variables 
including treatment-emergent adverse events, laboratory tests, vital signs, 
and ECGs, will be summarized using appropriate descriptive statistics by 
treatment group. 
The statistical analysis plan will provide full details of all planned analyses.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
Adverse Event
ALP
ALkaline Phosphatase
ALT
ALanine aminoTransferase
AML
Acute Myeloid Leukemia
ANC
Absolut Neuthrophils Count
Anti-HBc
Antibody against hepatitis B core antigen
Anti-HBs
Antibody against hepatitis B surface antigen
AST
ASpartate aminoTransferase
AUC
Area Under the Curve
AZA
AZAcitidine
BM
Bone Marrow
BMI
Body Mass Index
BSA
Body Surface Area
BSC
Best Supportive Care
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CCI
Charlson Comorbidity Index
cCR
Composite Complete Remission
CI
Confidence Interval
CL
Plasma CLearance
CNS
Central Nervous System
CO2
Carbon diOxide
CR
(Morphologic) Complete Remission
CRc
Cytogenetic Complete Remission
CRi
Morphologic Complete Remission with incomplete blood count 
recovery
CRMRD-
Complete Remission without minimal residual disease


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Abbreviation
Definition
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
DLCO
Lung Diffusion Capacity for carbon monoxide
DMC
Data Monitoring Committee
DNA
DeoxyriboNucleic Acid
DR
Duration of Response
EC
Ethics Committee
ECG
ElectroCardioGram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
e.g.
For example
EMA
European Medicines Agency
EORTC
European Organization for Research and Treatment of Cancer
EU
European Union
FAB
French-American-British classification
FEV1
Forced Expiratory Volume in 1 second
FDA
Food and Drug Administration
FISH
Fluorescence based In Situ Hybridization
GCP
Good Clinical Practice
GI
GastroIntestinal
GMP
Good Manufacturing Practice
HBV
Hepatitis B Virus
HBsAg
Hepatitis B surface Antigen 
HCT-CI
Hematopoietic Cell Transplant Comorbidity Index
HCV
Hepatitis C Virus
HDAC
Histone DeACetylases
HDACi
Histone DeACetylases inhibitors
HIV
Human Immunodeficiency Virus


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Abbreviation
Definition
HMA
HypoMethylating Agent
HR
Hazard Ratio
HSCT
Hematopoietic Stem Cell Transplant
IB
Investigator Brochure
IC50
half maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IDMC
Independent Data Monitoring Committee
ITT
Intent To Treat
IND
Investigational New Drug (application)
INR
International Normalized Ratio
IRB
Institutional Review Board
IV
IntraVenous
IWG
International Working Group
IWRS
Interactive (voice and) Web Response System
K2EDTA
Di-potassium ethylenediaminetetraacetic acid
LC
Liquid Chromatography
LDAC
Low Dose Cytarabine
LDH
LactatDeHydrogenase
LVEF
Left Ventricular Ejection Fraction
MDS
MyeloDysplastic Syndrome
MedDRA
Medical Dictionary for Drug Regulatory Activities
MedPT
(MedDra) Preferred Term
MFC
Multi-flow cytometry
MLFS
Morphologic Leukemia Free State
MRD
Minimal Residual Disease
MS
Mass Spectrometry
MTD
Maximum Tolerated Dose


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Abbreviation
Definition
Na-Heparin
Heparin Sodium
NCI
National Cancer Institute
NYHA
New York Heart Association
OS
Overall Survival
PD
Progressive Disease
PE
Physical Examination
PH
Proportional Hazards
PK
PharmacoKinetic
PK/PD
PharmacoKinetic/Pharmacodynamic
PP
Per Protocol
PLT
Platelet 
PR
Partial Remission
Pri
Partial Remission w incomplete blood count recovery
PS
Performance Status
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
RAEB
Refractory Anemia with Excess Blasts
RAEB-T
Refractory Anemia with Excess Blasts in Transformation
RBC
Red Blood Cell
RFS
Relapse Free Survival
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
SubCutaneous
SD
Stable Disease
SOC
(MedDra) System Organ Class
SOP
Standard Operating Procedure
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction


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Abbreviation
Definition
SWOG
SouthWest Oncology Group
TEAE
Treatment-Emergent Adverse Event
THU
Tetrahydrouridine
ULN
Upper Limit of Normal
QTc
QT interval corrected 
QTcF
QT interval corrected using Fridericia’s formula
US
United States of America
vs.
Versus
WBC
White Blood Cell
WHO
World Health Organisation


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1
INTRODUCTION
1.1
Overview of Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a heterogeneous group of malignancies of the bone 
marrow. The underlying AML pathophysiology involves a maturational arrest of bone 
marrow cells in the earliest stages of development of the myeloid-cell lineage. The
mechanism of this arrest is poorly understood and involves in many cases the activation 
of abnormal genes through chromosomal translocations and other genetic abnormalities.
Approximately about 21,380 new cases and 10,590 deaths from AML are expected to 
occur in the United States (US) in 2017, with the disease most commonly diagnosed in 
older people [American Cancer Society, 2017]. According to the Surveillance of Rare 
Cancers in Europe (RARECARE) project, the incidence of AML in Europe is 3.7 per 
100,000 [Visser, 2012], similar to an incidence in the US of 4.1 per 100,000 based on 
2009-2013 cases [SEER 2016] The average age of patients with AML is 67 years
[American Cancer Society, 2017]. AML is a rapidly progressing disease, often fatal, and 
survival among elderly patients is typically short. Population-based studies have reported 
3-year survival rates of 9% to 10% in patients 60 years of age, compared with 5-year 
survival rates of up to 50% for patients <60 years [Luger, 2010]. This poor survival 
expectancy applies to approximately half of adult patients with AML, in that the median 
age at onset is 65 to 70 years [Estey, 2014].
Curative therapy for AML, excluding acute promyelocytic leukemia, consists of intensive 
anthracycline-based remission induction therapy, followed by post remission treatment 
intensification, including myeloablative therapy and hematopoietic stem cell transplant 
(HSCT). As AML is a disease of older people, many patients diagnosed with AML are 
unable to undergo intensive (curative) therapies due to co-morbid conditions and/or poor 
performance status [Estey, 2002]. In addition, a small proportion of younger patients with 
AML are unable to receive intensive chemotherapy regimens because of their medical 
history or concurrent comorbidities that expose them to an increased risk of fatal 
complications following induction chemotherapy.
In the US, there are currently no drugs approved to treat AML in patients who are unfit
for intensive induction chemotherapy. Therefore, participation in clinical studies
investigating less toxic and potentially effective therapeutic agents is important for these 
patients. In the EU, hypomethylating agents (HMAs) (Dacogen® - decitabine, Vidaza® -
azacitidine) are approved for the treatment of adult patients who are not candidates for 
intensive induction chemotherapy or for hematopoietic stem cell transplant. The efficacy 
of HMAs alone in this patient population, however, is modest and further improvement is 
needed. Other approaches for treatment of medically unfit patients with AML include 
low dose cytarabine (LDAC), clofarabine, and supportive care. As a result, new treatment 
approaches are needed for this patient population. 


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1.2
Histone deacetylase inhibitors and Hypomethylating agents
The importance of epigenetic processes, especially those resulting in the silencing of key 
regulatory genes, has led to the realization that genetics and epigenetics cooperate at all 
stages of cancer development [Jones & Baylin, 2007].
Histone deacetylases (HDACs) are enzymes involved in the remodeling of chromatin and 
therefore have a key role in the epigenetic regulation of gene expression. Abnormal 
epigenetic silencing of important regulatory genes has been described in cancer, 
including myelodysplastic syndrome (MDS) and AML. Histone deacetylase inhibitors 
(HDACi) have been extensively studied in both hematologic malignancies and solid 
tumors. In the US, four HDACi have been approved, all for the treatment of lymphoid 
malignancies such as cutaneous T-cell lymphoma (vorinostat and romidepsin), peripheral 
T cell lymphoma (belinostat), or multiple myeloma (panobinostat). No HDACi has been 
approved in the treatment of myeloid malignancies.
Studies have shown that AML cells demonstrate widespread hypermethylation of DNA 
promoter regions and that such hypermethylation leads to selective gene silencing. These 
observations led to the development of HMAs, such as azacitidine and decitabine, which 
were designed to reverse the hypermethylation and normalize gene expression, 
particularly in hematologic malignancies. Both of these agents have demonstrated clinical 
benefit in MDS, but have failed to provide sufficient clinical benefit in AML.
The therapeutic potential of combining HDACi’s and HMAs has been studied 
extensively in pre-clinical models, and synergistic interactions have been described 
[Cameron, 1999]. 
1.3
Background on Pracinostat
Pracinostat is a rationally designed, potent, oral, pan-HDAC (including Class I, II, and IV 
isoforms) inhibitor with favorable pharmacokinetic (PK) properties. In preclinical studies, 
the activity of pracinostat has been shown in xenograft tumor models of AML and 
synergistic interactions have been observed with multiple cytotoxic and targeted anti-
cancer therapeutics, including azacitidine (Investigator’s Brochure). More specifically, 
the IC50 of pracinostat across a broad range of human cancers in in-vitro cytotoxicity 
assays ranged from 0.05 to 2.2 μM, with the lowest values noted in leukemia and 
lymphoma cell lines. Notably, the combination index with azacitidine (AZA) ranged 
from 0.44 to 0.55.
Pracinostat has been administered to more than 400 patients, with both solid tumors and 
hematologic cancers, in multiple Phase I and Phase II clinical studies. The initial safety 
data for pracinostat monotherapy, which established the single-agent maximum tolerated 
dose (MTD) and recommended Phase II dose level of 60 mg was derived from Study 
SB939-2006-001. 
SB939-2006-001 was a Phase 1 open-label dose-escalation cohort study of pracinostat in 
subjects with advanced solid tumors (Arm A) and advanced hematologic malignancies 
including MDS, AML, lymphoma and myeloproliferative disorders (Arm B). The 
objectives of the trial included determining the DLTs and MTD of this drug when 
administered as a single agent, orally, once daily, every other day 3 times a week, for 3 


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consecutive weeks followed by 1 week rest, for a 28-day treatment cycle. The MTD of 
pracinostat in Arm A (solid tumors) was established, and the recommended dose is 60 
mg/d.  In Arm B (hematologic malignancies), the protocol defined MTD was not reached. 
Dose reductions in subjects at the 120 mg/d level prompted the decision to end the dose 
escalation phase, designate the 120 mg/d level as the MTD, and identify the 
recommended dose to be 100 mg/d. However, long-term exposure at 100 mg/d was not 
well tolerated and the recommended dose in subsequent hematologic malignancy studies 
was determined to be 60 mg/d.  
SB939-2006-001 Arm C investigated the safety and tolerability at the recommended dose 
of pracinostat (SB939) (60 mg/d) combined with standard azacitidine therapy in subjects 
with intermediate- or high-risk MDS.  Pracinostat was administered orally once daily 
every other day 3 times a week for 3 consecutive weeks followed by a 1 week rest, for a 
28 day treatment cycle.  Azacitidine 75 mg/m2 was administered SC on days 1‒5 every 
3‒6 weeks. Ten subjects (7 female, 3 male) were enrolled with a median age of 65 years 
(range, 18 to 73 years).  There were no DLTs in this study [Quintás-Cardama , 2012].
The most common adverse events (all grades) from the Phase I and Phase II clinical 
studies of single-agent pracinostat included thrombocytopenia (44%), fatigue (42%), 
nausea (32%), anemia (30%), and neutropenia (29%). While the most common clinically 
important (Grade 3) adverse events (AEs) included thrombocytopenia (13%), fatigue 
(9%), neutropenia (9%), and QT prolongation (5%) (Investigator’s Brochure). These data 
collectively support a single-agent dose and schedule of 60 mg, orally, given 3 times a 
week, every other day for 3 consecutive weeks followed by 1 week of rest and repeated 
in 28-day cycles. Two of 15 patients with AML treated in Arm B achieved a CR lasting 
206 and 362 days.
These patients were enrolled at the 80 mg/day and 120 mg/day dose levels, respectively.
One responder required 2 dose reductions due to Grade 3 fatigue, but went on to 
complete 11 cycles before his death from chronic obstructive pulmonary disease 
unrelated to pracinostat. The second responder sustained a cytogenetic complete 
remission (CRc) from Cycle 4 onward and was judged as no longer requiring treatment 
after completing Cycle 8. These data suggest that single-agent pracinostat provides 
modest clinical activity in AML.
On the basis of these SB939-2006-001 data, an open-label Phase II study (Protocol MEI 
004) has been conducted to evaluate the safety and efficacy of pracinostat plus AZA in 
patients ≥65 years with newly diagnosed AML who were not eligible to receive intensive 
induction chemotherapy [Garcia-Manero, 2019]. Pracinostat and AZA administration 
regimen was the same selected in the SB939-2006-001. Pracinostat was administered at a 
dose of 60 mg every other day, 3 days a week for 3 weeks of every 28-day cycle. AZA 
was administered according to the approved prescribing information. Between December 
2013 and November 2014, a total of 50 patients were enrolled at 15 academic centers in 
the US. Median age was 75 years (range, 66-84), with 26 patients (52%) aged ≥ 75 years. 
CR was achieved in 21 patients (42%), a CRi in 2 (4%) and MLFS in 3 (6%), resulting in 
a composite complete remission (cCR) rate, the study primary endpoint, of 52%. As of 
October 2016 the median overall survival was estimated at 19.1 months (95% CI: 10.0 -
26.5 months). Grade ≥ 3 adverse events (AEs) reported in > 10% of patients were 


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thrombocytopenia (46%), febrile neutropenia (44%), neutropenia (38%), fatigue (34%), 
and anemia (30%). There have been two deaths on study considered related to both 
pracinostat and azacitidine (neutropenic sepsis and febrile neutropenia).
See the pracinostat Investigator’s Brochure for additional details on nonclinical and 
clinical studies. 
1.4
Background on Azacitidine in AML
Azacitidine was approved by the Food and Drug Administration (FDA) in 2004 and the 
European Medicines Agency (EMA) in 2008 for the treatment of patients with MDS of 
all French-American-British classification (FAB) subtypes [Vidaza® SmPC, 2017]. Of
note, patients with the FAB classification of RAEB-T are considered to meet criteria for 
AML under the newer World Health Organization (WHO) classification, when the bone 
marrow blast count is 20% or more [Vardiman, 2009].
Azacitidine is approved in the EU [Vidaza® SmPC, 2017] for a subset of patients with 
AML, based on two studies. In a retrospective analysis of a study of 358 patients with 
higher risk MDS which included 113 patients with bone marrow blasts between 20% and 
30% [Fenaux, 2009], azacitidine was compared to best supportive care (BSC), BSC + 
LDAC, or intensive chemotherapy. This study demonstrated an improvement in overall 
survival (OS) (HR=0.47, p=0.005) in the subset of 113 patients with baseline blasts 
between 20% and 30%. Another Phase 3 study was conducted exclusively in patients 
aged ≥ 65 years with AML (>30% marrow blasts) who were not candidates for HSCT 
[Dombret, 2015]. This study compared azacitidine to BSC, BSC + LDAC, or intensive 
chemotherapy. The results showed no difference in response rates (CR+CRi: 28% vs. 
23%, p=NS) and a trend toward improved overall survival (10.4 vs. 6.5 months; HR=0.85, 
p=0.1009 for Azacitidine group vs. the composite group). Based on these results, 
azacitidine is considered as a standard of care in elderly patients with AML, also in 
countries where azacitidine has not been approved for this indication [National 
comprehensive Cancer Network Guidelines Acute Myeloid Leukemia. Version 1. 2016.].
It should be noted that 18% of the patient population in the azacitidine study in elderly 
AML [Dombret, 2015] were assigned to receive intensive chemotherapy (not delineated 
by age groups) such that the overall prognosis of this study population (both the control 
and experimental groups) may be superior to other studies of AML in the elderly 
population that did not permit intensive chemotherapy as a control treatment option [e.g., 
Kantarjian, 2012; Thepot , 2014].
1.5
Benefit-Risk Assessment
Population-based studies of patients aged 60 years and older have shown 3-year survival 
rates between 9% and 10% and 5-year survival rates from 3% to 8% [Luger, 2010].
Despite treatment advances in the last decade, the prognosis for older patients remains 
dismal, and there are only a few approved agents for patients who are unable to tolerate 
intensive chemotherapy. Thus, there is a great need to explore combinations of novel 
agents to improve outcomes in this population. 


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2
STUDY OBJECTIVES
2.1
Primary Objective
To show superiority in terms of overall survival (OS) of treatment with pracinostat 
(Group A – experimental group) versus placebo (Group B – control group) in patients 
treated with AZA as background therapy.
2.2
Secondary Objectives

To describe the efficacy of pracinostat by evaluating additional efficacy variables 

To assess the safety and tolerability

To evaluate the pharmacokinetics of pracinostat and its main metabolites

To assess the possible drug interaction of Pracinostat on the PK of Azacitidine

To perform a health-economic evaluation of treatment and control group


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3
STUDY PLAN
3.1
Study Design
This is a Phase III, double-blind, placebo-controlled, multicenter, randomized study of 
pracinostat in combination with azacitidine (AZA) in patients ≥18 years of age with 
newly diagnosed acute myeloid leukemia (AML) not fit to receive intensive induction 
chemotherapy. 
A maximum of 500 patients are planned to be enrolled over a period of approximately 30 
months at approximately 130 study centers. Patients who meet the eligibility criteria and
consent to participate will be randomized 1:1 to Group A (experimental group) or Group 
B (control group). Randomization will be stratified by cytogenetic risk category
(intermediate vs. unfavorable risk) and ECOG Performance Status (0-1 vs. 2).
Study treatment, defined as the treatment with pracinostat/placebo (study drug) in 
addition to the background therapy (AZA), will continue until there is documented 
disease progression or relapse from CR while receiving study treatment, or non-
manageable toxicity. There is no upper limit to the number of treatment cycles 
administered, and study treatment should be continued as long as patients derive a 
clinical benefit. 
In the Phase II study MEI-004, 6 patients (12%) required more than 6 cycles of 
pracinostat + AZA to achieve a CR. It is recommended, therefore, that patients who have 
no evidence of disease progression should receive a minimum of 6 cycles of study 
treatment to allow adequate exposure to study drug and background therapy before 
considering a switch to other therapies. 
Once permanently discontinued from study treatment, patients will be followed for AEs 
(for 30 days) and then they will enter the Long-term Follow-up phase of the study 
(Section 5.2). Patients in the Long-term Follow-up phase of the study will be followed 
every 3 months (±1 month) for documentation of disease progression, if applicable, and 
overall survival. Patients will be followed until death or until end of this study (refer to 
Section 3.2 for end of this study definition).
Based on data from previous studies, it is anticipated that patient participation in the main 
part of this study will be for an average of 9.5 months, including 28 days for screening 
procedures, 8 months for study treatment, and 4 weeks for safety follow-up after 
permanent study treatment discontinuation. In the Phase III study of azacitidine in elderly 
AML, patients received a median of 6 cycles of azacitidine, with a range from 1 to 28 
cycles (Dombret, 2015). In the Phase II study of pracinostat in elderly AML (Study MEI-
004), patients received a median of 6.5 cycles, with a range from 1 to 24 cycles. It is 
anticipated that patient participation in the Long-term Follow-up phase will be for an 
average of 6 months, but may exceed 12 months in some patients.
This is an event-driven study with an interim analysis for both futility and superiority.


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The Schedule of Assessments is provided in Appendix A. 
Figure 1 displays the study schema. 
Figure 1:
Study Schema
3.2
End of Study
The end of this study is defined when 390 events (deaths) have occurred. Patients who 
are receiving study treatment at the end of the study will continue to receive the study 
drug to which they were randomized to (Post-Study Observation Period, Section 5.3), 
until the Sponsor informs the Investigators of the appropriate course of action, based on 
the study results.
The study may be ended earlier, based on the results of the interim analysis (Section 
9.12). In this case the patients still on study will continue unchanged until the Sponsor 
informs the Investigators of the appropriate course of action, based on the study results.
3.3
Study Rationale
The higher complete remission (CR) rate and longer OS observed in the open-label Phase 
II study of pracinostat plus AZA in patients ≥65 years with newly diagnosed AML 
compared to historical controls treated with AZA alone, as well as the aggregate safety 
data from over 150 patients treated with pracinostat plus azacitidine in 4 studies support 
the evaluation of this combination regimen in a double-blind, placebo controlled, 
randomized Phase III trial in AML. 
3.3.1
Rationale for Patient Population
This Phase III study will enroll patients ≥18 years of age with newly diagnosed de novo
or secondary AML who are unfit to receive standard induction chemotherapy due to 
advanced age and/or comorbidities. Secondary AML is defined as secondary to 
antecedent hematologic disorders such as myelodysplastic or myeloproliferative disorders,
or occurring in a patient who has received chemotherapy and/or radiation therapy for a 
prior malignancy. It is anticipated that the median age of the study population will be 
approximately 75 years and that few patients under 65 years of age will be enrolled. This 
population is considered appropriate for this Phase III study, given the limited treatment 
Group A: 
Pracinostat + background 
therapy (AZA)
N ~ 250
Group B: 
Placebo + background 
therapy (AZA)
N ~250
Randomization
N ~ 500
Long-term
Follow-up
Long-term
Follow-up


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options and poor outcome for these patients, whose risk: benefit profile for intensive 
induction therapy is rarely favorable [Kantarjian, 2010; Pastore, 2014]. 
3.3.2
Rationale for Definition of Ineligibility for Intensive Induction 
Chemotherapy
Selection of the most appropriate treatment option for an individual patient with AML is 
best determined by the treating physician in agreement with the patient based on 
thorough risk:benefit assessment. However, general principles that define ineligibility for 
intensive therapy regimens can be delineated in the context of clinical trials.
An expert panel has developed a consensus-based definition of patient unfitness to 
intensive AML induction chemotherapy [Ferrara, 2013]. Factors considered relevant to 
defining unfitness to intensive induction chemotherapy include severe cardiac, pulmonary, 
renal or hepatic comorbidity, cognitive impairment, poor performance status, and any 
other comorbidity that the physician judges to be incompatible with chemotherapy. 
Another group has developed a hematopoietic cell transplant specific comorbidity index 
(HCT-CI) to define patient unfitness to receive myeloablative therapy for AML [Sorror, 
2005]. The HCT-CI was evaluated retrospectively in a cohort of older patients with AML 
[Giles, 2007] and validated in a large cohort of patients with myelodysplastic syndrome 
[Della Porta , 2011]. Another retrospective analysis of a cohort of 5’480 patients with 
AML treated between 2000 and 2007 in the US identified age and Charlson comorbidity 
index (CCI) as significantly associated with early death after leukemia therapy [Oran B, 
2012]. This protocol uses a compilation of these previously published criteria to 
characterize patient unfitness for intensive induction chemotherapy.
Several studies have shown a high rate of early death due to toxicity, ranging from 6% to 
18%, in elderly patients with AML treated with standard intensive
induction 
chemotherapy [reviewed in Luger, 2010]. Age ≥ 75 years is associated with particularly 
high risk of toxicity and has been used as prognostic scoring factor in AML [Kantarjian, 
2006; Appelbaum, 2006; Malfuson, 2008]. In this protocol, age ≥ 75 years with or 
without additional comorbidities is a sufficient criterion to characterize a patient as being 
unfit for intensive chemotherapy.
For fit patients < 75 years of age, intensive induction chemotherapy is the standard of 
care. Therefore, only patients who are considered unable to receive intensive induction 
chemotherapy due to comorbidities that preceded the diagnosis of AML will be eligible 
to be enrolled in the study. This includes poor performance status, significant impairment 
of cardiac function (a contraindication to anthracycline-based therapy), significant 
impairment of pulmonary function (a risk factor for respiratory failure in the presence of 
infection), or a chronic comorbidity with clinically significant functional impairment or 
end organ damage. 
The study excludes patients with acute promyelocytic leukemia, and AML patients with 
favorable cytogenetic risks, because they can be effectively managed with alternative 
standard therapies [Schiller, 2005]. 


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3.3.3
Clinical Rationale
The combination of pracinostat plus AZA was evaluated in a Phase II open-label, single-
arm, two-stage, multicenter study in patients aged 65 years with newly diagnosed AML 
(Study MEI-004). The favorable efficacy results of this study, with a CR rate of 42%, a 
composite complete remission (cCR) rate of 52%, and a median overall survival of 19.1
months, indicate that pracinostat plus AZA warrants further evaluation in a Phase III 
study in AML. 
Data from the recent Phase III study of azacitidine versus conventional care regimens in 
488 elderly patients with newly diagnosed AML revealed the following Grade 3 to Grade 
4 treatment emergent AEs with azacitidine: febrile neutropenia (28%), neutropenia 
(26.3%), thrombocytopenia (23.7%), pneumonia (19.1%), anemia (15.7%) leukopenia 
(6.8%), and hypokalemia (5.1%) [Dombret, 2015]. Thus, when comparing safety data 
from studies of single-agent AZA, single-agent pracinostat, and pracinostat + AZA in 
combination, the safety profiles appear to be similar. Importantly, no new events of 
special interest were identified in the combination as compared to single-agent AZA or 
pracinostat studies, suggesting that the combination is not more toxic than single-agent 
therapies.
The observations of strong pre-clinical synergy between AZA and pracinostat, and the 
improved efficacy results from the Phase II study in AML compared to historical controls 
treated with AZA alone, suggest the combination may provide important clinical benefit 
in the defined patient population. The combination dose and schedule selected for Phase 
II development was pracinostat 60 mg orally, given 3 times a week, every other day for 
3 consecutive weeks followed by 1 week of rest and repeated in 28-day cycles and 
azacitidine 75 mg/m2 IV or subcutaneous (SC) for 7 days of each 28-day cycle. The same 
regimen will be evaluated in this Phase III study.
Collectively, these safety, tolerability, and clinical activity data support the testing of this 
combination dose and schedule in a pivotal, fully powered Phase III study in patients who 
are newly diagnosed with AML and who are not currently candidates for intensive 
induction chemotherapy. 
3.3.4
Rationale for the Control Arm
Based on data from the azacitidine Phase III study in newly diagnosed patients with AML
aged ≥ 65 years who are unfit for stem cell transplant therapy [Dombret, 2015] and in 
patients with AML with 20-30% blasts [Fenaux, 2009], azacitidine [Vidaza® SmPC, 2017]
was approved in the EU for a subset of patients with AML. Retrospective studies of 
azacitidine in patients with AML unfit for intensive chemotherapy [Thepot, 2014; Pleyer , 
2015] justify the use of azacitidine as the background therapy and therefore its 
combination with pracinostat. In order to optimize the interpretation of the final results 
and to avoid bias in both safety and efficacy reporting, placebo in combination with 
azacitidine will be used as the control group.


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3.4
Eligibility and Enrollment
3.4.1
Inclusion Criteria
Patients must meet the following criteria for study entry:
1. Male or female patients ≥ 18 years of age with newly diagnosed, histologically or 
cytologically confirmed, AML including de novo, secondary to antecedent 
hematologic disorders, or treatment-related disease with intermediate or unfavorable-
risk cytogenetics (Appendix B)
2. Unable to receive intensive chemotherapy regimens at enrollment, based on one of 
the following:
I.
Age ≥ 75 years, or
II.
Age < 75 years with at least 1 of the following co-morbidities:
a. An ECOG performance status of 2
b. Clinically significant cardiovascular disease defined as:
i.
Left ventricular ejection fraction (LVEF) ≤50% measured 
within 3 months prior to Day 1, confirmed by ECHO/MUGA
ii.
Congestive heart failure requiring medical therapy
iii.
Chronic stable angina requiring medical therapy
iv.
Prior cerebrovascular accident with sequelae
c. Clinically significant pulmonary disease defined as:
i.
Forced expiratory volume in 1 second (FEV1) ≤ 65% of 
expected
ii.
Lung diffusing capacity for carbon monoxide (DLCO) ≤65% 
of expected
Confirmed by pulmonary tests within 3 months prior to Day 1. 
d. Diabetes mellitus with symptomatic end-organ damage (e.g., retinopathy, 
nephropathy, neuropathy, vasculopathy)
e. Autoimmune inflammatory conditions (e.g., rheumatoid arthritis, systemic 
lupus erythematous, inflammatory bowel disease, or similar) requiring 
chronic disease modifying therapy (e.g., etanercept, adalimumab, 
infliximab, rituximab, methotrexate, or similar)
f. Class III obesity defined as a Body Mass Index (BMI) > 40 kg/m2
g. Renal impairment defined as serum creatinine > 1.3 mg/dL (> 115 µmol/L)
or creatinine clearance < 70 mL/min, but still fulfilling criterion #7.
3. ≥ 20% blasts in bone marrow
4. Peripheral white blood cell (WBC) count 30,000/µL
For cyto-reduction, hydroxyurea is allowed during screening and up to 
Cycle 1, Days 1-14, to reduce WBC count to < 30,000 µL prior to Day 1. 
After Cycle 1, Day 14, hydroxyurea is prohibited.
5. ECOG performance status ≤ 2
6. Adequate organ function as evidenced by the following laboratory findings:


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a.
Total bilirubin ≤2 × upper limit of normal (ULN) or < 3 × ULN for 
patients with Gilbert-Meulengracht Syndrome
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 
2.5 × ULN
7. Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min according to 
institutional standards
8. QT-interval corrected according to Fridericia’s formula (QTcF) ≤ 450 ms on 
electrocardiogram (ECG) at Screening
9. Male patient who is surgically sterile, or male patient who is willing to agree with the 
true abstinence (refrain from heterosexual intercourse) or who uses barrier 
contraceptive measures during the entire study treatment period and for 3 months 
after the last administration of study drug, and agree to refrain from donating sperm
during the entire study treatment period and for 3 months after the last administration 
of study drug (Appendix J)
10. Female patient who is of childbearing potential willing to use a highly effective
contraceptive measure while participating on study, or willing to agree with the true 
abstinence from heterosexual intercourse during the entire study treatment period and 
for 3 months after the last administration of study drug (Appendix J) 
11. Female patient who is of childbearing potential must have a negative serum 
pregnancy test result within 1 week prior to starting study drug. 
12. Willing to provide voluntary written informed consent before performance of any 
study related procedure not part of normal medical care 
13. Willing and able to understand the nature of this study and to comply with the study 
and follow-up procedures.
3.4.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1. Able to receive intensive induction chemotherapy 
2. AML-associated inv(16)/t(16;16)/del(16q), t(15;17) (i.e., promyelocytic leukemia) 
with/without secondary aberrations; t(8;21) lacking del (9q) or lacking complex 
karyotypes
3. Presence of an active malignant disease within the last 12 months, with the exception 
of adequately treated cervical cancer in-situ, non-melanoma skin cancer and 
superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 
[tumor invades lamina propria]). Other malignancies may be considered after 
consultation with the Medical Monitor
4. Life-threatening illnesses other than AML, uncontrolled medical conditions or organ 
system dysfunction that, in the Investigator’s opinion, could compromise the patient’s 
safety or put the study outcomes at risk
5. Uncontrolled arrhythmias; any Class 3-4 cardiac diseases as defined by the New York 
Heart Association (NYHA) functional classification (Appendix E)
6. Evidence of central nervous system (CNS) involvement
7. Previous therapy for AML except for the following, which are allowed:


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a.
Hydroxyurea for cytoreduction
b. One course of hypomethylating agent therapy (i.e., up to 7 doses of 
azacitidine or 3-5 days of decitabine) within 30 days prior to enrollment
(Day1)
8. Use of experimental drugs 30 days prior to screening
9. Received any prior HDAC inhibitor therapy
10. Received prior treatment with a hypomethylating agent, except as allowed in 
Exclusion Criterion 7.b
11. Known hypersensitivity to any components of pracinostat, AZA, or mannitol
12. Human immunodeficiency virus (HIV) infection or an active and uncontrolled 
infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
13. Gastrointestinal (GI) tract disease that causes an inability to take oral medication, 
malabsorption syndrome, or a requirement for IV alimentation; prior surgical 
procedures affecting absorption; or uncontrolled inflammatory GI disease (e.g., 
Crohn’s disease, ulcerative colitis)
14. Any disease(s), psychiatric condition, metabolic dysfunction, or findings from a 
physical examination or clinical laboratory test result that would cause reasonable 
suspicion of a disease or condition, that contraindicates the use of pracinostat and/or 
AZA, that may increase the risk associated with study participation, that may affect 
the interpretation of the results, or that would make the patient inappropriate for this 
study
15. Breast-feeding woman
16. Current smokers (Use of patches, chewing gums or vaping nicotine containing fluids 
is permitted). Patients who stopped smoking at least 8 days prior to first pracinostat 
dosing can be enrolled, provided they refrain from smoking during the whole study.
17. Prohibited concomitant medications
18. Uncontrolled infections
19. Received more than 1 prior cycle of HMA or bone marrow transplant for any prior 
hematological disorder antecedent to AML


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4
STUDY TREATMENTS
4.1
Study Treatment Groups
Patients will be randomized to one of the following regimens:

Group A (experimental): pracinostat + background therapy
Pracinostat: one 60 mg capsule orally, once a day, 3 times a week (e.g., Monday, 
Wednesday, and Friday) for 3 weeks, followed by 1 week of rest of each 28-day 
cycle. [See Section 4.5 for pracinostat dose reduction]

Group B (control): placebo + background therapy 
Placebo: 1 capsule orally, once a day, 3 times a week (e.g., Monday, Wednesday, 
and Friday) for 3 weeks, followed by 1 week of rest of each 28-day cycle. [See 
Section 4.5 for pracinostat dose reduction]
As a background therapy azacitidine (AZA) will be administered to both treatment 
groups at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. 
[See Section 4.5 for AZA dose reduction].
Pracinostat/placebo oral administration is to be taken before SC or IV injection of 
azacitidine.
4.2
Pracinostat and Placebo
4.2.1
Pracinostat and Placebo Supply, Storage and administration
4.2.1.1
Study drug packaging
Study drug will be supplied in form of blistered capsules, packaged in a child-proof 
wallet card. The wallet card contains overall 9 individually blistered capsules, i.e., the 
medication to be used for a single treatment cycle of 4 weeks. The packaging solution 
will allow an easy identification of the 3 capsules to be taken in each of the three 
treatment weeks (i.e., Week 1-2-3 and Day 1-3-5).
The wallet card has to be considered as a sealed, blinded and appropriately labeled study 
kit.
Each study kit is patient-specific and carries a single panel label or a booklet label 
(depending on the area where the kit is supplied) reporting all the necessary information 
in English as well as in the local languages for clinical site staff and patients. The 
information reported is fully in accordance with FDA IND regulations, Annex 13 of the
Good Manufacturing Practice (GMP) guidelines (published by the Commission in The 
rules governing medicinal products in the European Community, Volume 4) and any 
applicable local requirements. 
Each study kit reports an identification number; this will allow the management of the 
drug supply and the drug accountability.
Pracinostat capsules will be supplied by Helsinn Healthcare SA in two strengths of 45 mg 
and 60 mg. Identically looking placebo capsules will be provided for each pracinostat 
capsule strength. Placebo formulations are packaged in a fully blinded manner in order to 
avoid identification of treatment groups.


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Study kit label will carry a removable (peel-off) portion to be applied on study drug 
accountability/administration form in order to certify the correct distribution and 
administration of the drug. The hospital pharmacist or a designated responsible person 
from the site staff will be requested to select the IWRS-assigned study kit and provide the 
drug to the Investigator or designee. The pharmacist or designated responsible person 
will fill-in the blank space on the study kit label with the patient number generated after 
randomization confirmation.
Please note that all the details regarding the use of the study kit will be reported in the 
Study Drug Manual to be supplied to each clinical site before the study start.
4.2.1.2
Study drug depot and distribution
Study kit packaging will be performed by PCI Pharma Services (Rockford, IL, US), 
which will also act as the central depot. In some countries, local depots will be defined 
and involved in the distribution process of the study kits.
The study kits, together with relevant documentation, will be supplied directly by PCI or 
by the defined local depot, either to a designated pharmacist at the hospital site or directly 
to the Investigator or designee, as applicable.
4.2.1.3
Study drug storage
The study kit will be delivered and stored at controlled room temperature of 20°C to 
25°C (68°F to 77°F) with excursions permitted to 15º-30º C (59º-86º F), in a secure area 
with limited access and protected from direct sun light. At the study site, the designated 
person responsible for storage of the investigational product (the site pharmacist or the 
Investigator or a designee) should also make sure that study kits are kept separately from 
the other medications available on site and in no circumstance should be mixed up with 
any other medications used at the trial site.
4.2.1.4
Study drug allocation through IWRS
Separate randomization lists will be prepared for assignment of treatments to patients and 
study medication packaging. Sealed cartons (kits) containing the study medications will 
be prepared according to the packaging list. An appropriate amount of study kits will be 
supplied to the designated person at the investigational sites at the beginning of the study,
with further re-supplies scheduled once the number of available study kits decrease to a 
pre-set threshold at each site.
Considering each stratum, patients meeting inclusion and not meeting exclusion criteria 
will be assigned to one of the two treatment groups, in a balanced design (1:1), according 
to specific procedures using the integrated system of eCRF (electronic CRF) / IWRS 
(Interactive Web Response System). 
On Day 1 of Cycle 1, after confirmation of patient eligibility, the Investigator will get 
connected to the eCRF/IWRS for randomization and communicate to the system the 
unique patient identification number (assigned by eCRF/IWRS at the screening visit).
The IWRS will assign the first free randomization number to patient according to the 
relevant strata and select a study kit number among the kits available at the site and 


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containing the selected treatment. The unique patient identification number, the study kit 
number assigned to the patient, the patient randomization number as well as the other 
patient characteristics, are stored in the system. The randomization procedure is possible 
only if study kits of both treatments are available at site.
The hospital pharmacist or designated responsible person will select the appropriate study 
kit based on the number supplied by the IWRS.
Relevant peel-off label from the selected study kit will be attached on the drug 
accountability log by the pharmacist or designated person to document the correct kit’s 
assignment.
On Day 1 of each subsequent cycle, the Investigator will get connected to the 
eCRF/IWRS to access the study kit number to be assigned to the patient (i.e., a study kit 
containing the same treatment as assigned in the first cycle will be automatically 
selected). For patients requiring a pracinostat dose reduction, this is to be selected during 
the eCRF/IWRS study drug allocation procedure. The IWRS will then allocate a new 
study kit from the same treatment group (pracinostat active vs. pracinostat placebo) and 
communicate the selected study kit number for the new cycle.
Due to the blinded study design, neither the pharmacist, nor the Investigator, the patient 
or the CRO will know which treatment is administered. The monitor who will check the 
drug accountability forms will also be blinded with regard to the treatment administered.
4.2.1.5
Study drug intake
Pracinostat/placebo capsules will be self-administered orally, once a day, 3 days a week 
with approximately 48 hours (+/- 2 hours) between each dose (e.g., Monday, Wednesday, 
and Friday) for 3 weeks, followed by 1 week of rest to complete a 28-day cycle.
On Day 1, Day 3, and Day 15 of Cycle 1, and on Day 1 of Cycle 2, pracinostat/placebo 
capsule must be administered by the study personnel at the study site to allow ECG 
recording and pharmacokinetic (PK) blood sample collection in relation to pracinostat 
time of administration (see Sections 6.2.3 and 6.3). On all other days, pracinostat or 
placebo may be self-administered at home.
Pracinostat/placebo capsule should be taken with water in either a fed or fasted state, at 
approximately the same time on each of the scheduled dosing days. Capsule should not 
be chewed or crushed, it should be swallowed whole. If vomiting occurs, no attempt 
should be made to replace the vomited dose. 
Pracinostat or placebo should not be taken with grapefruit or Seville orange. Refer to 
Section 4.7 for information on precautionary concomitant medications to be taken with 
pracinostat.
If a dose (pracinostat or placebo) is missed, then that dose should be withheld for that day. 
Patients should not take the missed dose later on the same day. For example, if a patient
does not take a dose on Monday, then the dose should be started on Tuesday, and the 
subsequent doses should be taken on Thursday and Saturday. Also, if a patient takes a 
dose on Monday but not on Wednesday, then the next doses should be on Thursday and 


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Saturday. The doses for the following week can be taken on Monday, Wednesday, and 
Friday as long as they are taken 48 hours from each other.
Refer to Section 8.2.6.2 for the handling of overdose or incorrect study drug 
administration. 
4.2.1.6
Study drug accountability
Once the study kits are received at the study site, the pharmacist or designated 
responsible person will sign the drug receipt form and notify via IWRS the clinical 
supplies receipt. Adequate records of the receipt, dispensation and return of study kits
must be maintained throughout the study. Used study kits will be retained until the drug 
accountability forms have been checked by a designated monitor. Unused study kits 
remaining at investigational sites at the end of the study will be either destroyed locally, 
or returned to the depots where they will be destroyed. 
At the end of the study, delivery records will have to be reconciled with those of used and 
returned stocks. Any discrepancy will have to be accounted for. Destruction of unused 
study kit will be documented in writing, according to FDA IND regulation 21CFR312.59, 
ICH Good Clinical Practice (GCP) and the drug depot Standard Operating Procedures 
(SOPs). Any destruction of remaining study medication material is to be first approved in 
writing by the study Sponsor. 
4.2.2
Precautions and Risks Associated with Pracinostat 
4.2.2.1
General Signs and Symptoms
The most common related treatment-emergent adverse events (TEAEs) (occurring in 
≥10% of subjects) by SOC are gastrointestinal disorders (68%), general disorders and 
administration site conditions (56%), blood and lymphatic system disorders (46%), 
investigations (28%) and metabolism and nutrition disorders (24%).
Nausea (48.0%); fatigue (40.0%); thrombocytopenia (38.0%); neutropenia (30.0%); 
vomiting (26.0%); diarrhea, anemia, febrile neutropenia, and decreased appetite (22.0% 
each) were the events (by PT) reported in ≥20% of subjects.
Related SAEs occurring in 2 or more subjects were febrile neutropenia (16.0%), fatigue 
(4.0%), and pneumonia (4.0%).
See the pracinostat Investigator’s Brochure for additional details.
4.2.2.2
Hematologic Symptoms
Pracinostat 
has 
been 
associated 
with 
myelosuppression 
including 
anemia, 
thrombocytopenia, and neutropenia (including neutropenic fever). Patients should be 
monitored for adverse hematologic effects, with dose modification allowed as described 
in Section 4.5.
Since myeloid malignancies may be characterized by thromboembolic events – including 
disseminated intravascular coagulation and hemorrhage – caution should be taken in 
concomitant administration of the following:


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
Fibrinolysis inhibitors

Anticoagulant and antiplatelet drugs
4.2.2.3
Gastrointestinal Symptoms
Disturbances of the GI tract, including nausea, vomiting, and diarrhea, have been 
reported in patients treated with pracinostat. In the Phase II study of pracinostat + AZA in 
AML, nausea, diarrhea and vomiting were among the most frequently reported 
manifestations of GI toxicity, with most cases graded as 1 or 2. Standard antiemetic and 
antidiarrheal medications and appropriate supportive care should be used per normal 
clinical practice. Pre-existing nausea, vomiting, and diarrhea should be adequately 
controlled before starting study drug administration.
4.2.2.4
QTc Prolongation/Cardiac Events
The cardiac safety of pracinostat compared to placebo on the QTcF or the individually 
corrected QT interval (QTcI) was assessed in 43 healthy subjects in study MEI-010.
Following single oral doses of 60 and 120 mg pracinostat, there were dose-proportional 
increases in HR and QTcF, with peak increases that did not correlate with Cmax (6 and 
24 hours postdose for HR and QTcF, respectively). No clinically meaningful effect on PR 
or QRS intervals or on T-wave morphologies was noted.
Patients with a prolonged QTcF interval > 450 ms at Screening will not be permitted to 
participate in the study.
Prior 
to 
pracinostat 
administration, 
hypokalemia, 
hypophosphatemia 
and 
hypomagnesaemia should be corrected and consideration should be given to monitoring 
potassium and magnesium in symptomatic patients (e.g., patients with nausea, vomiting, 
diarrhea, fluid imbalance, or cardiac symptoms). Concomitant medications with a known 
risk of prolonging the QT interval and/or causing Torsades de Pointes are prohibited. In 
addition, caution should be taken when using concomitant medications with a possible or 
conditional risk of prolonging the QT interval and/or causing Torsades de Pointes.
Medications with a possible or conditional risk may be used at the discretion of the 
Investigator (Appendix I).
Subjects requiring any medications that have the potential to alter serum electrolytes (e.g., 
diuretics) should be monitored closely for electrolyte abnormalities as these can 
contribute to the risk of QT prolongation and ventricular arrhythmias.
4.2.2.5
Procreation
Among the observed adverse effects of pracinostat in 28-day repeated oral dose toxicity 
studies conducted in CD1 mice, also testicular effects were reported (Investigator’s 
Brochure). Investigators should advice male patients to consider cryopreservation of 
semen.
4.2.2.6
Phototoxicity
Pracinostat was evaluated for phototoxicity in murine fibroblasts, using the neutral red 
uptake assay, up to a concentration of 100 μg/mL. The calculated IC50 value after 


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exposure with and without irradiation was 22 and 12 μg/mL, respectively. This resulted 
in a Photo Irritation Factor (PIF) of 0.54 and a Mean Photo effect of -0.004 leading to the 
classification ‘nonphototoxic’ (PRAN-17-39). No measures are therefore to be taken to 
minimize exposure to UV light.
4.3
Azacitidine
4.3.1
Azacitidine Supply, Storage and Administration
According to the local regulation in place in the different countries involved, Azacitidine 
will be either supplied by the study sponsor, or procured by the clinical site in case the 
treatment is reimbursed for use in AML by a third party payers (according to the health 
insurance plan in that country).
4.3.1.1
Azacitidine supply and distribution
Azacitidine to be used for PRAN-16-52 study is provided as commercial packs in form of 
Lyophilized powder in 100 mg single-use vials for SC or IV administration. 
The Azacitidine 100 mg vial has to be considered as patient-specific, i.e., its content 
(even if partially used) is to be considered for treatment of a single patient only (cannot 
be shared between two or more patients).
Commercial Azacitidine packs may be purchased by the sponsor from different markets, 
depending on the local regulation in the country the drug is used. All the commercial 
packs supplied by Helsinn to the sites will be clearly identified with a label reporting 
reference to the PRAN-16-52 study and all the necessary information. Each label applied 
on the pack carries a peel-off portion with reference information to be attached on the 
drug accountability log by the pharmacist or designated person in order to document the 
vial’s assignment and the global site accountability. This procedure does not apply for 
Azacitidine directly procured by site, according to local regulation for procurement; in 
this case the drug accountability log needs anyway to be completed with information 
regarding the product used for treatment of the patient, i.e., number of vials used, batch 
number and expiry date.
In case Azacitidine is procured by study sponsor, supply management will be performed 
by means of IWRS as done for the pracinostat kits. An appropriate amount of vials will 
be supplied to the designated person at the investigational sites at the beginning of the 
study, with further automatic re-supplies scheduled once the number of available vials
decreases to a pre-set threshold at each site.
Adequate records of the receipt, dispensation and return of the vials must be maintained 
throughout the study. Used packs will be retained until the drug accountability forms 
have been checked by a designated monitor. Unused vials remaining at investigational 
sites at the end of the study will be either destroyed locally or returned to the drug depots 
where they will be destroyed. At the end of the study, delivery records will have to be 
reconciled with those of used and returned stocks. Any discrepancy will have to be 
accounted for.


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4.3.1.2
Azacitidine administration
All patients (Group A and Group B) will receive a standard regimen of AZA at 75 mg/m2
for 7 days of each 28-day cycle. Azacitidine will be administered via SC injection or as 
an IV infusion. The IV infusions are generally administered over a period of 10-40 
minutes.
Azacitidine must be administered on Days 1 through 7 (Schedule 1) of each cycle. If the 
site is unable to accommodate this schedule, azacitidine may be given as a ‘5-2-2 
schedule’ wherein patients receive AZA for 5 consecutive weekdays (Days 1 through 5; 
Monday-Friday) and resume azacitidine dosing the first 2 weekdays of the next week 
(Days 8 and 9) of each 28-day cycle (Schedule 2). Switch between Schedule 1 and 
Schedule 2 during the study period is acceptable.
The daily AZA dose will be calculated based on the patient’s weight and height at Day 1 
of Cycle 1 (or up to 3 days before). The dose should be recalculated if the patient’s 
weight changes by ≥10% during the study. Sites may follow their institutional guidance 
for assessing the BSA used for dosing. 
The Investigator must ensure azacitidine administration information is collected for the 
study, including dose changes and administration route. 
Azacitidine is to be prepared in accordance with the terms of its regional marketing 
authorization by reconstitution of the lyophilized powder. Detailed information on how to 
prepare AZA is provided in the Package Insert, Prescribing Information, Summary of 
Product Characteristics (SmPC) or Country-specific azacitidine label, as appropriate.
Please note, all the details regarding the use of azacitidine will be reported (in local 
language) in the Study Drug Manual supplied to each clinical site before the study start.
4.3.2
Warnings and Precautions for Azacitidine
Prior to the initial AZA administration and at subsequent cycles, complete blood count 
(CBC), liver chemistries and serum creatinine should be monitored. Detailed information 
on the risks associated with the use of AZA is provided in the country-specific product 
labeling.
The following are the relevant Warnings and Precautions listed in azacitidine [Vidaza®
SmPC, 2017] product labeling information.
4.3.2.1
Azacitidine Most Frequent Adverse Reactions 
Based on the Vidaza® SmPC, 2017, the most frequent non-hematologic adverse reactions 
reported with AZA included injection site reactions (usually Grade 1-2), gastrointestinal 
disorders (constipation, nausea, vomiting and  diarrhea, usually Grade 1-2), and pyrexia 
(usually Grade 1-2). 
There may be overlapping adverse events between AZA and pracinostat related to 
myelosuppression, fatigue and gastrointestinal toxicities.


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4.3.2.2
Anemia, Neutropenia and Thrombocytopenia
Azacitidine causes anemia, neutropenia, leukopenia and thrombocytopenia (usually 
Grade 3-4). Complete blood counts for toxicity should be frequently monitored, at a 
minimum prior to each dosing cycle. After administration of the recommended dosage 
for the first cycle, dosage adjustment for subsequent cycles based on nadir counts and 
hematologic response should be done.
Refer to Section 4.5 for guidance on dose modifications in the presence of toxicity.
4.3.2.3
Toxicity in Patients with Severe Pre-existing Hepatic Impairment
Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic 
impairment, caution is needed in patients with liver disease. Safety and effectiveness of 
azacitidine in patients with MDS and hepatic impairment have not been studied as these 
patients were excluded from the clinical trials. Azacitidine is contraindicated in patients 
with advanced malignant hepatic tumors.
4.3.2.4
Renal Toxicity
Renal toxicity ranging from elevated serum creatinine to renal failure and death has been 
reported in patients treated with IV AZA in combination with other chemotherapeutic 
agents for non-MDS conditions. In addition, renal tubular acidosis, defined as a fall in 
serum bicarbonate to < 20 mEq/L in association with an alkaline urine and hypokalemia 
(serum potassium < 3 mEq/L) were observed in 5 patients with chronic myelogenous 
leukemia treated with AZA and etoposide. If unexplained reductions in serum 
bicarbonate < 20 mEq/L or elevations of blood urea nitrogen (BUN) or serum creatinine 
occur, the dosage should be reduced or held.
Patients with renal impairment may be at increased risk for renal toxicity. Also, AZA and 
its metabolites are primarily excreted by the kidney. Therefore, these patients should be 
closely monitored for toxicity. 
4.4
Duration of Therapy
Because disease response to low intensity chemotherapy regimens such as AZA requires 
prolonged exposure, patients should receive a minimum of 6 cycles of therapy as long as 
there is no evidence of disease progression or non-manageable toxicity.
There is no upper limit to the number of study treatment cycles that may be administered. 
Because there are no data on optimal length of therapy with low intensity chemotherapy, 
patients who achieve stable disease or an objective response should remain on study 
treatment as long as they derive a clinical benefit. 
Prophylactic therapies and/or study treatment (pracinostat/placebo and azacitidine) dose 
adjustments (Section 4.5) may be needed to manage treatment-related toxicities and keep 
patients on therapy as long as they derive clinical benefit. 


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4.5
Dose Modifications and/or Dose Interruptions
Dose modifications are permitted to manage drug-related toxicities and to improve 
treatment tolerability in order to maintain the patient on therapy and prolong exposure to 
study treatment. 
Dose modifications in Cycle 1 and Cycle 2 are discouraged to maximize exposure to 
study treatment and increase the likelihood of achieving an objective response. 
Dose reduction is not allowed within each 28-day cycle, but only between cycles. 
The Medical Monitor will review with the Investigator any decision to reduce, interrupt,
or permanently discontinue either of the two components of the study treatment
(pracinostat/placebo or azacitidine).
If a dose modification is required, a dose reduction should be implemented first, as 
described in the tables below. 
One pracinostat dose reduction is allowed as shown in table below:
Table 1: 
Pracinostat Dose Reduction
Dose Level
Pracinostat/Placebo
Starting Dose
One 60 mg capsule/3 days per week/ 3 weeks in every 28-day cycle
Dose Level -1
One 45 mg capsule/3 days per week/ 3 weeks in every 28-day cycle
Up to two AZA dose reductions are allowed as shown in the table below:
Table 2: 
AZA Dose Reductions
Dose Level
Azacitidine 
Starting Dose
75 mg/m2 for 7 days of each 28-day cycle 
Dose Level -1
37.5 mg/m2 (50%) for 7 days of each 28-day cycle
Dose Level -2
25 mg/m2 (33%) for 7 days of each 28-day cycle
Prior to dose reduction, the Investigator must assess if the toxicity is thought to be due to 
pracinostat, based on the safety information provided in the Investigator Brochure, or 
AZA, based on the safety information provided in the AZA product labeling. Severe 
fatigue, anorexia, weight loss, diarrhea, vomiting and QT prolongation are adverse 
reactions likely related to pracinostat, whereas pyrexia, injection site reaction, 
constipation and renal toxicity are adverse reactions likely related to AZA. 
Myelosuppression (i.e., thrombocytopenia, anemia, leukopenia, and neutropenia) has 
been reported with similar frequency with pracinostat and AZA therapy.
If toxicity is judged by the Investigator as likely related to pracinostat, then the 
pracinostat/placebo dose should be reduced first (Table 1). If the toxicity is judged by the 
Investigator as likely related to AZA, then the AZA dose should be reduced first (Table 
2). If the Investigator is not able to ascertain the relationship of an adverse reaction to 
pracinostat or AZA, then dose reduction will begin with AZA, since AZA is administered 
to all patients whereas pracinostat is administered to only 50% of patients (i.e., those 
randomized to Group A). If azacitidine dose is reduced first, and it is determined that 
further dose modifications are still required after two AZA dose reductions, then 
pracinostat dose should be reduced.


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Dose re-escalations are not allowed for either pracinostat or AZA after a dose reduction. 
If dose reduction is not sufficient to manage toxicity, then dose interruption of both 
pracinostat and azacitidine is permitted. 
If study treatment is delayed due to toxicity, then the first day when treatment is resumed 
will be defined as Day 1. The subsequent cycles should return to 28 days in length.
4.5.1
Dose Modification or Interruption for Hematologic Toxicity
Dose modification for hematologic toxicity in the setting of AML is not allowed during 
the first cycle of treatment (Cycle 1) and not recommended in general, unless the patient
is in remission as dose delays and/or reductions may decrease exposure to therapeutically 
effective levels of drugs.
Since myelosuppression (i.e., thrombocytopenia, anemia, leukopenia, and neutropenia) 
has been reported with similar frequency with pracinostat and AZA therapy, the AZA 
dose should be reduced first.
From cycle 2 onwards the following criteria are recommended:
a) Subjects with baseline ANC <1,500 cells/μL or platelets <75,000 cells/μL and 
have a ≥ Grade 3 decrease in cell counts before starting next treatment cycle:
1. ≤50% decrease: may continue treatment with no delay or dose adjustment.
2. >50% decrease and a bone marrow evaluation is not required per 
study protocol: delay treatment. If recovery is achieved within 14 days, 
no dose adjustment is required. If recovery is not achieved within 14 days, 
at day 42 a bone marrow evaluation is suggested and dose adjustment is 
outlined in Figure 2.
3. >50% decrease and a bone marrow evaluation is required per study 
protocol: follow dose adjustment outlined in Figure 2.


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Figure 2: 
Dose Adjustment
*Recovery= count ≥ nadir count + [0.5 x (baseline count – nadir count)]
b) Subjects without reduced baseline counts (ANC ≥ 1,500 cells/μL and platelets 
≥75,000 cells/μL) and have a ≥ Grade 3 decrease in cell counts before starting 
next treatment cycle: delay treatment. If recovery is achieved within 14 days, no 
dose adjustment is required. If recovery is not achieved within 14 days the dose 
should be adjusted as follows:
1. ANC >1.000 cells/μL and PLT >50.000 cells/μL: no dose adjustment is 
required;
2. ANC ≤1.000 cells/μL and/or PLT ≤ 50.000 cells/μL: consider reduction 
of AZA to dose level -1.
If it is determined that further dose modifications are still required after two AZA dose 
reductions, then pracinostat dose should be reduced. Unless a patient achieves < 5% 
blasts in the bone marrow, a cycle should not be interrupted beyond 28 days due to 
hematologic toxicity.
Patients with drug interruptions for prolonged myelosuppression (defined as > 56 days [2 
cycles] with ANC < 500/mm3 or platelet count < 10.000/mm3 in a bone marrow with < 
Bone 
marrow 
evaluation
Blasts ≥5%
Continue 
treatment 
without dose 
modification
Blasts <5%
Cellularity 
<15%
Delay study drug 
administration until 
recovery*
If recovery > 21 days 
consider dose 
reduction of AZA to 
dose level -2
Cellularity 
15-50%
Delay study drug 
administration until 
recovery* 
If recovery > 21 days 
consider reduction of 
AZA to dose level -1
Cellularity 
>50%
No dose 
adjustment


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5% blasts and no evidence of disease or dysplasia), may only restart treatment after 
discussion with the Medical Monitor.
4.5.2
Dose Modification or Interruption for Non-Hematologic Toxicity
From Cycle 2 onwards in case of Grade ≥3 non-hematologic toxicities a dose reduction 
or, as subsequent option, a dose interruption of both pracinostat and azacitidine is 
permitted, after prior discussion with the Medical Monitor. 
Patients with Grade ≥3 non-hematologic toxicities may have both pracinostat/placebo and 
azacitidine held up to a maximum of 4 weeks, or until return to Grade 1 or baseline 
(whichever comes first). However, in patients who are experiencing a reduction in 
marrow blasts but have not achieved counts < 5%, dose interruptions beyond 28 days are 
permitted, but require prior discussion with the Medical Monitor. 

If unexplained reductions in serum bicarbonate levels (or carbon dioxide - CO2- if 
bicarbonate is not routinely measured at the site) to <20 mmol/L occur, then the AZA
dose should be reduced by 50% for all subsequent cycles.

If unexplained elevations of urea/BUN or serum creatinine to ≥ 2-fold above baseline 
values and above ULN occur, then the next cycle should be delayed until values 
return to normal or baseline and the AZA dose should be reduced by 50% for all 
subsequent cycles.

When a QT prolongation is observed for the first time, the patient should be followed 
with additional ECGs as determined by the Investigator. Both pracinostat/placebo and 
azacitidine should be held  in patients who develop any of the following, unless there 
is a clear alternative cause for the changes:
o
Sustained (at least two ECG measurements, approximately 30 minutes apart) 
QTcF that is ≥ 500 ms and/or > 60 ms longer than the baseline value at 
screening
o
New ECG finding of clinical concern.
Study drug and azacitidine may be resumed when QTcF returns to baseline (i.e., 450 ms 
in case of absolute increase ≥ 500 ms or the patient’s screening value +30 ms in case of 
increase > 60 ms), any other ECG abnormalities have been resolved, and underlying 
causes have been addressed, the patient remains clinically stable and is appropriately 
monitored. Clinical judgment should be applied.
4.5.3
Dose Interruption in Patients with < 5% Bone Marrow Blasts 
(“Drug Holiday”)
A single dose interruption of study treatment for up to 1 cycle (28 days) is allowed but is 
not recommended in patients who request a “Drug Holiday” and meet all the following 
criteria:

Received a minimum of 12 cycles of pracinostat/placebo + azacitidine

Achieved BM blasts < 5% (i.e., CR, CRi or MLFS) 

Have been in clinical remission (CR, CRi, MLFS) for a minimum of 3 cycles


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
If abnormal cytogenetics at baseline, have achieved a cytogenetic CR (CRc)
Both pracinostat/placebo AND AZA must be interrupted during this Drug Holiday. Also, 
no other treatments for AML, including another investigational product from a different 
research study, may be administered during this Drug Holiday. Patients who receive 
another treatment for AML during the Drug Holiday must be discontinued from the 
active phase of the study and will enter the Long-term Follow-up. Every effort should be 
made to complete the End of Study Treatment visit prior to the patient starting any AML 
treatment regimen other than pracinostat/placebo + AZA. 
Prior to starting the “Drug Holiday”, the Drug Holiday Commencement visit (Section 
5.1.13.1) must be completed. This study visit should occur on Day 1 of a cycle. For 
example, if the patient is at Cycle 18 Day 8, then the patient should complete the 
remaining study visits for that cycle, including study treatment administration 
(pracinostat/placebo + AZA). 
To monitor patients for safety and potential disease progression during the Drug Holiday, 
study visits must be performed within 4 weeks (+/- 4 days) (Section 5.1.13.2). 
When patients complete the Drug Holiday period, they will resume their randomized 
study treatment assignment, i.e., pracinostat/placebo + AZA. Patient may resume study 
treatment during the Drug Holiday period at any time after disease evaluation. 
4.6
Management of Toxicity 
Patient management, including transfusions, use of growth factors, prophylaxis and 
treatment of infections, will be performed according to institutional guidelines. Palliative 
and supportive care for disease related symptoms may be administered at the 
Investigator’s discretion and institutional guidelines.
4.6.1
Prophylactic Therapies
Patients should be pre-medicated for nausea and vomiting. Other prophylactic measures 
(i.e., anti-infectives) may be used as indicated.
4.7
Prior and Concomitant Medications
Information about prior and concomitant medication is to be collected from 28 days prior 
to Day 1 of Cycle 1 up to the End of treatment visit (Section 5.1.14) and recorded in the 
CRF.
Infusion of blood products is to be recorded. Particular attention should be paid to the 
collection of information regarding red blood cell and platelet transfusions: specifically 
date of transfusion, type of transfusion (red blood cells or platelets), and number of 
events (e.g., 2 units of red blood transfused at the same moment are considered as one 
transfusion event).
62
All medications administered in relation to diagnostic procedures, e.g., anesthetics and
antibiotics are to be recorded.


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Prophylactic infusion of saline solution prior to chemotherapy in order to prevent toxic 
reactions related to chemotherapy should be recorded as well.
4.7.1
Medications Affecting Metabolism of Pracinostat via Cytochrome 
P450
Few clinical information is available on drug interactions for pracinostat. Pracinostat is 
substrate of cytochrome P450 1A2 (CYP1A2), P450 2C8 (CYP2C8) and cytochrome 
P450 3A4 (CYP3A4). Caution in use of pracinostat is required with drugs that inhibit 
3A4 and 2C8 or induce CYP1A2, 2C8 and 3A4 (see Investigator Brochure and study 
PRAN-17-14). Lists of 3A4 and 2C8 inhibitors and 1A2, 2C8 and 3A4 inducers are 
provided in Appendix G. 
Patients should avoid grapefruit juice and Seville oranges during the study since they are 
known to be inhibitors of CYP3A4.
Smoking results in CYP1A2 induction and has been shown to decrease pracinostat Cmax 
and AUC by ~60%. This effect is known to be caused by substances created by tobacco 
smoke, such as polycyclic aromatic hydrocarbons (potent inducers of CYP1A2, a primary 
CYP450 isoform responsible for pracinostat metabolism). Therefore, current smokers are 
excluded from the study but the use of patches, chewing gums or vaping nicotine 
containing fluids is permitted. Patients who stopped smoking at least 8 days prior to first 
pracinostat dosing can be enrolled, provided they refrain from smoking during the entire
study.
4.7.2
Possible Effects of Pracinostat on Other Drugs via Cytochrome 
P450
In hepatocytes pracinostat is an inducer of CYP1A2 and CY2B6, while is a suppressor of 
CYP3A4 mRNA expression and enzymatic activity (see Investigator Brochure and 
PRAN-17-04).
Pracinostat should be used with caution in patients receiving concomitant medications 
that are primarily metabolized through CYP3A4. The plasma concentrations of CYP3A4 
substrates can increase when co-administered with pracinostat. Lists of CYP3A4 
substrates are provided in Appendix H.
Pracinostat should be used with caution in patients receiving concomitant medications 
that are primarily metabolized through CYP1A2 and CY2B6. The plasma concentrations 
and the efficacy of CYP1A2 and CY2B6 substrates can decrease when co-administered 
with pracinostat. Lists of CYP1A2 and CYP2B6 substrates are provided in Appendix H.
4.7.3
Prohibited Concomitant Medications
The following treatments and/or medications are prohibited while on study:

Any other investigational product taken within 4 weeks prior to Day 1 of Cycle 1 
and/or through the entire study treatment period is not allowed. For this purpose 
“Other investigational product" has to be intended as any agents tested in clinical 
trials, even those which are tested for indications that are already approved.


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o
Anticancer agents. If such agents are required, then the patient must 
discontinue study treatment prior to receiving the anti-cancer therapy and 
disease progression should be documented. For patients at Cycles 1 through 6, 
it is recommended to contact the Medical Monitor prior to study treatment
discontinuation. Every effort should be made to complete the End of Study 
Treatment visit prior to the patient starting any AML treatment regimen 
other than pracinostat/placebo + AZA.
o
Hydroxyurea is allowed until Cycle 1, Days 1-14, to reduce WBC count to 
<30,000 µL prior to Day 1. After Cycle 1, Day 14, hydroxyurea is prohibited.

HDAC inhibitors.

Medications with a known risk of prolonging the QT interval and/or causing Torsades 
de Pointes. (Appendix I).

Herbal products are not allowed throughout the study. Subjects should stop using 
these prior to the first dose of study treatment.
4.8
Treatment compliance
During each cycle a patient will be considered to be compliant with therapy if s/he takes 
at least 8 of the 9 capsules of study drug provided in the clinical study medication kit and 
at least 6 of the 7 AZA doses. 


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5
STUDY CONDUCT
This study will consist of three phases: Screening, Treatment, and Long-term Follow-up. 
During the treatment phase, there is a ±4-day window, while during the Long-term 
Follow-up there is a ± 1-month window for the visits/calls.
5.1
Study Procedures
5.1.1
Informed Consent
Prior to performing any study-specific evaluation, written informed consent is to be 
obtained from each patient. The consent may be obtained at the earliest one week before 
the start of screening activities.
5.1.2
Screening Assessments
Screening examinations will only be performed after the patient has given written 
Informed Consent. 
The following evaluations and procedures will be performed within 28 days prior to the 
first study treatment administration (Cycle 1 Day 1):

Obtain demographic information: age, gender, and self-reported race/ethnicity

Collect medical history, concomitant illnesses, prior surgeries, and smoking status:
clinically significant diseases, prior cancer history, including cancer therapies and 
relevant procedures, should be collected 

Assess protocol-qualifying comorbidities. This may require measurement of the left 
ventricular ejection fraction (LVEF) and/or pulmonary function tests (ECHO/MUGA 
and/or pulmonary function tests are required to satisfy inclusion criteria IIb and IIc) 

Perform a complete physical examination (Section 6.2.1)

Obtain vital signs (Section 6.2.2), including height, weight, blood pressure (sitting or 
in semi-supine position), pulse rate, and body temperature 

Assess ECOG performance status

Obtain 12-lead ECG in triplicate (Section 6.2.3) 

Collect information about prior and concomitant medications (Section 4.7)

Assessment of adverse events

Collect adequate bone marrow aspirate/biopsy (Section 6.1.1)
o
Morphologic diagnosis of AML (a morphologic evaluation of bone marrow 
already performed within 30 days prior to the ICF signature will be accepted as
screening evaluation)
o
Classical cytogenetic analysis - karyotyping (central evaluation) to assess 
cytogenetic risk category and allow stratification by cytogenetic risk factor 
(intermediate vs. unfavorable) at randomization and to evaluate cytogenetic 
response to therapy in patients with abnormal cytogenetics at baseline. If a bone 
marrow aspirate sample at screening has been already submitted for central 
cytogenetic analysis but the result is not available to confirm patient eligibility 


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and a local cytogenetic analysis (karyotyping) has been already performed as per 
clinical routine within 30 days prior to the ICF signature, the local result will be 
considered acceptable to enroll the patient. In case of discrepancy between the 
local and the central result of the baseline cytogenetic analysis leading to 
different cytogenetic risk categories, the patient should be randomized in the risk 
category defined by the central assessment. In case the central result should not 
be available, the local result will be used for randomization.
o
Unknown cytogenetic risk results according to SWOG classification will be 
stratified as intermediate risk, as suggested by ELN 2017 classification.
o
MRD panel determination
o
If no bone marrow blood can be aspirated at screening (“dry tap”, even at 
repeated attempts) the patient will be considered a screen failure.

Biobanking for mutational analysis (mandatory in all patients). Peripheral blood and 
bone marrow fluorescence in situ hybridization (FISH) analysis for cytogenetic study 
and molecular analysis are not required. However, if FISH testing or molecular 
analysis are part of the institution’s standard of care, the results will be recorded in 
the Case Report Forms.
The following evaluations and procedures will be performed within 8 days prior to the 
first study treatment administration (Cycle 1 Day 1):

Laboratory assessments (Section 6.2.4)

Serum pregnancy test for women of childbearing potential (Section 6.2.4)
Screening evaluations must be completed and patients must meet all eligibility criteria 
prior to randomization. Eligibility criteria, including the co-morbidities that define 
unfitness to receive intensive induction chemotherapy, must be reviewed and approved 
by the Medical Monitor prior to randomization.
Re-screening of a patient who has previously failed study entry will require appropriate 
discussion with the Medical Monitor and will be approved on a case by case basis.
If one or more screening laboratory tests do not support eligibility, laboratory re-test is 
permitted only once. Only the laboratory tests which resulted out of range need to be 
repeated.
In case of re-screening of a patient after one course of hypomethylating agent therapy, all 
the screening assessments need to be repeated, excluding cytogenetic test.

Biomarker analysis (if consent obtained by patient): Peripheral blood samples and/or 
aspirate bone marrow samples will be collected and stored for potential molecular 
studies (Section 6.4)
5.1.3
Cycle 1 on Day 1
After confirmation of eligibility, the patient will be randomized to one of the two 
treatment groups using the IWRS. The following activities are to be performed before 
study treatment administration:


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
Assess transfusions of red blood cells or platelets performed during the previous 8 
weeks (Section 6.1.2 ). 

Perform a limited physical examination

Measure blood pressure and pulse rate –pre-dose (sitting or in semi-supine position), 
body temperature, and weight

12-lead ECG measurement in triplicate - pre-dose

Collect concomitant medications and any new medical conditions since the screening 
visit

Assess ECOG performance status

Administer the Quality of Life questionnaire

Urine pregnancy test for women of childbearing potential – pre-dose

Re-check of all eligibility criteria

Assessment of adverse events

Randomization via IWRS: The IWRS will provide the investigator with the kit 
number stored in the site stock to be dispensed to the patient. 

Treatment administration: The study treatment administration schedule is the 
following: 
o Pracinostat/placebo administration (see Section 4.2): according to the indication 
reported on the study kit internal panel, the patient will receive 1 capsule of 
study drug or matching placebo (week 1, day 1). Patient must begin study 
treatment within 24 hours after randomization.
o Azacitidine administration: according to indication reported in Section 4.3.1.2
azacitidine is administered to patient.
Pracinostat/Placebo oral administration is to be taken before administration of 
azacitidine.
The date and the precise time (hh:mm) of the study drug and Azacitidine 
administration as well as other information related to the quantity and origin of the 
Azacitidine vials must be recorded in the source records as well as on the relevant 
eCRF page for each medication given. The relevant peel-off labels from the study kit 
and from the Azacitidine commercial packs used for the treatment at this visit will be 
attached to the drug accountability log (pharmacist or designated responsible).
Activities to be performed after study drug administration (for all patients EXCEPT 
those participating in the AZA/pracinostat PK sub-study. See Section 6.3):

Collect three pharmacokinetic (PK) blood samples:
o
30 minutes (± 15 minutes) post pracinostat/placebo administration
o
3 hours (± 30 minutes) post pracinostat/placebo administration
o
6 hours (± 30 minutes) post pracinostat/placebo administration


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(IN SELECTED SITES ONLY) AZA/pracinostat PK sub-study: Assessment of the 
possible drug interaction of Pracinostat on the PK of Azacitidine (See Section 6.3.2):

Collect 8 pharmacokinetic (PK) blood samples:
o
15 minutes (± 2 minutes) post pracinostat/placebo and AZA administration
o
30 minutes (± 2 minutes) post pracinostat/placebo and AZA administration
o
1 hour (± 5 minutes) post pracinostat/placebo and AZA administration
o
2 hours (± 5 minutes) post pracinostat/placebo and AZA administration
o
3 hours (± 5 minutes) post pracinostat/placebo and AZA administration
o
4 hours (± 5 minutes) post pracinostat/placebo and AZA administration
o
6 hours (± 30 minutes) post pracinostat/placebo and AZA administration
o
8 hours (± 30 minutes) post pracinostat/placebo and AZA administration
(optional sampling)

Triplicate ECGs will be done 90 minutes (± 30 minutes) and 6 hours (± 30 minutes)
post pracinostat/placebo administration.

Measure blood pressure and pulse rate (sitting or in semi-supine position), 90
minutes (± 30 minutes) post pracinostat/placebo administration.
5.1.4
Cycle 1 on Day 2 
The following activities are to be performed on Day 2 of the first cycle:

Collect one PK blood sample at 24 hours (1 hour) after the first pracinostat/placebo 
dose, prior to AZA administration (for all patients EXCEPT those participating in 
the AZA/pracinostat PK sub-study. See Section 6.3)

Collect one PK blood sample at 24 hours ( 1 hour) after the first pracinostat/placebo 
dose, 
prior
to 
AZA 
administration
(IN 
SELECTED 
SITES 
ONLY)
AZA/pracinostat PK sub-study (See Section 6.3.2)

Triplicate ECGs will be done at 24 hours
(± 1 hour)
after the first 
pracinostat/placebo administration, prior to AZA administration

Administer the second AZA dose. Administration should be performed 24 hours (± 1
hour) after the first dose.

Review concomitant medications since the previous study visit

Assess AEs since the previous visit
5.1.5
Cycle 1 on Day 3
The following activities are to be performed on Day 3 of the first cycle:

Collect one PK sample at 48 hours (2 hours) after the first pracinostat/placebo dose, 
prior to second pracinostat administration (for all patients, including those in the 
AZA PK sub-study)

Pracinostat/placebo administration, 48 hours (± 2 hours) after first pracinostat/placebo 
dose and after PK sampling


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
Triplicate ECGs will be done at 48 hours
(± 1 hour)
after the first 
pracinostat/placebo administration, prior to AZA administration

AZA administration (to be administered after PK sample collection )

Review concomitant medications and therapies (in particular transfusions) since the 
last study visit

Assess AEs since the previous visit

Hand-out to the patient the study medication for the first cycle and give clear 
instructions regarding the intake (see Section 4.2.1.2).  
5.1.6
Cycle 1 on Days 4 to 7 (or 9)

Pracinostat/placebo administration

Review concomitant medications since the previous study visit

Assess AEs since the previous visit

Administer azacitidine according to the chosen schedule (1-7 or 5-2-2)
The Investigator must ensure azacitidine administration information is collected for the 
study, including dose changes and administration route.
5.1.7
Cycle 1 on Day 15
The following activities are to be performed on Day 15 of the first cycle:

Body temperature measurement

Central laboratory assessment – pre dose

Pracinostat/placebo dosing

Blood pressure and pulse rate (in sitting or in semi-supine position) to be measured 90 
minutes (± 30 minutes) post pracinostat/placebo administration

12-lead ECG measurement in triplicate at 90 minutes (± 30 minutes) post
pracinostat/placebo administration

Collect one PK sample: any time within 24 h after pracinostat/placebo dosing (for all 
patients, including those in the AZA PK sub-study)

Assess AEs since the last study visit

Review concomitant medications since the last study visit

Assess study drug dosing compliance
5.1.8
Cycle 2 and All Subsequent Cycles on Day 1
At every Cycle, Day 1 visit, the following will be collected and/or performed (unless 
specified differently):

A limited physical examination

Body temperature and body weight measurement 


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
Blood pressure and pulse rate (in sitting or in semi-supine position) to be measured 
predose (Cycle 2 only)

12-lead ECG measurement in triplicate – predose (Cycle 2 only)

Central laboratory assessments – predose (Cycle 2 only)

Serum pregnancy test for women of childbearing potential (Section 6.2.4) (Cycle 2 
only)

Assess ECOG performance status

Assess pracinostat/placebo dosing compliance for the previous cycle

Review concomitant medications and concomitant therapies (including transfusions) 
since the last study visit 

Assess AEs since the last study visit

Administer study drug (pracinostat/placebo) and AZA

Blood pressure and pulse rate (in sitting or in semi-supine position) to be measured 
90 minutes (± 30 minutes) post pracinostat/placebo administration 

12-lead ECG measurement in triplicate at 90 minutes (± 30 minutes) post
pracinostat/placebo administration (Cycle 2 only)
After patient has been re-evaluated, including review of laboratory parameters results, the 
Investigator will get connected to the IWRS for the assignment of a new study kit. The 
patient will be administered the same treatment assigned at Cycle 1 (active or placebo), 
but in case the dose reduction from 60mg to 45mg is considered to be necessary by the 
Investigator, this needs to be reported into IWRS according to dedicated section. The 
procedures to be completed are the same as for Cycle 1 (Day 1, Visit 2), except for 
randomization, i.e., for new cycle IWRS will only provide a new kit number for the 
patient according to the patient’s randomization at Cycle 1.
5.1.9
Cycle 2 and All Subsequent Cycles on Days 2 to 7 (or 9)

Pracinostat/placebo administration

Review concomitant medications and therapies since the last study visit

Assess AEs since the previous visit

Administer azacitidine as detailed in Section 4.3.1.2 according to the chosen schedule 
(1-7 or 5-2-2)
The Investigator must ensure azacitidine administration information is collected for the 
study, including dose changes and administration route.
5.1.10
Cycle 2 and All Subsequent Cycles from Day 21 to 26
The last visit during Cycle 2 and following Cycles is to be scheduled within Day 21 and 
Day 26 (included) ensuring that the results of the performed analyses are available at the 
time of Day 1 of subsequent Cycles.
From Day 21 to 26 of each cycle, the following will be collected and/or performed 
(unless specified differently):


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
12-lead ECG measurement in triplicate at any time during the visit (cycle 2 only)

Blood pressure and pulse rate (in sitting or in semi-supine position) to be measured at 
any time (cycle 2 only)

Central laboratory assessments

Serum pregnancy test for women of childbearing potential (Section 6.2.4)

Assess AEs since the last study visit

Review concomitant medications and concomitant therapies (including transfusions) 
since the last study visit 
5.1.11
Cycle 2 and Subsequent Even Cycles from Day 21 to 26

Response evaluation
Patients will be evaluated for disease response on Day 1 of each odd Cycle. 
To assess response to therapy, a bone marrow aspirate/biopsy has to be performed 
between Day 21 and Day 26 of each Even Cycle (i.e., Cycles 2, 4, 6, 8 …)
If the aspirate is a dry tap, then a bone marrow biopsy is required for the pathology 
interpretation of response, including bone marrow blasts.
Morphologic response evaluation is required until a complete remission is achieved and 
confirmed after 2 further cycles of treatment. At subsequent cycles, a bone marrow 
evaluation is no longer required, unless there is a suspicion of disease progression or 
relapse.
Classical Cytogenetic (karyotyping), with analysis of preferably 20 metaphases, is to be 
performed only if the screening cytogenetic test result was abnormal. After the patient 
has achieved a cytogenetic complete remission, the cytogenetic evaluation is no longer 
required at subsequent cycles.
MRD evaluation will be performed only 2 cycles after first CR.
A small quantity of bone marrow aspirate will be collected for biobanking for mutational 
analysis (mandatory in all patients).  
FISH as part of cytogenetic testing and molecular analysis are not required. However, if 
FISH testing or molecular analyses are part of the patient’s standard procedure, then the 
results will be recorded in the Case Report Form.
Since transfusion independence is required to differentiate CR from CRi or MLFS, 
transfusions of red blood cells or platelets in the preceding weeks must be assessed.

Biomarker analysis (if consent obtained by patient): Peripheral blood samples and/or 
aspirate bone marrow samples will be collected and stored for potential molecular 
studies (Section 6.4).
5.1.12
Cycle 3 and Subsequent Odd Cycles on Day 1
In addition to the data collected at each cycle, the following will be collected and/or 
performed on Day 1 of every Odd Cycle (i.e., Cycles 3, 5, 7, 9 …):


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
Single 12-lead ECG measurement at 90 minutes (± 30 minutes) post
pracinostat/placebo administration

Administer the Quality of Life questionnaire 
5.1.13
Study Treatment Interruption/ Drug Holiday Schedule
If requested by the patient and with Investigator discretion, a unique Drug Holiday (i.e., 
period of study treatment interruption) of pracinostat/placebo + AZA for up to 1 cycle (28 
days) is allowed, but not recommended, as described in Section 4.5.3.
The start of a Drug Holiday must begin on Day 1 of a scheduled treatment cycle. 
When a patient starts a Drug Holiday schedule, the following study visits must be 
completed: Drug Holiday Commencement Visit (refer to Section 5.1.13.1) and Drug 
Holiday Follow-up Visits (refer to Section 5.1.13.2).
5.1.13.1
Drug Holiday Commencement Visit 
The following procedures must be completed during this visit, which coincides with the 
Day 1 visit of that cycle:

Verify patient achieved a clinical remission (i.e., < 5% blasts and no circulating blasts)
for a minimum of 3 cycles, and if abnormal cytogenetics at enrollment, achieved a 
cytogenetic CR

Verify patient completed at least 12 cycles of pracinostat/placebo + azacitidine

Perform a complete physical examination

Obtain vital signs, including weight, blood pressure (sitting or in semi-supine 
position), pulse rate, and body temperature 

Assess ECOG performance status

Administer the Quality of Life questionnaire

Assess AEs since the last study visit

Review concomitant medications since the last study visit 

Assess study drug dosing compliance at prior cycle 

Collect all unused study drug
Note: any AE occurrences should continue to be collected and reported during the Drug 
Holiday period.
5.1.13.2
Drug Holiday Follow-up Visits 
The Drug Holiday Follow-up Visits will occur within 4 weeks (+/- 4 days) from Drug 
Holiday Commencement Visit and in any case before resuming the study treatment.
The following procedures must be completed:

Confirm patient has not taken or started another treatment regimen for AML, 
including another investigational product.


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
Obtain vital signs, including weight, blood pressure (sitting or in semi-supine 
position), pulse rate, and body temperature 

Assess ECOG performance status.

Administer the Quality of Life questionnaire

Central laboratory assessments

Assess AE occurrence(s) since last contact 

If there is a suspicion of AML recurrence based on CBC results or clinical findings, a 
bone marrow biopsy/aspirate must be obtained to verify disease progression. In case 
of disease relapse from CR, patient will proceed with end of treatment visit.
5.1.14
End of Treatment Visit
Study treatment will continue until there is documented disease progression or relapse 
from CR while receiving study treatment, or non-manageable toxicity. 
End of treatment evaluations are required 30 days (+/- 2 days) after treatment ends or 
prior to starting new treatment, if urgent treatment is required.
The following procedures will be completed:

Obtain vital signs

Assess ECOG performance status.

Administer the Quality of Life questionnaire

Central laboratory assessments

For women of childbearing potential, a highly sensitive urine or serum pregnancy test 
to confirm absence of pregnancy

Assess AEs until 30 calendar days  (+/- 2 days) after last study drug intake

Review concomitant medications since the last study visit

Collect all unused study drug

Assess study drug dosing compliance

Biomarker analysis (if consent obtained by patient): Peripheral blood samples will be 
collected and stored for potential molecular studies (Section 6.4)
5.2
In-Study Long-term Follow-Up
After patients permanently discontinue pracinostat/azacitidine or placebo/azacitidine, 
they will be followed every 3 months (±1 month) from the date when study drug was last 
administered until the end of the study. The following information will be obtained 
during these Follow-up contacts:

Collect any new AML treatment

Collect any evidence of disease progression

Assess survival status


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
When there is a suspicion of disease progression, a bone marrow evaluation is 
required to confirm disease progression
Every effort must be made to follow patients from the time of treatment discontinuation 
until death. Patients may be contacted during outpatient visits or by telephone.
5.3
Post-Study Observation Period
The Post-Study Observation Period is defined as the period starting from the end of the 
study (Section 3.2) for a maximum of 24 months.
Patients still on treatment at the end of the study may have the opportunity to continue to 
receive the study drug to which they were randomized, until the Sponsor informs the 
Investigators of the appropriate course of action, based on the study results.
5.3.1
Patients on treatment at the end of study
For patients still on treatment at the end of study the following information will be 
collected in a dedicated CRF:

End of treatment (date of last study drug administration)

Any new AML treatment

Any evidence of disease progression 

Serious Adverse Reactions (SARs) and follow-up information of SARs 

Death
5.3.2
After discontinuation of the treatment each patient enters in the 
post-study long-term follow-up as described below.Post-study 
long-term follow-up
After the end of the study, patients on post-study long-term follow-up will continue to be 
followed every 3 months (±1 month). The following information will be obtained during 
these Follow-up contacts and recorded in a dedicated CRF:

Any new AML treatment

Any evidence of disease progression

Survival status

Serious Adverse Reactions (SARs) and follow-up information of SARs 
Every effort must be made to follow patients from the end of the study until Death. 
Patients may be contacted during outpatient visits or by telephone.
Results of this post-study observation period will be described in a separate study report.


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6
METHODS OF ASSESSMENT AND ENDPOINTS
6.1
Efficacy Assessments
6.1.1
Bone Marrow Aspirate/biopsy
Bone marrow aspirate/biopsy sample will be collected for 
o
Morphologic diagnosis of AML at screening and evaluation of morphologic 
response to therapy
o
Classical cytogenetic analysis -
karyotyping
(central evaluation) to assess 
cytogenetic risk category and allow stratification by cytogenetic risk factor 
(intermediate vs. unfavorable) at randomization and to evaluate cytogenetic 
response to therapy in patients with abnormal cytogenetics at screening. If the 
screening bone marrow aspirate sample for central cytogenetic analysis has been 
submitted but is the only pending result to confirm patient eligibility and a local 
cytogenetic analysis (karyotyping) has been already performed as per clinical 
routine within 30 days prior to the ICF signature, then the local result will be 
considered acceptable to enroll the patient.
o
MRD evaluation by MFC
o
Biobanking for mutational analysis
o
If no bone marrow blood can be aspirated at screening (“dry tap”, even at repeated 
attempts) the patient will be considered a screen failure.
Evaluation of bone marrow aspirate is to be performed at screening (a morphologic 
evaluation of bone marrow already performed within 30 days prior to the ICF signature 
will be accepted as screening evaluation) and then at the end of every even cycle 
(between Day 21 and 26), to evaluate the disease response to therapy at the beginning of 
each odd cycle. Response evaluation will be performed upon investigator’s assessment,
according to IWG criteria. A bone marrow biopsy is only required in case of dry tap for 
the pathology interpretation of response, including bone marrow blasts. 
A local anesthetic (i.e., lidocaine, equimolar 50% nitrous oxide gas) may be applied to 
the skin and to the bone to numb the area where the aspirate/biopsy will be performed, 
preventing or reducing the pain associated to the procedure.
Morphologic response evaluation assessment will be required until a complete response
is achieved and confirmed after 2 further cycles of treatment. At subsequent cycles, bone 
marrow evaluation is no longer required, unless there is a suspicion of disease 
progression or relapse from CR.
Classical Cytogenetics (karyotyping), with analysis of preferably 20 metaphases, is to be 
performed only if the screening cytogenetic test result was abnormal. After the patient 
has achieved a cytogenetic complete remission, the cytogenetic evaluation is no longer 
required at subsequent cycles.
MRD evaluation by MFC will be performed only at screening and after 2 cycles from 
first CR.


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A small quantity of bone marrow blood will be collected and stored for retrospective 
analysis of mutations of six genes known to have a prognostic impact in patients affected 
by AML: NPM1, FLT3, CEBPA, RUNX1, ASXL1, TP53 (Döhner, 2016). The 
biobanking for these mutational analyses will be mandatory for study inclusion.
6.1.2
RBC and platelet transfusions
Information regarding red blood cell and platelet transfusions is to be collected on a 
regular basis, specifically date of transfusion, type of transfusion (red blood cells or 
platelets).
6.1.3
Quality of Life Questionnaire
Quality of life will be evaluated using the EORTC QLQ-C30 questionnaire (Appendix K). 
The questionnaire is to be administered to the patients during the first visit of each odd 
cycle. Data of the questionnaire are to be reported in the eCRF.
6.2
Safety Assessments
Safety will be assessed primarily by means of adverse events (AEs) collection and 
reporting. See Section 8 below for specific definitions.
Additionally to the adverse events reporting, other safety assessments will include:
-
Physical examination (PE)
-
Vital signs
-
12-lead electrocardiogram (ECG)
-
Laboratory tests (hematology, blood chemistry)
6.2.1
Physical Examination
A complete PE will be performed at Screening and during the Drug Holiday 
Commencement Visit. This evaluation will include an examination of general appearance, 
head, eyes, ears, nose, throat, skin, neck, lungs, cardiovascular, breast, lymph nodes, 
abdomen, musculoskeletal and neurological. 
A limited physical examination, covering general appearance, cardiovascular, lungs and 
abdomen body systems, will be performed at Day 1 of each cycle to assess any changes 
that may have occurred since the last examination. 
Information about the physical examination will be recorded in the source documentation 
at the site. Any abnormalities will be recorded in the eCRF. Clinically significant 
findings/illnesses, reported after the first complete PE and which meet the definition of an 
AE, must be recorded in the eCRF as an AE.
6.2.2
Vital Signs
Vital signs assessments will include: pulse rate, systolic and diastolic blood pressure, 
body temperature, body weight, and height (at screening only).


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Pulse rate, systolic and diastolic blood pressure will be measured after the patient has 
been in the sitting or in semi-supine position for at least 5 minutes. Measurements are 
done at Screening, on Day 1 of Cycle 1 (predose and 90 ±30 minutes postdose), on Day 
15 of Cycle 1 (90 ±30 minutes postdose) on Day 1 of Cycle 2 (predose and 90 ±30 
minutes postdose), at any time during the visit between Day 21 and Day 26 of Cycle 2 
and 90 ±30 minutes postdose on Day 1 of all subsequent Cycles. Additionally these 
parameters are measured also during Drug Holiday Commencement and Follow-up Visits, 
as well as at End of Treatment Visit.
Body temperature is measured at Screening, on Day 1 of Cycle 1 (predose), on Day 15 
of Cycle 1, on Day 1 of all subsequent Cycles (predose), as well as during Drug Holiday 
Commencement and Follow-up Visits, and at End of Treatment Visit.
Body weight is measured at Screening, on Day 1 of all Cycles, as well as during Drug 
Holiday Commencement and Follow-up Visits, and at End of Treatment Visit.
6.2.3
12-lead ECG
Twelve-lead ECGs will be recorded for each patient as triplicates or as single 12-lead 
ECG, as indicated in Section 5.1.
All ECGs will be recorded after the patient has been in sitting or in semi-supine position 
for at least 5 minutes. Triplicate ECGs are to be collected at a distance of 5±2 minutes 
between the ECGs.
Triplicate 12-lead ECGs are collected at Screening, on Day 1 of Cycle 1 (predose, 90 ±30 
minutes and 6 hours ±30 minutes post pracinostat/placebo administration), on Day 2 of 
Cycle 1 (at 24 hours ± 1 hour post pracinostat/placebo administration), on Day 3 of Cycle 
1 (at 48 hours ± 1 hour after the first pracinostat dose), on Day 15 of Cycle 1 (90 ±30 
minutes post pracinostat/placebo administration), on Day 1 of Cycle 2 (predose and 90 
±30 minutes post pracinostat/placebo administration), and at Day 21-26 of Cycle 2 (at 
any time).
Single 12-lead ECGs are collected 90 ±30 minutes post pracinostat/placebo 
administration on Day 1 of each subsequent Odd cycle (i.e., Cycles 3, 5, 7 …).
Each ECG has to be signed and dated by the Investigator and evaluated as 
normal/abnormal. Abnormal clinically significant values detected at screening are not 
considered as AEs, but need to be reported in the medical history page, as appropriate. 
Clinically significant findings reported after screening have to be entered in the eCRF as 
AEs.
A digitally recorded ECG will be transmitted from the site to a central reading facility, 
where ECG interpretations will be timely performed by a cardiologist blinded to the 
treatment received by patients. ECG interpretation scheme will include the analysis of the 
morphology, rhythm, conduction, heart rate, ST segment, PR, QRS, QT and QTc 
intervals, T waves, U waves and the presence or absence of any pathological changes. 
After review, the Investigator must sign and date each ECG report received from the 
central reading facility.


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The Investigator will receive more detailed information regarding the ECG recording and 
assessment procedures in a separate manual.
6.2.4
Laboratory Assessments
Blood samples will be collected at the relevant visits as indicated in Section 5.1 (i.e., 
Screening, Day 15 of Cycle 1, Day 1 of Cycle 2, ,between Day 21-26 of Cycle 2 and all 
subsequent cycles and End of Treatment Visit). All blood samples will be sent to the 
central laboratory for analysis (for details regarding processing and shipment please refer 
to the separate manual).
Females of childbearing potential will perform serum beta-hCG pregnancy tests at 
screening visit, Day 1 of Cycle 2, between Day 21 and Day 26 of Cycle 2 and all 
subsequent cycles and End of Treatment Visit. Pregnancy will be re-evaluated by urine 
pregnancy test (dipstick done locally at study site) predose on Day 1 of Cycle 1. 
The following parameters will be analyzed for each sample:
Hematology panel: complete blood count (CBC): hematocrit, hemoglobin, erythrocytes
(RBC),
platelets, leukocytes
(WBC) with differential (neutrophils, lymphocytes, 
basophils, eosinophils, monocytes and blasts).
HBV serology (HBsAg, antibody to HBsAg [anti-HBs], anti-HBc, HCV serology (anti-
HCV) and HIV will be required only at screening.  
HIV will be performed based on local regulation at local laboratory. HIV test already 
performed within 30 days prior to the ICF signature will be accepted as screening 
evaluation.
Blood chemistry panel: glucose, blood urea nitrogen/urea, creatinine, creatinine clearance 
(derived from blood creatinine value by Cockcroft formula), sodium, potassium, chloride, 
calcium, phosphorus, magnesium, bicarbonate /carbon dioxide
(CO2), alkaline 
phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
total bilirubin, total protein, uric acid, albumin, and lactic acid dehydrogenase (LDH)
Coagulation panel: PT, INR, PTT, fibrinogen, D dimer
After review of the laboratory data, the Investigator must sign and date each laboratory 
report. The laboratory will provide normal reference ranges on the laboratory results 
report and will flag all abnormal values. The Investigator will assess the clinical 
relevance of values outside the normal range and repeat, if needed, any clinically 
significant abnormal laboratory test. 
Only clinically significant abnormal laboratory values should be recorded and reported as 
AEs or SAEs depending on the evaluation performed by the Investigator. Abnormal 
clinically significant laboratory values detected at screening are not considered AE, but 
the underline disease needs to be reported in the medical history page, as appropriate. 
Whenever possible, the etiology of the abnormality should be identified and the diagnosis 
should be recorded as an AE.


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6.3
PK Assessments
6.3.1
Pracinostat Population PK Assessments
Sparse blood samples will be collected in Cycle 1 on Days 1, 2, 3 and 15 in all study 
patients (except for patients participating in the AZA/pracinostat PK sub-study; refer to 
Section 6.3.2) to characterize the pracinostat population PK and assess the effect of drug 
exposure on safety and efficacy.
The following population PK samples are to be collected post pracinostat/placebo 
administration:

30 minutes ± 15 minutes

3 hours ± 30 minutes

6 hours ± 30 minutes

24 hours ± 1 hour  (before AZA administration)

48 hours ± 2 hours (before next pracinostat/placebo dose intake)

Day 15 (any time within 24 h after pracinostat/placebo dosing for the day)
The cannula will be rinsed, after each sampling, with about 1 mL of sterile saline solution 
containing 20IU/mL Na-heparin. The first 1.0-1.5 mL of blood will be discarded to 
eliminate the heparin solution before any sample collection. 
Blood samples of 1.5 mL will be collected into tubes containing K2EDTA as 
anticoagulant. 
Plasma will be obtained by centrifugation in a refrigerated centrifuge and divided in two 
Eppendorf tubes. Each tube will be filled with at least 150 µL of plasma for the assay of 
pracinostat and its metabolites (sample and back-up sample).
The samples will be stored frozen and sent to the central laboratory for analysis. The 
validated LC-MS/MS analytical method requires 50 µL of plasma for the assay of 
pracinostat and its metabolites.
Please refer to the laboratory manual for more detailed information.
6.3.2
AZA/Pracinostat PK sub-study (IN SELECTED SITES ONLY): 
Assessment of the possible drug interaction of Pracinostat on the 
PK of Azacitidine
The azacitidine PK in individual patients with/without the concomitant administration of 
pracinostat will be studied in the two groups of patients according to a dense blood 
sampling scheme and non-compartmental analysis (NCA). Each group will be composed 
of at least 12 subjects. The possible interaction of pracinostat on the PK of azacitidine 
will be assessed by comparing the descriptive statistics of PK parameters of azacitidine in 
the two groups. The sub-study will be performed at selected sites and only in patients 
administered subcutaneous AZA. This approach will be preferred over a population PK 
approach because of the known instability of azacitidine in blood and plasma, which 


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makes the correct and reliable application of a strict sample handling procedure at each 
clinical site difficult.
Blood samples will be collected at the following time points on Cycle 1 Day 1 after start 
of AZA administration:

15 minutes ± 2 minutes

30 minutes ± 2 minutes

1 hour ± 5 minutes

2 hours ± 5 minutes

3 hours ± 5 minutes

4 hours ± 5 minutes

6 hours ± 30 minutes 

8 hours ± 30 minutes (optional sampling)
On Cycle 1 Day 2 before start of AZA administration:

24 hours ± 1 hour
The cannula will be rinsed, after each sampling, with about 1 mL of sterile saline solution 
containing 20IU/mL Na-heparin. The first 1.0-1.5 mL of blood will be discarded to 
eliminate the heparin solution before any sample collection. 
Blood samples of about 4 mL will be collected for each timepoint (until 24 hours ± 1 
hour) in two tubes containing K2EDTA as anticoagulant:
-
One tube containing 2 mL of blood will be processed for the assay of 
Azacitidine and it must be stabilized by adding, immediately after collection, 
the appropriate stabilizer tetrahydrouridine (THU). After centrifugation, the 
plasma obtained will be divided in two tubes to be filled in with at least 500 
µL of plasma each (sample and back-up sample). 
-
The second tube containing 2 mL of blood will be processed for the assay of 
Pracinostat and its metabolites. After centrifugation, the plasma obtained will 
be divided in two tubes to be filled in with at least 150 µL of plasma each
(sample and back-up sample).
Only for the assay of Pracinostat and its metabolites, two additional blood samples of 1.5 
mL each will be collected into tubes containing K2EDTA as anticoagulant at the 
following time points on Cycle 1:

Day 3: 48 hours ± 2 hours (before next pracinostat/placebo dose intake)

Day 15: (any time within 24 h after pracinostat/placebo dosing for the day)
Plasma obtained by refrigerated centrifugation will be divided in two Eppendorf tubes. 
Each tube will be filled in with at least 150 µL of plasma (sample and back-up sample).
The samples will be immediately stored frozen at -20°C (pracinostat/placebo samples) or 
at -70°C (azacitidine samples) and sent to the central laboratory for analysis. 
The validated LC-MS/MS analytical methods require 200 µL of plasma for the assay of
azacitidine and 50 µL of plasma for the assay of pracinostat and SB991.


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Please refer to the laboratory manual for more detailed information.
6.4
Biomarker Analysis (Optional)
The purpose of this exploratory study is to assess the presence, type, and frequency of 
AML-related molecular mutations in this patient population and whether there is an 
association between specific mutations and disease outcome with the study therapy.
The planned biomarker analyses involve the analysis of protein and nucleic acids (i.e., 
RNA and/or DNA). Biomarkers deemed relevant to gain further knowledge about the 
pathomechanism of the disease or about the drug (i.e., mode of action or safety of the 
drug) may be measured, based on newly emerging data from other ongoing trials of these 
investigational drugs and/or literature data. However, the study sponsor reserves the right 
not to conduct all or part of the biomarker analysis. Data from this biomarker analysis 
may be correlated with various other data obtained in this study (e.g., clinical efficacy, 
pharmacokinetics, toxicity).
Peripheral blood samples and/or aspirate bone marrow samples will be collected and 
stored for potential molecular studies at screening, between day 21 and day 26 of every 
even cycle and at End of Treatment visit.
Specimens to study AML-related molecular mutations will be collected from patients 
who give specific consent to participate in this optional research. The Informed Consent 
Form will contain a separate section that addresses participation in the molecular 
mutation assessments. The Investigator or authorized designee will explain to each 
patient the objectives, methods and potential hazards of participation in this research. 
Patients will be told that they are free to refuse to participate and may withdraw their 
specimens at any time for any reason during the storage period. A separate, specific 
signature will be required to document a patient’s agreement for this purpose. 
Dates of consent should be recorded in the associate page of eCRF. For sampling 
procedures, storage conditions, and shipment instructions, see the laboratory manual.
Collection and submission of these samples is contingent upon the review and approval 
of the exploratory research portion of the Informed Consent Form by each site’s 
Institutional Review Board or Ethics Committee and, if applicable, appropriate regulatory 
body. If a site is not granted approval for these assessments, this section of the protocol 
will not be applicable at that site. 
6.5
Efficacy Endpoints
6.5.1
Primary Endpoint
The primary efficacy endpoint is the overall survival (OS) measured as the time from 
randomization until death from any cause.


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6.5.2
Secondary Endpoints
6.5.2.1
Morphologic Complete Remission (CR) rate
6.5.2.2
The CR rate is the proportion of patients who achieve a 
morphologic CR according to the IWG response criteria (Appendix 
F) in the absence of interceding therapies, including salvage 
treatments and HSCT, within the study period.Transfusion 
Independence (TI)
Transfusion independence rate is defined as the proportion of patients who achieve eight 
weeks or longer with neither red blood cell (RBC) nor platelet (PLT) transfusions during 
the study period [Fenaux, 2009; Silverman , 2006]. 
6.5.2.3
Complete Remission without minimal residual disease (CRMRD-)
rate
The CRMRD- rate is the proportion of patients who achieve a CR with MRD negativity by 
multi-color flow cytometry, according to the IWG response criteria (Appendix F) within 
the study period.  
6.5.2.4
Cytogenetic Complete Remission (CRc) rate
The CRc rate is the proportion of patients who achieve a reversion to a normal karyotype 
at CR (Appendix F) within the study period. This endpoint applies only to patients with 
abnormal cytogenetics at enrollment.
6.5.3
Exploratory Endpoints
6.5.3.1
Composite Complete Remission (cCR) rate
Composite complete remission (cCR) rate is the proportion of patients who achieve either 
a disease response of CR, CRi or MLFS (i.e., cCR = CR + CRi + MLFS) within the study 
period, (Appendix F).
6.5.3.2
Relapse Free Survival (RFS) 
RFS is defined as the time from the date of achievement of CR or CRi until the date of 
relapse (progression) or death from any cause, whichever occurs first. RFS is only 
defined for patients who achieve a CR or CRi.
6.5.3.3
Progression Free Survival (PFS) 
PFS is defined as the time from the date of randomization until the date of relapse 
(progression) or death from any cause, whichever occurs first.
6.5.3.4
Duration of Morphologic Complete Remission 
Duration of Morphologic Complete Remission is defined as the time from the date of
achievement of CR until the date of relapse (progression). Duration of CR is only defined 
for patients who achieve CR.


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6.5.3.5
Duration of Composite Complete Remission
Duration of cCR response is the time from the date of achievement of either CR, CRi or 
MLFS (F) until the date of relapse (progression). Duration of cCR is only defined for 
patients who achieve a cCR.
6.5.3.6
Time to CR 
Time to CR is defined as the time from the date of randomization until the date of CR in 
the absence of interceding therapies, including salvage treatments and HSCT.
6.5.3.7
Morphologic Complete Remission (CR) within 6 cycles rate
Morphologic complete remission (CR) within 6 cycles rate is defined as the proportion of 
patients who achieve CR in the absence of interceding therapies, including salvage 
treatments and HSCT, within 6 treatment cycles.
6.5.3.8
Quality of Life
Computation of the global health status and of selected functional scales and symptom 
scales from the EORTC QLQ-C30 questionnaire will be performed and their change from 
baseline over the study period will constitute the endpoints.
6.6
PK Endpoints

To characterize the pharmacokinetics (PK) of pracinostat and its main metabolites in 
AML patients by a population pharmacokinetic approach

To characterize demographic, physiopathological and therapeutic covariates that may 
influence pracinostat PK parameters and their interindividual variability

To characterize the pracinostat exposure-response relationship for safety and efficacy 
endpoints (PK/PD)

To assess the possible drug interaction of Pracinostat on the PK of AZA in AML 
patients by comparing the descriptive statistics of PK parameters of azacitidine in the 
two groups


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7
DISCONTINUATION FROM STUDY TREATMENT PHASE OF 
THE STUDY
7.1
Patient Treatment Discontinuation
If patients experience any of the following, then they must discontinue from the study 
treatment phase of the study:

Documented disease progression or relapse after CR by the International Working 
Group (IWG) criteria (Appendix F).

Lack of clinical benefit. Clinical responses may require at least 6 courses of study 
treatment. Therefore, discussion with the Medical Monitor is recommended prior 
to discontinuation of a patient on the basis of lack of clinical benefit. 

Irreversible or intolerable toxicity or abnormal and clinically significant 
laboratory findings that cannot be managed with study treatment dose reduction 
or interruption.

A patient’s request to discontinue treatment for any reason. If a patient requests 
discontinuation from study treatment due to an AE, the primary reason for 
discontinuation should be the adverse event.

Non-compliance
with study treatment or study-related assessments that 
compromise the proper evaluation of the patient’s safety

Lost to follow-up.

Sponsor decision: The Sponsor reserves the right to discontinue the study at any 
time for either clinical or administrative reasons. This decision will impact 
patients in the treatment and in the Long-term Follow-up phases of the study.

Pregnancy.
Upon study treatment discontinuation, assessments of the End of Treatment Visit must be 
completed (refer to Section 5.1.14). Discontinued patients will enter the Long-term 
Follow-up phase of the study (refer to Section 5.2). Every attempt must be made to 
contact the patient prior to assigning the patient a lost to follow-up status. For patients 
who are lost to follow-up, no Long-term Follow-up is expected.
7.2
Patient Withdrawal
Patients have the right to voluntarily withdraw from the study at any time and for any 
reason. In addition, a patient’s participation in the study may be discontinued at any time 
at the discretion of the Investigator. Reasons for withdrawal from the study may include, 
but are not limited to, the following:

Death

Lost to Follow-Up

Patient withdrawal of consent at any time during the patient’s study participation, 
including during the Long-term Follow-up phase of the study.
Every effort should be made to obtain survival information on patients who withdraw 
from the study. The primary reason for withdrawal from the study should be documented


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in the patient’s study records and in the eCRF. Patients who withdraw from the study will 
not be replaced.
7.3
Site Discontinuation
The Sponsor has the right to close a site at any time. Reasons for closing a site may 
include, but are not limited to, the following:

Non-compliance with ICH-GCP guidelines

Inadequate rate of patient recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
7.4
Study Termination 
Study termination is defined as the time when all study treatments, study related-
assessments, and study data collection are completed. Upon termination of the study, the 
Sponsor or designee will conduct site closure activities with the Investigator or site staff 
(as appropriate), in accordance with applicable regulations and the Study Manual.
The Sponsor reserves the right to temporarily suspend or terminate the study at any time 
for reasons including, but not limited to, safety issues or ethical reasons. The Sponsor or 
designee will also promptly inform the relevant regulatory authorities of the 
suspension/termination along with the reasons for such action, when applicable. Where 
required by applicable regulations, the Investigator or head of the medical institution 
must inform the Institutional Review Board (IRB)/Ethics Committee (EC).


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8
SAFETY
8.1
Safety Parameters and Definitions
Safety assessments will consist of evaluating and recording AEs, including serious 
adverse events (SAEs); measurement of protocol-specified safety laboratory assessments; 
measurement of protocol-specified vital signs, ECGs, and physical examinations.
8.1.1
Definition of Adverse Events
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE (also referred to as an adverse experience) 
can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, and does not imply any 
judgment about causality. An AE can arise with any use of a drug (e.g., off-label use, use 
in combination with another drug) and with any route of administration, formulation, or 
dose, including an overdose. 
Adverse reactions are defined as a subset of all adverse events for which there is 
reasonable possibility that the drug caused the event.
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.
8.1.1.1
Suspected Adverse Reaction
Suspected adverse reactions are the subset of all AEs for which there is a reasonable 
possibility that the drug caused the event. For the purposes of US Investigational New 
Drug (IND) safety reporting, ‘‘reasonable possibility’’ means there is evidence to suggest 
a causal relationship between the drug and the AE. Suspected adverse reaction implies a 
lesser degree of certainty about causality than adverse reaction, which means any AE 
caused by a drug.
8.1.1.2
Life-threatening AE or Life-Threatening Suspected Adverse 
Reaction
An AE or suspected adverse reaction is considered ‘‘life-threatening’’ if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an AE or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death.
8.1.1.3
Serious AE or Serious Suspected Adverse Reaction
An AE or suspected adverse reaction is considered ‘‘serious’’ if any of the following 
criteria is met:

Death, including death that appear unrelated to the study treatment  

Life-threatening AE

Inpatient hospitalization or prolongation of an existing hospitalization, excluding 
the following scenarios:
i. Emergency room visit or hospital visit without official admission


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ii. Prolongation due to management or progression of the underlying 
disease
iii. Hospitalization for a pre-existing condition, provided that any of the 
following criteria are met:
1. The hospitalization was planned
2. Hospitalization 
to 
accommodate 
study 
treatment
administration or required study procedures
3. Hospitalization due to disease progression

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
8.1.1.4
Unexpected AE or Unexpected Suspected Adverse Reaction
An AE or suspected adverse reaction is considered “unexpected” if it is not reported in 
nature, severity or incidence in the current version of the pracinostat IB (Section 7. 
Appendix). 
8.1.1.5
Treatment-Emergent Adverse Event
A TEAE is an adverse event that emerges, or a pre-existing adverse event that worsens in 
severity, any time after the patient receives Dose 1 of study drug (pracinostat/placebo) 
through the end of the AE reporting period. AEs with onset before the patient receives 
Dose 1 of study drug are considered as pre-treatment AEs. AEs with onset after the end 
of the reporting period (if any) are considered as post-treatment AEs.
Laboratory tests, vital signs, and ECG abnormalities will be reported as AEs only if the 
event is considered clinically significant or leads to medical intervention (e.g., additional 
concomitant medication or procedures, discontinuation of study drug). Refer to Section 
8.2.5.3 for details.
8.2
Adverse Event Reporting
All adverse events occurring from the informed consent signature until 30 calendar days 
after last study drug (pracinostat/placebo) intake, or until the initiation of new therapy for 
AML, whichever occurs first, are to be recorded on the appropriate eCRF section. 
Every effort must be made by the Investigator to categorize each adverse event according 
to its severity and its relationship to the study treatment (study drug and/or azacitidine).


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All AEs will be followed until symptom resolution or until the condition stabilizes, 
unless, in the Investigator’s opinion, the AE or laboratory abnormality/ies are not likely
to improve because of the underlying disease or unless the patient is lost to follow-up.
Whenever a change in the severity of an AE (such as a worsening) has occurred, a follow 
up of the initial AE should be entered in the eCRF reporting the new severity.
Outcome of ongoing serious and non-serious AEs will be reported in eCRF until the end 
of the reporting period as above defined. All non-resolved serious and non-serious AEs 
beyond such date will be recorded in eCRF as “ongoing” without further follow-up.
8.2.1
Serious Adverse Event (SAE) 
Any SAE, irrespective of the relationship to study treatment, must be reported by the 
Investigator to CRO. Within 24 hours of the study site staff becoming aware of any SAE, 
the Investigator or the Investigator’s designee must complete the eCRF with all necessary 
information. Any accompanying source documents (hospital records, autopsy report, etc.) 
should be faxed or e-mailed (as PDFs) at the following 24-hours contact information:
Email: Helsinn.safety@clinipace.com
Fax: +49 6196 7709 112 
SAEs should be collected from the informed consent signature until 30 calendar days 
after discontinuation or completion of study treatment, or until the initiation of new 
therapy for AML, whichever occurs first, and followed until resolution.
“Disease progression” or “relapse from remission”as such, should not be reported as 
SAEs. 
“Death” is an outcome and should not be reported as an SAE, unless the cause leading to 
death is unknown. When recording an SAE with an outcome of death, the event or 
condition that caused or contributed to the fatal outcome should be recorded as the single 
serious adverse event term.
The Investigator must immediately (within 24 hours) report follow-up information for
initial events to Clinipace and the Sponsor as described above. Follow-up information 
can include but is not limited to the following significant information:

New signs or symptoms or a change in the diagnosis

Clinically significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting of initial and 
follow-up SAEs to their Institutional Review Board (IRB)/ Ethics Committee (EC) 
according to their own interpretations of the regulations and their own institutional 
policies.


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The Sponsor/ designee is responsible for SAE reporting to the Regulatory Authorities 
where the study is conducted, according to reporting requirements as per local regulatory 
rules. 
8.2.2
Pregnancies
Male patients and female patients who are of childbearing potential must use an effective 
contraceptive/birth control while participating on study. Pregnancies in female patients or 
female partners of male patients must be notified by the Investigator to the 
Sponsor/designee within 24 hours from knowledge of the pregnancy. If a female patient 
becomes pregnant, study treatment must be immediately discontinued until delivery. The 
Investigator should obtain informed consent from the patient or from the patient’s partner 
allowing the Investigator to obtain information regarding the pregnancy and its outcome.
If the patient’s partner provides informed consent, the Investigator should follow the 
pregnancy until outcome and report this outcome to the Sponsor/designee.
An induced abortion or a spontaneous abortion is considered to be a SAE and should be 
reported in the same timeframe and in the same format as all other SAEs. 
8.2.3
Adverse Event Severity
All AEs will be graded for severity using the NCI CTCAE v4.03.
If an AE is not listed in the NCI CTCAE v4.03, refer to Table 3 for guidance on grading 
of AE severity.
Table 3:
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE
Grade Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.
Note: Based on the most recent version of NCI CTCAE (v4.03), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, 
using the toilet, and taking medications, as performed by patients who are not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious adverse event, per 
the definition of serious adverse event in Section 8.1.1.3.


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8.2.4
Adverse Event Causal Relationship to study treatment
The Investigator’s assessment of causality must be provided for all AEs whether serious 
or non-serious. Investigators should use their knowledge of their patients, the 
circumstances surrounding the event, and an evaluation of any potential alternative cause 
to determine whether or not an AE is considered to be related to the pracinostat, 
azacitidine, or both, indicating “yes” or “no” accordingly: see Table 4.
Table 4:
Adverse Event Causal Attribution Guidance
Yes, Related
A reaction that follows a plausible temporal sequence from 
administration of the study treatment and cannot be explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies, 
and/or follows a known response pattern to the suspected study 
treatment, and/or abates or resolves upon discontinuation of the study 
treatment or dose reduction and, if applicable, reappears upon re-
challenge.
No, not Related
The adverse event has no plausible temporal relationship to 
administration of the study treatment; and/or is related to other 
etiologies such as concomitant treatments or patient’s concurrent or 
pre-existing clinical state.
8.2.5
Procedures for Recording of Adverse Events
8.2.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded for that Adverse Event rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice and
elevated transaminases).
8.2.5.2
Persistent or Recurrent Adverse Events
A persistent AE is one that extends continuously, without resolution, between subject 
evaluation time points. The initial severity (intensity) of the event will be recorded at the 
time the event is first reported. Changes over time in toxicity grade should be recorded as 
follow up of the initial event.  
8.2.5.3
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an AE. Laboratory test results (including 
cytopenias) which are expected by the Investigator should not be reported as an AE
unless:

The event is accompanied by clinically significant symptoms which are new or 
worsened from baseline.

Result in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Result in a medical intervention (e.g., blood transfusion for anemia, potassium 
supplementation for hypokalemia) or a change in concomitant therapy.


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
The event is clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE.
If an abnormal laboratory value or vital sign is associated with clinical signs and/or 
symptoms, the sign or symptom should be reported as an AE or SAE.
8.2.6
Adverse Events of Special Interest
Adverse events of Special Interest are defined as pre-specified AEs, serious and non-
serious, under ongoing monitoring by the Sponsor. 
No specific reporting timelines or other activities are required by the Investigator in 
addition to the normal AE reporting practices as described in the above sections for the 
followings AE of special interest:  

Supraventricular arrhythmias

Sepsis, septic shock, grade ≥3 lung infection (pneumonia)

Any infection leading to death

Grade ≥3 anemia, neutropenia, febrile neutropenia and thrombocytopenia

Grade ≥3 haemorrhage
8.2.6.1
QTc prolongation
Any QTc prolongation ≥ 500 ms and/or > 60 ms change from baseline, irrespective of the 
relationship to study treatment, must be always reported as an AE. The Investigator or the 
Investigator’s designee must complete the AE pages of eCRF with all necessary 
information and any accompanying source documents (hospital records, ECG report, etc.) 
should be faxed or e-mailed (as PDFs) at the following contacts:
Email: Helsinn.safety@clinipace.com
Fax: +49 6196 7709 112 
8.2.6.2
Adverse Events Associated with an Overdose
An overdose is any dose of study treatment given to a patient or taken by a patient that 
exceeds the dose described in the protocol. An overdose is the accidental or intentional 
use of a drug in an amount higher than the dose being studied. An overdose or incorrect 
administration of study treatment is not itself an AE, but it may result in an AE. All 
overdoses should be recorded, independently from an association with AEs. 
All AEs associated with an overdose or incorrect administration of study treatment
should be recorded. 
If an overdose results in an SAE, it must be reported to the Sponsor as an SAE within 24 
hours of identifying the event. Currently, there are no safety data related to pracinostat
overdose. If overdose is suspected, administration of study drug should be stopped and 
general supportive measures instituted.


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8.2.7
Patient Unblinding For Safety Reasons
Unblinding of study treatment (i.e., pracinostat or placebo) for a specific patient will only 
be permitted in the event of a medical emergency that would require the investigator to 
be aware of the treatment allocation prior to the end of the study. For any study treatment 
unblinding, the reason must be documented in the patient’s medical record. Treatment 
identification information should be kept confidential. 
8.2.7.1
Unblinding Procedure
The Investigator has the possibility to unblind the study treatment in case of an 
emergency situation, when he/she considers essential to know what treatment the patient 
is receiving. To proceed with the unblinding procedure, he/she is allowed to access 
TEMPOTM system (available 24 hours 7 days coverage), select the patient identifier and 
choose the “Unblinding of study treatment” Form in the “Subject management” section. 
After confirmation of the request, the treatment regimen assigned to patient at the time of 
randomization will be shown together with the list of identifiers of the kits assigned. A 
notification email informing that the code has been broken, but not reporting the 
treatment assigned, is sent to the person performing the unblinding and to the Sponsor. If 
the code is broken by Investigator, the patient should be discontinued permanently from 
treatment and he/she will enter the long-term follow-up period.
When an event might be a Suspected Unexpected Serious Adverse Reaction (SUSAR)
the blind should be broken by the Sponsor for pharmacovigilance reporting purposes only 
for that specific subject. Unblinding information should only be accessible to those who 
need to be involved in the safety reporting to Regulatory Authorities, while the blind 
should be maintained for all other persons responsible for the ongoing conduct of the 
study. The patient will not be withdrawn from the study in case of unblinding by the 
Sponsor’s Drug Safety Department for pharmacovigilance reporting purposes.
8.3
Independent Data Monitoring Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will be established for this study to 
serve in an advisory capacity to the Sponsor. The IDMC will be primarily responsible for 
assessing emerging safety data on an ongoing basis as well as a one-time evaluation of an 
interim efficacy analysis and will recommend whether the study should be stopped based 
on 1) reaching the pre-specified criterion for superiority or the pre-specified criterion for 
futility and 2) the overall risk-to-benefit assessment.
The IDMC will consist of at least two AML disease experts and a biostatistician (none of 
them being employees of the Sponsor or of the CRO or investigators in the study). The 
IDMC will regularly review cumulative safety data and make recommendations, if 
necessary, to the Sponsor relating to the selection, recruitment, and retention of patients; 
patient management; improving adherence to protocol-specified treatments and 
assessments; and the procedures for data management and quality control. The IDMC 
may be unblinded for some or all patients according to the conditions established in the 
IDMC charter.


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The scope and details of obligations of the IDMC members and operational details of the 
committee will also be described in the IDMC Charter to be finalized before the start of 
patient enrollment.


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9
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
9.1
Statistical Design 
This is a Phase III, global, double-blind, randomized, placebo-controlled study comparing 
the efficacy and safety of pracinostat or placebo in combination with azacitidine in 
patients with previously untreated AML who are aged ≥ 18 years. This is an event-driven 
study and an interim analysis for both futility and superiority will be performed at 2/3 of 
information (260/390 events).
The primary efficacy endpoint is overall survival (OS) in the intent-to-treat (ITT) patient 
set using the log-rank test stratified by cytogenetic risk and ECOG. The null and 
alternative hypotheses to be tested for OS distribution, assuming proportional hazards,
are:
H0: HR ≥1 
H1: HR < 1
where HR is the hazard ratio of the pracinostat group over the placebo group.
Hazard Ratio equal to 1 is used as H0 for sample size calculations.
Secondary endpoints will be tested according to a fixed sequence method. If the primary 
endpoint is statistically significant, then the first secondary endpoint (according to the 
predefined list) will be tested, and so on for the other three secondary endpoints. When 
the sequence stops for a non-significant test the following tests will be downgraded to 
exploratory.
9.2
Randomization and Stratification 
This study will employ a 1:1 randomization. Patients will be stratified based on the 
following factors:

Cytogenetic risk category (intermediate vs. unfavorable-risk) 

ECOG 0/1 vs. 2
Information on pracinostat + AZA (Phase 2 study MEI-004) suggests some factors as 
influencing the OS. This information was combined with information provided by current 
literature on AZA [Dombret, 2015] and the most influencing factors emerged as 
candidates chosen as stratification factors at randomization to guarantee a proper balance 
between treatments. In particular ECOG was selected as grade 2 is generally much less 
frequent than grades 0/1, while Cytogenetic risk was included as showing a large 
difference between intermediate and unfavorable risk. 
If available, the central cytogenetic test result will be used to assess the cytogenetic risk 
category at randomization. If the central result is not available, the local result will be 
used.
Randomization will be conducted centrally via an IWRS.
9.3
Analysis Sets
The definitions of analysis sets are as follows:


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1) All randomized (Intent-to-Treat; ITT) - This set will comprise all randomized
patients, regardless if the patient was administered study drug. Patients will be 
assigned to treatment groups based on the randomized study drug assignment.
This set will be the primary set analyzed for the primary efficacy endpoint (OS) 
and will be also used for the efficacy endpoint RFS and the analysis of durations 
of response (limited to patients with response), transfusion independence, for the 
analysis of the efficacy endpoints CR rate , CRMRD- rate and for the exploratory 
endpoints..
2) Safety - This set will comprise all patients who received at least one dose of study 
drug (pracinostat/placebo). Patients will be assigned to treatment groups based on 
the actual drug received. This set will be the primary set analyzed for safety.
3) Per Protocol (PP) – This set will comprise patients who met all eligibility criteria 
and received randomized study treatment without substantial deviations or 
violations. This set will be the secondary set analyzed for the efficacy endpoint 
OS. 
4) ITT-2– This set will comprise patients in the ITT set with abnormal cytogenetics
at enrollment. This will be the primary set used for the analysis of the efficacy 
endpoint CRc rate.
5) Efficacy Evaluable 1 (EE-1) – This set will comprise patients in the ITT set who
had a complete disease response assessment. A complete disease response 
assessment is defined as at least 1 post-baseline peripheral blood count 
determined and 1 post-baseline bone marrow assessment performed, with an 
Investigator response reported. A peripheral blood count is defined as an 
assessment of absolute neutrophil count (ANC), platelets and peripheral blasts. In 
addition, patients who discontinued due to progressive disease (per the Study 
Discontinuation form) without a complete disease response assessment will also 
be included in this Efficacy Evaluable Set. This will be the secondary set used for 
the analysis of the efficacy endpoints CR rate, CRMRD- rate and cCR rate.
6) Efficacy Evaluable 2 (EE-2) –This Efficacy Evaluable Set will comprise all 
patients in the ITT-2 who had a complete disease response assessment. A 
complete disease response assessment is defined as at least 1 post-baseline 
peripheral blood count determined and 1 post-baseline bone marrow assessment 
performed, with an Investigator response reported. A peripheral blood count is
defined as an assessment of absolute neutrophil count (ANC), platelets and 
peripheral blasts. In addition, patients who discontinued due to progressive 
disease (per the Study Discontinuation form) without a complete disease response 
assessment will also be included in this Efficacy Evaluable Set. This will be the 
secondary set used for the analysis of the efficacy endpoint CRc rate.
Detailed information on these and other sets will be provided in the Statistical Analysis 
Plan.
The PK analysis set(s) will be defined in the Statistical Analysis Plan (SAP) dedicated to 
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9.4
Procedures for Handling Missing, Unused and Spurious Data
All available efficacy and safety data will be included in the data listings and tabulations. 
Handling of missing data and imputation of values for missing data is presented, however 
further details will be given in the SAP.
Censoring rules for time-to-event endpoints (e.g., OS and RFS) are described in Section 
9.7.
9.5
General Statistical Considerations
Continuous endpoints will be summarized using descriptive statistics, which will include 
the number of patients with a valid measurement (n), mean, standard deviation, median, 
minimum, and maximum.
All categorical endpoints will be summarized using 
frequencies and percentages. Time-to-event endpoints (in particular OS) will be analyzed 
using Kaplan-Meier product limit methods to estimate the survival distribution, median 
time-to-event with 95% confidence interval and survival probabilities at selected time 
points; numbers of patients at risk, patients with an event, patients censored at selected 
timepoints will be reported too.
For analyses of endpoints of a proportion of patients with disease response performed on 
the relevant ITT/EE set, the number of patients in the relevant ITT/EE set will be the 
denominator for the proportion. 
A summary table including the best response obtained for each subject during study 
course will also be presented (number of patients and related percentage). Absence of 
interceding therapies, including salvage treatments and HSCT is requested for 
considering the response (CR, CRi, MLFS, PR, SD) in the analysis, otherwise the 
response will be considered as not evaluable.
The analysis sets will be the ITT and the EE-1 set. The corresponding ITT-2 and EE-2 
sets will be the basis when CRc is considered.
The safety endpoints will be listed and/or summarized by relevant time points, as 
appropriate.
Unless specified otherwise, the baseline value for efficacy and safety variables is the last 
non-missing value before the first dose of study treatment. Data listings will be created to 
support each table and to present all data.
Unless otherwise specified, all statistical tests will be 1-sided and carried out at the 0.025 
α level. Further details regarding the statistical analysis are contained in the following 
sections and in the SAP.
9.6
Study Population Data
Patient disposition will be summarized for all screened patients. The total number of 
patients for each defined analysis set will also be tabulated. The demographic and 
baseline characteristics will be summarized for the ITT, ITT-2 and Safety sets, as 
relevant. Study treatment exposure and duration will be summarized using descriptive 
statistics for the Safety set.


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9.7
Efficacy Analyses
9.7.1
Primary Efficacy Analysis - Overall Survival
The primary efficacy endpoint is overall survival (OS) measured as the time from 
randomization until death from any cause.
OS time for patients alive or lost to follow-up at the time of analysis will be censored at 
the date when they were last known to be alive. 
OS will not be censored at the time of subsequent AML therapy. Both interim and final 
OS analyses will be performed on the ITT set. Final analysis will take place after the 
required number of events (390 deaths) has occurred. 
The primary OS analysis will be based on the log-rank test stratified by the factors used 
for randomization (cytogenetic risk and ECOG) at the overall one-sided alpha = 0.025 
level of significance (specific alpha levels will be used for interim and final analysis). 
Log-rank stratified by cytogenetic risk obtained by central laboratory (when available)
and ECOG at Day 1 Cycle 1, unstratified log-rank test and Cox PH model including 
factors used for randomization will be used as sensitivity analyses to support evidence of 
efficacy. Kaplan-Meier estimates of OS in each treatment group will be reported, both 
overall and within strata of patients. Estimates of median survival will be provided with 
two-sided 95% confidence intervals, along with the 25th and 75th percentiles, together 
with the HR estimates. The number of surviving patients, the number of deaths and the 
number of patients with censored values will be displayed as well. 
Checks on the proportionality of hazards will be performed.
Censoring patterns will be examined between treatment groups. The effect of subsequent 
therapy on OS will be analyzed, including an analysis that compares OS in the treatment 
groups with censoring at the start date of the new regimen subsequent AML therapy.
Other sensitivity analyses will be performed to assess the robustness of OS results, if 
relevant. 
The primary OS analysis (stratified log-rank test) will be repeated for the PP set.  
Further exploration of baseline/demographic factors of interest will be done by means of 
Cox PH model.
9.7.2
Secondary Efficacy Endpoints
The secondary efficacy outcome measures for this study are the following (the order is 
relevant to the sequence procedure for testing endpoints):

CR rate Transfusion independence

CRMRD-rate

CRc rate


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9.7.2.1
Morphologic Complete Remission (CR) rate
The rate of CR is defined as the proportion of patients who achieve a morphologic CR 
according to the IWG response criteria (Appendix F) in the absence of interceding 
therapies, including salvage treatments and Hematopoietic Stem Cell Transplant (HSCT), 
within the study period. The proportions in the two treatment groups will be compared at 
a 1-sided alpha = 0.025 level of significance using the Cochran-Mantel-Haenszel test 
stratified for cytogenetic risk and ECOG PS (values at randomization). In addition, the 
two-sided 95% CI for the difference between the responder proportions in the two 
treatment groups will be provided, using the stratified Newcombe method. 
The analysis will be primarily performed in the ITT set (patients for whom no efficacy 
assessment is available will be analyzed as not having CR) and then in the EE-1 set. 
Unstratified analysis will be done for sensitivity purpose by means of likelihood ratio Chi 
square test.
9.7.2.2
Further exploration of baseline/demographic factors of interest 
could be done by means of logistic regression models.Transfusion 
Independence
The proportion of patients who showed transfusion independence will be summarized by 
study treatment and transfusion dependence at baseline. The proportion of patients who 
are transfusion independent (by both RBCs and platelets) during study will be compared 
between the two treatment groups by using the same methods as those used for the CR 
rate analysis. The analysis set will be the ITT set. Rules for imputing missing data will be 
defined in the SAP. 
9.7.2.3
Complete Remission without minimal residual disease rate
The CRMRD- rate is the proportion of patients who achieve a CR with MRD negativity by 
multi-color flow cytometry, according to the IWG response criteria (Appendix F) within 
the study period (details will be given in the SAP). Absence of interceding therapies, 
including salvage treatments and HSCT is requested for considering the response in the 
analysis (for both CR and MRD negativity). CRMRD- rate will be analyzed on the ITT and 
EE-1 sets, using the same methods as those used for the CR rate analysis. Patients for 
whom no assessment with multi-color flow cytometry is available at the planned time 
points will be analyzed as not having reached CRMRD-. However, patients from sites for 
which no assessment of MRD was possible for logistic reasons will be excluded from the 
ITT/EE-1 sets. Additional rules will be defined in the SAP.
9.7.2.4
Cytogenetic Complete Remission rate
The rate of Cytogenetic Complete Remission (CRc) is defined as the proportion of 
patients who achieve a reversion to normal karyotype at CR (Appendix F) within the 
study period. Absence of interceding therapies, including salvage treatments and HSCT is 
requested for considering the response in the analysis.
CRc rate will be analyzed on the ITT-2 set (as this endpoint applies only to patients with 
abnormal cytogenetics at enrollment). CRc rate will be analyzed using the same methods 
as those used for the CR rate analysis. The endpoint will also be analyzed in EE-2 set.


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9.7.3
Exploratory Efficacy Outcome Measures
The exploratory efficacy outcome measures for this study are the following:

cCR rate 

Relapse Free Survival (RFS)

Progression Free Survival (PFS)

Duration of Responses (CR, cCR)

Time to CR

CR within 6 cycles
9.7.3.1
Composite Complete Remission rate
Composite complete remission (cCR) rate is defined as the proportion of patients who 
achieve either a disease response of CR, CRi or MLFS (ie, cCR = CR + CRi + MLFS) 
within the study period (Appendix F). Absence of interceding therapies, including 
salvage treatments and HSCT is requested for considering the response in the analysis.
Composite CR rate will be analyzed on the ITT and the EE-1 sets. Composite CR rate 
will be analyzed using the same methods as those used for the CR rate analysis. Patients 
for whom no efficacy assessment is available will be analyzed as not having cCR when 
considering the ITT set. 
9.7.3.2
Relapse-free Survival (RFS)
RFS is defined as the time from the date of achievement of CR or CRi until the date of 
relapse (progression), or death from any cause, whichever occurs first.
Censoring rules will include the following:

Time to relapse (progression) will be censored at the date of the last assessment of 
patient status excluding relapse (progression). In case of no post-baseline disease 
assessments after CR, censoring will be at the date of CR/CRi. 
RFS will be analyzed using the same methods as those used for OS (Kaplan Meier 
estimates and stratified log-rank test). In addition, possible RFS analyses based on other 
RFS censoring criteria (e.g. censoring at the date of start of a new therapy) will be 
specified in the SAP. The analysis set will be the ITT set limited to patients who achieve 
a CR/CRi in absence of interceding therapies, including salvage treatments and HSCT.
9.7.3.3
Progression-free Survival (PFS)
PFS is defined as the time from the date of randomization until the date of relapse 
(progression), or death from any cause, whichever occurs first.
Censoring rules will include the following:

Time to relapse (progression) will be censored at the date of the last assessment of 
patient status excluding relapse (progression). In case of no disease assessments, 
censoring will be at the date of randomization. 
PFS will be analyzed using the same methods as those used for OS (Kaplan Meier 
estimates and stratified log-rank test). In addition, possible PFS analyses based on other 


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PFS censoring criteria (e.g. censoring at the date of start of a new therapy) will be 
specified in the SAP. The analysis set will be the ITT set.
9.7.3.4
Duration of Morphologic complete Remission (CR)
Duration of CR is defined as the time from the date of achievement of CR until the date 
of relapse (progression). Kaplan-Meier methods will be used to estimate duration of 
response in each treatment group. Estimates of median duration will be provided with 
95% confidence intervals, along with the 25th and 75th percentiles. Stratified log-rank 
test will be used to compare treatment groups.
Censoring rules will include the following:

Time will be censored at the date of the last adequate assessment of patient status 
excluding relapse (progression). In case of no disease assessments after CR, 
censoring will be at the date of CR.
In addition, possible analyses based on other censoring criteria (e.g. censoring at the date 
of start of a new therapy) will be specified in the SAP. The analysis set will be the ITT 
set limited to patients who achieve a CR in absence of interceding therapies, including 
salvage treatments and HSCT.
9.7.3.5
Duration of Composite Complete Remission
Duration of cCR response is defined as the time from the date of achievement of either 
CR, CRi or MLFS until the date of relapse (progression), and will be analyzed as the 
duration of CR response. 
Censoring rules will include the following:

Time will be censored at the date of the last assessment of patient status excluding 
relapse. In case of no disease assessments after cCR, censoring will be at the date 
of cCR.
In addition, possible analyses based on other censoring criteria (e.g. censoring at the date 
of start of a new therapy) will be specified in the SAP. The analysis set will be the ITT 
set limiting to patients who achieve a cCR in absence of interceding therapies, including 
salvage treatments and HSCT.
9.7.3.6
Time to CR
Time to CR is defined as the time from the date of randomization until the date of CR in 
the absence of interceding therapies, including salvage treatments and HSCT. The 
analysis set will be the ITT set.
Time to CR will be censored at the date of the last assessment of patient status excluding 
CR in the case no CR occurred by time of analysis. In case of interceding therapies, PD 
or death, time to CR will be censored to the new AML treatment start date, PD 
assessment date or death date, respectively. Cumulative Incidence Function (CIF) will be 
computed as 1-Kaplan Meier curve and treatment groups will be compared by the log-
rank test.


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9.7.3.7
Morphologic Complete Remission (CR) within 6 cycles rate
Morphologic complete remission (CR) within 6 cycles rate is defined as the proportion of 
patients who achieve CR in the absence of interceding therapies, including salvage 
treatments and HSCT, within 6 treatment cycles. Analysis will be performed in the ITT 
set.
CR within 6 cycles rate will be analyzed using the same methods as those used for the 
CR rate analysis, limiting to the stratified analysis. Patients for whom no efficacy 
assessment is available will be analyzed as not having CR. 
9.7.4
Subgroup Analyses
The primary endpoint of OS and the secondary endpoints of CR, CRc, CRMRD- and 
transfusion independence will be also explored in subgroups based on stratification 
variables, as well as demographic and baseline patient characteristics. Details will be 
provided in the SAP.
In each defined subgroup, the analysis will be carried out using the same type of 
methodology as described for the overall analysis of the corresponding endpoint. These 
results will be considered exploratory because of the multiplicity issue and also smaller 
sample sizes that cannot be pre-specified. For subgroups without an adequate number of 
patients, the analyses will not be performed.
9.7.5
Quality of Life
Quality of life will be evaluated using the EORTC QLQ-C30 questionnaire. 
Summary tables of absolute value and change from baseline at the different timepoints 
will be produced. Baseline will be the last value available before the first study drug 
administration on Day 1 of Cycle 1. The global health status and some of the functional
scales or symptom scales, which will be defined in the SAP, will be analyzed.
9.7.6
Compliance to study treatment
Compliance with therapy (as defined in Section 4.8) will be summarized (number of 
patients compliant and percentage related to patients in the cycle) by cycle and by 
treatment group for pracinostat / placebo and for AZA.
Compliance over the whole study period will also be summarized. Specific rules to 
evaluate the overall compliance will be presented in the SAP.
9.8
Safety Analyses
Tolerability, safety and adverse events (AEs) will be assessed as follows:

Incidence, nature, seriousness and severity of AEs and relationship to study treatment

Discontinuations from drug or dose modifications due to AEs

Values/findings and changes in vital signs, physical examinations (only listing of 
findings), electrocardiograms (ECGs) and laboratory values


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9.8.1
Analysis of Adverse Events
The analyses of safety will be performed on the Safety set.
Terminology from the Medical Dictionary for Drug Regulatory Activities (MedDRA) 
will be used to assign System Organ Class (SOC) and Preferred Terms (PT) classification 
to AEs and diseases, based on the original terms entered on the CRFs. 
The number and percentage of patients reporting TEAEs and study drug related TEAEs 
will be summarized by SOC and PT. Tables by worst CTCAE grade will be also 
produced. The number and percentage of patients reporting treatment-emergent SAEs 
and drug-related SAEs will be tabulated, as well as TEAEs leading to dose modification, 
to discontinuation of study treatment or leading to death. Pre-treatment AEs and post-
treatment AEs (if any) will be listed. TEAEs of special interest will be presented also in 
specific summary table(s) and listing(s).
A by-patient AE (including treatment-emergent, pre-treatment and post-treatment (if any)) 
data listing including, but not limited to, verbatim term, PT, SOC, CTCAE grade, and 
relationship to study treatment will be provided. Deaths, other SAEs, including those 
leading to discontinuation of study treatment, will be listed.
The above described analyses will be performed overall. Further details and analysis by 
cycle will be described in the SAP.
In consideration of the study population, to better evaluate tolerability in elderly unfit 
subjects, part of the overall analysis described above will be performed also by age group, 
by ECOG class and by renal impairment category at baseline (based on glomerular 
filtration rate).
9.8.2
Clinical Laboratory Evaluation Analyses
Descriptive statistics will be provided for the clinical laboratory results by scheduled time 
of evaluation for the Safety set, as well as for the change from baseline. The baseline 
value is defined as the last non-missing value before the initial administration of study 
treatment. In addition, mean change from baseline will be summarized for the maximum 
and minimum post-treatment values and the values at the End of Treatment visit (or the 
last value obtained under treatment).
Abnormal clinical laboratory results will be graded according to NCI CTCAE version 
4.03, if applicable, and the grade will be presented in a by-patient data listing. A shift 
table, presenting the 2-way frequency tabulation for baseline and the worst post-treatment 
value according to the NCI CTCAE grade, will be provided for clinical laboratory tests.
Abnormal clinical laboratory test results of Grade 3 or 4 will be listed.
9.8.3
Vital Sign Analyses
Descriptive statistics will be provided for the vital signs measurements by scheduled time 
of evaluation for the Safety set, as well as for the change from baseline. The baseline 
value is defined as the last non-missing value before the initial administration of study 
treatment. In addition, mean change from baseline will be presented for the maximum 
and minimum post-treatment values and the values at the End of Treatment visit.


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9.8.4
Electrocardiogram Analyses
Descriptive statistics will be provided for the central ECG measurements by scheduled
time of evaluation for the Safety set, as well as for the change from baseline. The baseline 
value is defined as the last non-missing value before the initial administration of study 
treatment. For triplicate measurements the mean value will be used for analysis. ECG 
abnormalities will be graded according to the CTCAE criteria. The number and 
percentage of patients with QTcF interval values less than or equal to 450, between 451 
and 480, between 481 and 500, as well as >500 ms will be tabulated and changes from 
baseline of  less than 30 ms, 30-60 ms and >60 ms over all post treatment evaluations and 
by cycle will be summarized and described in relation to baseline values. ECG data will 
also be presented in the data listings.
9.9
Pharmacokinetic Analyses
The sparse concentration-time data collected for pracinostat and its metabolites will be 
analyzed by non-linear mixed effect modeling according to a population PK data analysis 
approach. The purpose of this analysis is to obtain exposure data in patients with AML, 
to characterize the PK parameters of pracinostat and its metabolites, and to identify 
relevant covariates affecting pracinostat exposure. In addition, exposure variables will be 
correlated to both efficacy and safety (AE) variables in a PK/PD analysis. The possible 
drug interaction of Pracinostat on the PK of AZA will be evaluated by comparing the 
descriptive statistics of PK parameters of azacitidine in the two groups. The analysis will 
be performed in the PK analysis set(s). 
Additional details on the PK/PD methods and analysis will be provided in a dedicated
SAP.
9.10
Health Economics Analysis
The analytical approach will be a cost efficacy analysis. The health economics analysis 
will be managed and conducted separately. Relevant patient data and analyses results will 
be presented in a separate report. Further details will be outlined in the Health Economics 
analysis plan.
9.11
Power and Sample Size Determination
This is an event-driven study. Sample size was computed for a group-sequential design 
with stopping rules for both futility and superiority (study-wise one-sided alpha 
level=0.025, power 0.90) with one interim analysis at 67% (2/3) of information and a 
final analysis. The error spending function is from the Gamma Family, using γ=-3.6
(similar to O’Brien Fleming) for superiority and γ=-5.5 (more conservative than O’Brien 
Fleming) for futility (non-binding). Proportionality of hazards is assumed. Assuming that 
median OS is 10.0 months in the Group B (placebo + AZA) the aim is to detect, by 
means of the log-rank test or equivalent, an increase to 14.0 months in Group A
(pracinostat + AZA), i.e., a HR of 0.714. A total of 390 events (deaths) allows to meet a 
power requirement of at least 90% (actually 90.78%) at a study-wise one-sided 
significance level of 0.025. 


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Patient accrual is assumed to occur over a 30-month period. Assuming a non-constant 
accrual rate (100 patients during the first year and the remain patients during the 
following 1.5 years) and a 3% yearly drop-out rate, and considering that 500 patients will 
be recruited, it is expected that the post-recruitment follow-up period will take about 18 
additional months to reach 390 events for final OS analysis.
Sample size calculations were made using SAS 9.2.
The overall event rate (blinded) will be constantly monitored. Before the expected 
recruitment end, the observed placebo hazard rate will be derived from the (blinded) 
overall observed hazard rate at that time, assuming a hazard ratio of 0.714. Based on the 
computed value the decision to adapt the sample size to enable study end within a 
reasonable amount of time from the end of recruitment might be taken. This procedure 
does not introduce bias and no statistical adjustments to preserve the study-wise alpha 
error are required.
A group-sequential procedure will be applied also to the secondary endpoints, adopting 
as the error spending function for superiority the Gamma Family, using γ=-3.6. Details on 
the procedure and power calculation for the secondary endpoints will be provided in the 
SAP.
9.12
Interim Analysis
One formal interim analysis on the primary endpoint, OS, is planned and will be assessed
by the IDMC. The interim analysis is to be performed when 2/3 of the total number of 
events (260/390 deaths due to any cause) have occurred in the study, according to the
group sequential testing design described in Section 9.11. Events should be reported to 
sponsor as soon as they become known to investigators and entered in the eCRF in a 
short time. As soon as the 260th event is reported to the sponsor, the set of 260 events will 
be considered as complete. This set of events will be submitted to final validation before 
analysis. Data emerged on a later time point (including events occurred earlier than the 
260th event) will not be considered for the interim analysis. The same rule will be applied 
at the time of final analysis, if relevant. Further data will be considered in an addendum 
to the CSR. 
Further details will be provided in the SAP and DMC Charter prior to the implementation 
of this interim analysis.


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10 ETHICAL AND REGULATORY CONSIDERATIONS
10.1
Compliance with Laws and Regulations
This global clinical study will be conducted in full conformance with the protocol, 
International Conference on Harmonization, Good Clinical Practice Guidelines E6 (ICH-
GCP), and the principles of the Declaration of Helsinki, and the applicable laws and 
regulations of the country in which the research is conducted.
10.2
Institutional Review Boards and Ethics Committees
This protocol and any accompanying material that will be provided to the patient (e.g.; 
patient information sheet or patient diary) must be submitted to the IRB/EC and approval 
obtained prior to study start. 
10.3
Informed Consent
The Investigator is responsible for obtaining written informed consent(s) from each study 
patient prior to conducting any study-related procedures. The Investigator must use the 
most current IRB/EC-approved consent form when obtaining consent.
At any time, all signed and dated Consent Forms must be available for Sponsor/designee
verification.
10.4
Source Data Documentation
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
documents include Investigator’s Study Files and patient clinical source documents. The 
Investigator must be able to provide the Sponsor/designee access to applicable source 
documents and reports. 
10.5
Use of Computerized Systems
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document, if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research. An 
acceptable computerized data collection system allows preservation of the original entry 
of data. If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
10.6
Quality control
To ensure compliance with GCP and all applicable regulatory requirements, site audits
may be conducted at applicable participating sites. Regulatory agencies may also conduct 
regulatory site inspections of this study. Such audits/inspections can occur at any time 
during or after completion of the study. If an audit or inspection occurs, then the 
Investigator and institution agree to allow the auditor/inspector direct access to all 


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relevant documents. The Investigator and the site staff also agree to allocate adequate 
time to discuss findings and any relevant issues with the auditor/inspector.
The Investigator and study staff are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for audits at 
any time by the Sponsor, its designees, and/or inspections by regulatory agencies. In 
signing this protocol, the Investigator understands and agrees to give access to the 
necessary documentation and files.
As applicable, the Sponsor or designee is responsible for implementing and maintaining 
quality control and quality assurance systems to ensure that this study is conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules 
and regulations relating to the conduct of the clinical study.
10.7
Retention of Records
All clinical study documents must be retained by the Investigator until at least 2 years 
after the last approval of a marketing application in an ICH region (i.e., US, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH 
region; or, if no application is filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and regulatory authorities 
have been notified. Investigators may need to retain documents longer, if required by 
applicable regulatory requirements or if requested by the Sponsor. The Investigator must 
notify the Sponsor, in writing, prior to destroying any clinical study records.
Should Investigator wish to assign the study records to another party or move them to 
another location, the Investigator must notify the Sponsor/designee, in writing, prior to 
the transfer.
If the Investigator cannot guarantee this archiving requirement at the study site, for any or 
all of the documents, special arrangements must be made between the Investigator and 
the Sponsor/designee to store these in sealed containers in an off-site storage location so 
that they can be returned to the Investigator in case of a regulatory inspection. Where 
source documents are required for the continued care of a patient, appropriate copies 
should be made for off-site storage.
10.8
Confidentiality
The Sponsor and the CRO must ensure that the Investigator keeps secret from third 
parties any confidential information disclosed or provided by the Sponsor and regarding 
the Sponsor and its study-related products. The Investigator agrees to use such 
information only to accomplish the present study tasks and not to use it for any other 
purposes without the prior written consent by the Sponsor. Prior to the study start-up, 
each Investigator as well as each subcontractor to be involved in the study should sign a 
confidentiality agreement with the CRO acting for and on behalf of the Sponsor.


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10.9
Insurance
The Sponsor will obtain liability insurance, which covers health impairments resulting 
from drugs and/or substances/investigational products administered in the course of this 
study for which the patient has given his/her written Informed Consent.


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11 PUBLICATION POLICY
Helsinn Healthcare SA is committed to public disclosure of research results that involve 
Helsinn Healthcare products. For Helsinn sponsored publications, the rules of the 
International Committee of Medical Journal Editors (ICMJE) will apply to all named 
authors. As a general rule, the Sponsor and the Investigator(s) agree that no publications 
presenting or discussing data and/or results from clinical trials sponsored by Helsinn 
Healthcare SA will take place until the participating center(s) has/have completed the 
study, the data have been interpreted, and the final report has been issued. The Sponsor is 
free to use the data collected in the sponsored study for the drug registration, world-wide 
scientific product documentation, and for publication. In general, the Sponsor has no 
objections if the Investigator publishes the results of the study obtained by the 
Investigator/Institution sponsored by Helsinn Healthcare SA; however, the Investigator is 
requested to provide the Sponsor with a copy of the manuscript for review before 
submitting it to the publisher, with a cover letter informing the Sponsor about the 
intention to publish the study results. Such a procedure is necessary to prevent premature 
disclosure of trade secrets or otherwise patent-protected material and is not intended as a 
restrictive measure concerning the study results or the opinions of the Investigators. After 
the review of the manuscript by the Sponsor, the Investigator will be provided with the 
Sponsor’s comments, if any, and the opinion of the Sponsor regarding study results 
publication. The Investigator shall however consider the Sponsor’s comments and 
proposed revisions. If requested by the Sponsor, the Investigator shall delay the 
presentation or publication of the study data in order to allow the Sponsor sufficient time 
to obtain Intellectual Property Protection. The Sponsor is entitled to include as authors of 
the publication all Sponsors’ personnel who have contributed substantially to the 
theoretical or experimental activities.
Costs for publication must be regulated by written agreement between the parties. Data 
resulting from multicenter clinical trials have to be prepared and submitted prior to any 
publications from individual sites. For multicenter studies, the Investigators who will be 
quoted as authors of the publication(s) should be agreed upon with the Sponsor. If 
publication of the results of the study, either in part or in full, is prepared by the Sponsor, 
the agreed Investigator(s) will be asked in writing if he/she/they agree(s) to be listed as 
one of the authors of the publication. Answers should be sent in writing to the Sponsor 
within a reasonable time limit (30 days).


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13 APPENDICES
Appendix A: 
Schedule of Assessments
Assessments
ScreeningA
Study Treatment Cycles (28 days)B
End of 
Treatment 
Visit 
In-Study 
Long-Term 
FollowUpV
Study Day
Day -28
to -1
Day -8
to -1
Day 1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Day
9
Day 15
Day
21-26
30 Days (±2) 
after last 
study drug 
intake
Obtain Informed 
Consent C
X
Randomization via 
IWRS
[X]D
C1 only
Medical history, 
demographics
X
[X]D
C1 only
Bone Marrow 
aspirate/biopsy and 
classic cytogenetic
testing E
X
X
even 
cycles
Smoking status F
X
Vital signs G
X
X
[X]
X
C2 only
X
Physical 
examinationH
X
X
ECOG Performance
Status I
X
X
X
Information on 
transfusion of RBC
or  platelets J
X
X
even 
cycles
Quality of Life 
Questionnaire K
X
Odd 
cycles
X


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Assessments
ScreeningA
Study Treatment Cycles (28 days)B
End of 
Treatment 
Visit 
In-Study 
Long-Term 
FollowUpV
Study Day
Day -28
to -1
Day -8
to -1
Day 1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Day
9
Day 15
Day
21-26
30 Days (±2) 
after last 
study drug 
intake
12 Lead ECG L
X
X
X
X
[X]
X
CBC, Serum  
Chemistry, 
coagulation, serum 
pregnancy test M
X
X
C2 only
[X]
C1 only
X
X
HIV, HBV and 
HCV serology  N
X
Urine dipstick 
pregnancy test O
[X]
Pracinostat Pop PK 
Sampling  P
[X]
[X]
[X]
[X]
Pracinostat/  
placebo   
Administration Q
3 times a week/x 3 weeks
X
X
X
X
X
Azacitidine  
Administration
(Days 1-7) R
X
X
X
X
X
X
X
Azacitidine 
Administration
(Days 5-2-2) S
X
X
X
X
X
X
X
Study Drug
accountability/
dispensation T
X
[X]
Compliance
X
Adverse 
events/toxicity 
assessment U
X
X
X
X
X
X
X
X
X
X
[X]
X
X
Concomitant 
medication   
review U
X
X
X
X
X
X
X
X
X
X
[X]
X
X


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Assessments
ScreeningA
Study Treatment Cycles (28 days)B
End of 
Treatment 
Visit 
In-Study 
Long-Term 
FollowUpV
Study Day
Day -28
to -1
Day -8
to -1
Day 1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Day
9
Day 15
Day
21-26
30 Days (±2) 
after last 
study drug 
intake
Sub-study 
pracinostat/AZA PK 
sampling (ONLY IN 
SELECTED 
SITES) W
[X]
[X]
[X]
[X]
Biomarker Analysis Z
X
X
even 
cycles
X
Assessments noted with [X] are to be done during Cycle 1 only. All other assessments are to be done during all cycles including Cycle 1, unless otherwise
specified. C = cycle.
A   Screening Visit should occur  28 days before commencement of Cycle 1 Day 1.
B   There is ± 4 days window allowable between each clinic visit Day 1 Cycle.
C  Written informed consent must be obtained prior to initiation of study related procedures
D  Inclusion/exclusion criteria must be met prior to randomization. Patients <75 years of age must have at least 1 co-morbidity, per inclusion criterion 2. 
Eligibility criteria, including co-morbidities, must be reviewed by Medical Monitor prior to randomization.
E   Bone marrow aspirate/biopsy samples will be collected and evaluated for:
-
Morphologic evaluation: at Screening (Section 6.1.1) to confirm AML diagnosis (local evaluation) and at the end of every even cycle, between Day 21 and 
Day 26, to evaluate the disease response to therapy at the Day 1 of each odd cycle (local evaluation). A morphologic evaluation of bone marrow already 
performed within 30 days prior to the ICF signature will be accepted as screening evaluation. Morphologic response assessment is required until a complete 
response is achieved and confirmed after 2 further cycles of treatment. At subsequent cycles, a bone marrow evaluation is no longer required, unless there is a 
suspicion of disease progression or relapse from CR. A bone marrow biopsy is only required in case of dry tap for the pathology interpretation of response, 
including bone marrow blasts.
-
Classical cytogenetics (karyotyping), with analysis of preferably 20 metaphases (central evaluation): at screening and at each subsequent bone marrow 
assessment, only if screening cytogenetic is abnormal, until the patient achieves a cytogenetic complete remission.
-
MRD evaluation by MFC: at screening and after 2 cycles from first CR
-
Biobanking for mutational analysis (mandatory in all patients)
-
If no bone marrow blood can be aspirated at screening (“dry tap”, even at repeated attempts) the patient will be considered a screen failure 
Peripheral blood and bone marrow fluorescence in situ hybridization (FISH) analysis for cytogenetic study and molecular analysis are not required. 
However if FISH testing or molecular analysis are part of the institution’s standard of care, the results will be recorded in the Case Report Forms.
F   Smoking status will be collected at screening
G   Vital signs assessments will include: pulse rate, systolic and diastolic blood pressures (after the patient has been in the sitting or in semi-supine position for 
at least 5 minutes),  body temperature, body weight. 
    Height will be only taken at screening.


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   Pulse rate, systolic and diastolic blood pressures will be measured:
       (1)  at screening
       (2)  pre-dose on Day 1 of Cycle 1 and Day 1 of Cycle 2
       (3)  at 90 minutes (±30minutes) post pracinostat/placebo administration on Day 1 of  all Cycles and at Day 15 of Cycle 1 
       (4)  at any time during the visit between Day 21 and Day 26 of Cycle 2
       (5)  at any time during EoT visit
   Body temperature will be measured:
(1) at screening
(2) on Day 1 of all Cycles (pre-dose)
(3) on Day 15 of Cycle 1 only
(4) at any time during EoT visit
   Body weight will be measured:
(1) at screening
(2)  on Day 1 all Cycles
(3)  at any time during EoT visit
H Complete physical examination will be performed at Screening.This evaluation will include an examination of general appearance, head, eyes, ears, nose, 
throat, skin, neck, lungs, cardiovascular, breast, lymph nodes, abdomen, musculoskeletal and neurological. 
    Limited physical examination, covering general appearance, cardiovascular, lungs and abdomen body systems, will be performed at Day 1 of each cycle to 
assess any changes that may have occurred since the last examination.
I  ECOG performance status will be evaluated at screening and on Day 1 of each Cycle and EoT visit
J   Information on transfusion of RBC or platelets (including date and type of transfusion) will be collected: at Day 1 of Cycle 1 (Section 5.1.2) and between 
Day 21 and Day 26 of Cycle 2 and all subsequent even cycles
K   Quality of Life Questionnaire to be administered on Day 1 Cycle 1 and on each Day 1 of odd Cycles and EoT visit
L   Triplicate 12-lead ECGs will be recorded (after the patient has been in sitting or in semi-supine position for at least 5 minutes):
   (1) at screening 
   (2) on Day 1 of Cycle 1(predose; at 90 minutes ±30minutes and 6 hours ±30minutes post pracinostat/placebo administration), on Day 2 of Cycle 1 (at 24 
hours ±1hours post pracinostat/placebo administration), on Day 3 of Cycle 1 (at 48 hours ±1hours post pracinostat/placebo administration), on Day 15 of 
Cycle 1(at 90 minutes ±30minutes post pracinostat/placebo administration), 
   (3) on Day 1 of  Cycle 2 (predose; at 90 minutes ±30minutes post pracinostat/placebo administration), 
   (4) during the visit from Day 21 to Day 26 of Cycle 2 (any time)
    Single 12-lead ECGs will be collected 90 ±30 minutes post pracinostat/placebo administration on Day 1 of each subsequent Odd cycle (i.e., Cycles 3, 5, 7, 
9, …).
M  Laboratory tests will be performed at a central laboratory. Samples for CBC, serum chemistry and coagulation are to be collected:
    (1) at screening within 8 days prior to Day1 of Cycle 1
    (2) at Day 15 of Cycle 1 only 
    (3) at Day 1 of Cycle 2 only 
    (4) between Day 21 and Day 26 starting from Cycle 2 and for all the subsequent Cycles
    (5) at any time during EoT visit
    Hematology panel: complete blood count (CBC): hematocrit, hemoglobin, erythrocytes (RBC), platelets, leukocytes (WBC) with differential (neutrophils, 
    lymphocytes, basophils, eosinophils, monocytes and blasts).     


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    Blood chemistry panel: glucose, blood urea nitrogen/urea, creatinine, creatinine clearance (derived from 
    blood creatinine value by Cockcroft formula), sodium, potassium, chloride, calcium, phosphorus, magnesium, bicarbonate/carbon dioxide (CO2), alkaline 
phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total
    bilirubin, total protein, uric acid, albumin, and lactic acid dehydrogenase (LDH). 
    Coagulation panel: PT, INR, PTT, fibrinogen, D dimer
    Serum beta-hCG pregnancy tests: will be performed only of women childbearing potential at the Screening visit, on Day 1 of Cycle 2,
    between Day 21 and Day 26 of Cycle 2 and subsequent Cycles and EoT visit.
N   HBV serology (HBsAg, antibody to HBsAg [anti-HBs], anti-HBc and HCV serology (anti-HCV) will be evaluated centrally only at screening.
HIV will be performed based on local regulation at local laboratory at screening only. HIV test already performed within 30 days prior to the ICF
signature will be accepted as screening evaluation.
O Urine dipstick pregnancy test will be performed locally at predose on Day 1 of Cycle 1 only for women of childbearing potential.
P Pracinostat Population Pharmacokinetic (PK) samples will be collected on Cycle 1: 30 minutes (±15minutes), 3 hours (±30minutes) and 6 hours 
(±30minutes); 24 hours (±1 hour) before AZA administration; 48 hours (±2 hours) before next pracinostat/placebo dose; Day 15 any time within 24 hours 
after pracinostat/placebo dosing for the day. 
Q Pracinostat/placebo will be dispensed at the beginning of each cycle. The capsules are to be taken 3 times a week (e.g., Monday, Wednesday, and Friday) 
for 3 weeks, followed by 1 week of rest; this scheme will be repeated every 28-day cycle. Following Cycle 1, study medication compliance will also be 
assessed on Day 1 of each cycle. Pracinostat/Placebo oral administration is to be taken before SC or IV injection of AZA.
R- S The Investigator must ensure azacitidine administration information is collected for the study, including dose changes and administration route. 
AZA administration: 75 mg/m2 via SC injection or as IV infusion on the first 7 days of every 28-day cycle. If unable to accommodate the Days 1-7
schedule, then the 5-2-2 schedule may be followed. Switch between Schedule 1 and Schedule 2 during the study period is acceptable.
T Pracinostat/placebo will be dispensed at Day 1 of each cycle and study drug compliance will be checked. At cycle 1, compliance will be checked on Day 
15 as well.
U AEs and concomitant medications: assessed from the signature of ICF (concomitant medications from 21 days prior to Day 1 of Cycle 1) until 30 days
from last study drug administration or until initiation of new AML treatment, whichever occurs first.
V In-StudyLong-term Follow-up: After patients permanently discontinue study treatment, they will be followed every 3 months (±1 month) from the date 
when study drug was last administered. Patients may be contacted during outpatient visits or by telephone. The following information will be obtained 
during these Follow-up contacts:

Collect any new AML treatment

Collect any evidence of disease progression

Assess overall survival

When there is a suspicion of disease progression, a bone marrow evaluation is required to confirm disease progression
W (IN SELECTED SITES ONLY) Sub-study pracinostat/AZA Pharmacokinetic (PK) samples will be collected on Cycle 1: 15 minutes (± 2 minute), 30 
minutes (± 2 minute), 1 hour (± 5 minutes), 2 hours (± 5 minutes), 3 hours (± 5 minutes), 4 hours (± 5 minutes), 6 hours (± 30 minutes), 8 hours (± 30 
minutes – optional sampling) after start of AZA administration; 24 hours (±1 hour) before AZA administration; 48 hours (±2 hours) before next 
pracinostat/placebo dose; Day 15 any time within 24 hours after pracinostat/placebo dosing for the day.
Z Biomarker Analysis (if consent obtained by patient): Peripheral blood samples and/or aspirate bone marrow samples will be collected and stored for 
potential molecular studies at screening and between day 21 and day 26 of every even cycle  and at EoT visit (Section 6.4).


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Schedule of Assessments - Drug Holiday Schedule - Not recommended
A Drug Holiday Follow-up visit will occur within 4 weeks (+/- 4 days) from Drug Holiday Commencement visit. A Drug Holiday for up to 1 Cycle (28 days) 
is allowed.  
B If there is a suspicion of AML recurrence based on CBC results or clinical findings, a bone marrow biopsy/aspirate must be obtained to verify disease 
progression. In case of disease relapse from CR, patient will proceed with end of treatment visit.
C During the Drug Holiday Follow-up visit, confirm patient has not taken or has started another treatment regimen for AML, including another investigational 
product.
D Pregnancy test for women of childbearing potential only     
Notes: 
(1) Both pracinostat/placebo AND azacitidine must be discontinued while on the Drug Holiday schedule. 
(2) No other AML treatment regimen, including other investigational product from another research study may be taken while on 
this schedule. 
(3) Patients may return from their Drug Holiday schedule and resume their randomized treatment assignment at the dose that was 
administered prior to the Drug Holiday Commencement visit only if no relapse from CR is suspected. If there is evidence of 
disease progression (based on bone marrow aspirate/biopsy and/or peripheral blood) patient will proceed with End of Treatment 
visit. 
(4) To collect overall survival information, it is important that the patient remains compliant and is responsive to the 
Investigator/site staff. It is strongly recommended that the patient provide back-up contact while on the Drug Holiday schedule.
Assessments
Drug Holiday
Commencement Visit
Drug Holiday
Follow-up Visit A
Verify patient achieved a clinical remission (i.e., < 5% blasts and no circulating blasts) for a minimum of 3 
cycles, and if abnormal cytogenetics at enrolment, achieved a cytogenetic CR
X
Verify patient completed at least 12 cycles of pracinostat/placebo + azacitidine 
X
Vital signs, including weight, blood pressure, pulse rate and body temperature 
X
X
Complete Physical Examination
X
ECOG Performance Status and Quality of Life Questionnaire
X
X
Complete Blood Count (CBC) D, Serum Chemistry
X
Bone Marrow aspirate/ biopsy & Classic cytogenetic testing 
XB
Assess study drug compliance at prior cycle and collect all unused study drug
X
Adverse events/toxicity assessment since last study visit
X
X
Concomitant medication review 
X
XC


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Appendix B: 
SWOG Cytogenetic Risk Category Definitions
Risk Status
SWOG Coding
Favorable
inv(16)/t(16;16)/del(16q), t(15;17) with/without secondary 
aberrations; t(8;21) lacking del (9q) or lacking complex 
karyotypes.
Intermediate
Normal, +8, +6, -Y, del(12p)
Unfavorable
del(5q)/-5, -7/del(7q), abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), 
t(9;22) and complex karyotypes (≥3 unrelated abnormalities)
Unknown
All other abnormalities
Slovak, 2000


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Appendix C: 
ECOG Performance Status
Grade
Descriptions
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 (e.g., light housework, office 
work).
2
Ambulatory and capable of all selfcare, but unable to carry out any work 
activities; and about more than 50% of waking hours.
3
Capable of only limited self-care; 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 
Oken, 1982


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Appendix D: 
Acute Myeloid Leukemia Classification - WHO 2016
CLASSIFICATION
AML with recurrent genetic abnormalities
t(8;21)(q22;q22.1); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
APL with PML-RARA
t(9;11)(p21.3;q23.3); MLLT3-KMT2A
t(6;9)(p23;q34.1); DEK-NUP214
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1
AML with mutated BCR-ABL1 (provisional entity)
AML with mutated NPM1 
AML with biallelic mutations of CEBPA 
AML with mutated RUNX1 (provisional entity)
AML with myelodysplasia-related changes
Therapy-related myeloid neoplasms
AML, not otherwise specified
AML with minimal differentiation
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic/monocytic leukemia
Pure erythroid leukemia 
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Arber, 2016


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Appendix E: 
New York Heart Association (NYHA) Classification of 
Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting 
limitations of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
No objective evidence 
of cardiovascular 
disease.
II
Patients with cardiac disease resulting in slight 
limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at 
rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to 
carry on any physical activity without discomfort.
Symptoms of heart failure or the anginal syndrome 
may be present even at rest. If any physical activity is 
undertaken, discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease.
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis 
of 
Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 1994:253-256.
http://trove.nla.gov.au/work/9164796?q&versionId=13288061


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Appendix F: 
Response Criteria
Parameter
Definition
Morphologic 
Leukemia Free 
State (MLFS)

<5% blasts in an aspirate sample with marrow spicules and 
with a  count of at least 200 nucleated cells

There should be no blasts with Auer rods

No extramedullary disease (EMD)
Morphologic 
Complete 
Remission (CR)

<5% blasts in a bone marrow aspirate sample with spicules 

There should be no blasts with Auer rods

No EMD 

Absolute Neutrophil Count (ANC) ≥1,000/μL 

Platelet count of ≥100,000/μL

Patient must be independent of transfusions (for at least 1 
week before each assessment)
No duration of response is required for this category.
There is no requirement to repeat a bone marrow examination if a 
patient normalizes their peripheral blood counts after a bone 
marrow sample has confirmed the presence of <5% blasts (that is, 
converts from MLFS or CRi to CR over time)
Cytogenetic 
Complete 
Remission (CRc)

Morphologic CR plus reversion to a normal karyotype (defined 
as no clonal abnormalities detected in a minimum of 20 mitotic 
cells)
Complete 
Remission without 
minimal residual 
disease (CRMRD-)

Morphologic CR 

Minimal Residual Disease (MRD) by MFC negative
Morphologic 
Complete 
Remission with 
incomplete blood 
Count Recovery 
(CRi)

Morphologic CR with:
-
residual neutropenia (ANC<1,000/μL) or
-
residual thrombocytopenia (PLT<100,000/μL)

Does not require transfusion independence 
Partial Remission 
(PR)

Absolute neutrophil count (ANC) ≥1000/μL 

Platelet count of ≥100,000/μL

A decrease of at least 50% in the percentage of blasts to 5% to 
25% in the bone marrow aspirate*

A value of ≤5% blasts may be considered a PR if Auer rods are 
present
* If the pretreatment bone marrow blast percentage was 50% to 
100%, the percentage of blasts must decrease to a value between 
5% and 25%.
If the pretreatment blast percentage was 20% to <49%, they must 
decrease by at least half to a value of ≥5%.
Stable Disease (SD)
Any designation that does not meet criteria for any CR, PR, or 
disease progression (PD).


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Parameter
Definition
Relapse after CR

Reappearance of leukemic blasts in the peripheral blood or 
≥5% blasts in the BM not attributable to any other cause (e.g., 
BM regeneration after consolidated therapy)**

Appearance of new dysplastic changes

Reappearance or development of cytologically proven EMD
Molecular or cytogenetic relapse: reappearance of a cytogenetic or 
molecular abnormality
** In the setting of recent treatment, if there are no circulating 
blasts and the bone marrow contains 5% to 20% blasts, a repeat 
bone marrow performed at least a week later is necessary to 
distinguish relapse from bone marrow regeneration. In such 
instances the date of recurrence is defined as the first date that 
more than 5% blasts were observed in the marrow.
Cheson, 2003


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Parameter
Definition
Progressive 
disease
(PD)
Evidence for an increase in bone marrow blast percentage and/or 
increase of absolute blast counts in the blood:

>50% increase in marrow blasts over baseline (a minimum 15% 
point increase is required in cases with <30% blasts at baseline; 
or persistent marrow blast percentage of >70% over at least 3 
months; without at least a 100% improvement in absolute 
neutrophil count (ANC) to an absolute level [>0.5 x 109/L 
(500/μL), and/or platelet count to >50 x 109/L (50,000/μL) non-
transfused]; 
or

>50% increase in peripheral blasts (WBC x % 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, may cause a differentiation syndrome, i.e., a transient 
increase in the percentage of bone marrow blasts and an absolute 
increase in blood blasts; in the setting of therapy with such 
compounds, an increase in blasts may not necessarily indicate 
progressive disease.
Döhner, 2016


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Appendix G: 
Examples of CYP450 1A2, 3A4 and 2C8 inducers, and 
CYP3A4 and CYP2C8 inhibitors of clinical relevance.
For a complete list please refer to source: FDA website - Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers (Sept. 26th, 2016)
Examples of clinical inducers of CYP1A2
Strong Inducers
Moderate Inducers
Weak Inducers
CYP1A2
Phenytoin, Rifampin, 
Ritonavir, Smoking, 
Teriflunomide
Examples of clinical inhibitors of CYP2C8
Strong Inhibitors
Moderate Inhibitors
Weak Inhibitors
CYP2C8
clopidogrel, gemfibrozil
deferasirox, 
teriflunomide
telithromycin, 
trimethoprim
Examples of clinical inducers of CYP2C8
Strong Inducers
Moderate Inducers
Weak Inducers
CYP2C8
rifampin
Examples of clinical inhibitors of CYP3A4
Strong Inhibitors
Moderate Inhibitors
Weak Inhibitors
CYP3A4
boceprevir, cobicistat, 
conivaptan, danoprevir 
and ritonavir, 
elvitegravir and 
ritonavir, grapefruit 
juice, indinavir and 
ritonavir, itraconazole, 
ketoconazole, lopinavir 
and ritonavir, 
paritaprevir and 
ritonavir and 
(ombitasvir and/or 
dasabuvir), 
posaconazole, ritonavir, 
saquinavir and 
ritonavir, telaprevir, 
tipranavir and ritonavir, 
troleandomycin, 
voriconazole
aprepitant, cimetidine, 
ciprofloxacin, 
clotrimazole, crizotinib, 
cyclosporine, 
dronedarone, 
erythromycin, 
fluconazole, 
fluvoxamine, imatinib, 
tofisopam, verapamil
chlorzoxazone, 
cilostazol, 
fosaprepitant, 
istradefylline, 
ivacaftor, lomitapide, 
ranitidine, ranolazine, 
tacrolimus, ticagrelor


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Examples of clinical inducers of CYP3A4
Strong Inducers
Moderate Inducers
Weak Inducers
CYP3A4
carbamazepine, 
enzalutamide, mitotane, 
phenytoin, rifampin, St. 
John’s wort
bosentan, efavirenz, 
etravirine, modafinil
armodafinil, 
rufinamide


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Appendix H: 
Examples of CYP1A2, CYP2B6 and CYP3A4 substrates
For the complete list please refer to source: FDA website - Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers (Sep 26th, 2016):
Examples of CYP1A2 substrates
Sensitive substrates
Moderate sensitive substrates
CYP1A2
alosetron, caffeine, duloxetine, 
melatonin, ramelteon, tasimelteon, 
theophylline, tizanidine
clozapine, pirfenidone, 
ramosetron
Examples of CYP2B6 substrates
Sensitive substrates
Moderate sensitive substrates
CYP2B6
bupropion
efavirenz
Examples of CYP3A4 substrates
Sensitive substrates
Moderate sensitive substrates
CYP3A4
alfentanil, avanafil, buspirone, 
conivaptan, darifenacin, darunavir, 
ebastine, everolimus, ibrutinib, 
lomitapide, lovastatin, midazolam, 
naloxegol, nisoldipine, saquinavir, 
simvastatin, sirolimus, tacrolimus, 
tipranavir, triazolam, vardenafil, 
budesonide, dasatinib, 
dronedarone, eletriptan, 
eplerenone, felodipine, indinavir, 
lurasidone, maraviroc, quetiapine, 
sildenafil, ticagrelor, tolvaptan
alprazolam, aprepitant, 
atorvastatin, colchicine, eliglustat, 
pimozide, rilpivirine, rivaroxaban, 
tadalafil


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Appendix I: 
Drugs with A Risk of Prolonging the QT Interval and/or 
Torsades de Pointes
Medications with a known risk of prolonging the QT interval and /or causing Torsades de 
Pointes are prohibited. In addition, caution should be taken when using concomitant 
medications with a possible or conditional risk of prolonging the QT interval and/or
causing Torsades de Pointes.
The list of medications in this appendix represents an example but it is not exaustive.
The following website should be referenced as a guide for updated list of drugs which 
may prolong the QT interval and/or cause Torsades de Pointes: 
https://www.crediblemeds.org
Drugs with a Known Risk of Prolonging the QT Interval and/or Torsades de Pointes
Amiodarone
Arsenic trioxide
Astemizole
Azithromycin
Bepridil
Chloroquine
Chlorpromazine
Ciprofloxacin
Cisapride
Citalopram
Clarithromycin
Disopyramide
Dofetilide
Domperidone
Dronedarone
Droperidol
Erythromycin
Escitalopram
Flecainide
Fluconazole
Gatifloxacin
Grepafloxacin
Halofantrine
Haloperidol
Ibutilide
Levofloxacin
Levomethadyl
Mesoridazine
Methadone
Moxifloxacin
Ondansetron
Pentamidine
Pimozide
Probucol
Procainamide
Quinidine
Roxithromycin
Sevoflurane
Sotalol
Sparfloxacin
Terfenadine
Thioridazine
Vandetanib
Drugs with a Possible Risk of Prolonging the QT Interval and/or Torsades de Pointes
Alfuzosin
Artenimol+piperaquine
Bedaquiline
Clomipramine
Clozapine
Desipramine
Dolasetron
Eribulin mesylate
Felbamate
Fingolimod
Gemifloxacin
Granisetron
Iloperidone
Isradipine
Lapatinib
Lithium
Mirtazapine
Moexipril/HCTZ
Nicardipine
Norfloxacin
Nortriptyline
Ofloxacin
Oxytocin
Paliperidone
Palonosetron
Pasireotide
Perflutren 
Lipid 
Microspheres
Promethazine
Risperidone
Ritonavir
Saquinavir
Sertindole
Sunitinib
Tacrolimus
Tamoxifen
Telithromycin
Tizanidine
Trimipramine
Tramadol
Tropisetron
Tolterodine
Vardenafil
Venlafaxine


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Drugs with a Conditional Risk of Prolonging the QT Interval and/or Torsades de 
Pointes (Should be used with Investigator discretion)
Amantadine
Amisulpride
Amitriptyline
Atazanavir
Chloral Hydrate
Diphenhydramine
Doxepin
Famotidine
Fluoxetine
Furosemide
Galantamine
Hydroxychloroquine
Imipramine
Indapamide
Itraconazole
Ketoconazole
Lansoprazole
Loperamide
Metoclopramide
Metronidazole
Olanzapine
Paroxetine
Quetiapine
Quinine Sulfate
Ranolazine
Sertraline
Solifenacin
Trazodone
Voriconazole 
Ziprasidone


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Appendix J: 
Acceptable Contraception Methods for male and female 
patients of childbearing potential or female partners of 
male patients
I.
Definition of Women of Childbearing Potential and of Fertile Men
A woman is considered of childbearing potential, i.e., fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone level in the postmenopausal range 
may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormone replacement therapy. However, in the absence of 12 months of 
amenorrhea, a single follicle stimulating hormone measurement is insufficient.
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy.
II:
Birth Control Methods Which May Be Considered as Highly Effective
These are considered methods that result in a low failure rate [<1% per year] when used 
consistently and correctly:

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o oral
o intravaginal
o transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o oral
o injectable
o implantable

Intrauterine device

Intrauterine hormone-releasing system

Bilateral tubal occlusion

Vasectomised partner

True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject.
Since Pracinostat may reduce the efficacy of steroid-based contraception, the use of a 
barrier method (male condom) is required for patients or their partners during the entire 
study treatment period and for 3 months after the last administration of study drug.


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III.
Birth Control Methods Which Are Considered Unacceptable

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus interruptus)

Spermicides only

Lactational amenorrhoea method 

Female condom and male condom should not be used together


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Appendix K:
Patient- Reported Outcomes Instrument


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Patient- Reported Outcomes Instrument (Cont.)

SAP_001.pdf: 




Statistical Analysis Plan 
 
Helsinn Healthcare SA 
Protocol number: PRAN-16-52 
 
11 November 2020 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 3 of 58 
 
Table of Contents 
1 
INTRODUCTION .............................................................................................................8 
2 
STUDY OBJECTIVES, TREATMENTS, AND ENDPOINTS .......................................8 
2.1 
Study Objectives ......................................................................................................8 
2.1.1 
Primary Objective ..........................................................................................8 
2.1.2 
Secondary Objectives.....................................................................................8 
2.2 
Treatment Groups ....................................................................................................8 
2.3 
Study Endpoints .......................................................................................................9 
2.3.1 
Primary Efficacy Endpoint ............................................................................9 
2.3.2 
Secondary Efficacy Endpoints .......................................................................9 
2.3.3 
Exploratory Endpoints ...................................................................................9 
2.3.4 
PK Endpoints .................................................................................................9 
3 
STUDY DESIGN.............................................................................................................10 
3.1 
Overall Study Design .............................................................................................10 
3.2 
Schedule of aSSESSMENTS .................................................................................11 
3.3 
Sample size considerations ....................................................................................16 
4 
ANALYSIS SETS ...........................................................................................................17 
4.1 
All randomized (intention to treat; ITT) ................................................................17 
4.2 
Safety (SAF) ..........................................................................................................17 
4.3 
Efficacy Evaluable (EE) ........................................................................................17 
4.3.1 
EE-1 .............................................................................................................17 
4.3.2 
EE-2 .............................................................................................................17 
4.4 
Per Protocol (PP)....................................................................................................18 
4.5 
Pharmacokinetics (PK) ..........................................................................................18 
5 
CONSIDERATIONS FOR DATA ANALYSIS .............................................................19 
5.1 
Programming Environment ....................................................................................19 
5.2 
Strata and Covariates .............................................................................................19 
5.3 
Subgroups ..............................................................................................................19 
5.4 
Multiple Comparisons and Multiplicity .................................................................20 
5.5 
Significance Level .................................................................................................20 
5.6 
Statistical Notation and Methodology ...................................................................21 
5.7 
Documentation of clinical response .......................................................................22 
6 
DATA HANDLING METHODS ....................................................................................23 
6.1 
Missing Data ..........................................................................................................23 
6.1.1 
Date Values ..................................................................................................23 


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6.1.2 
Non-Date Values ..........................................................................................27 
6.2 
Visit Windows .......................................................................................................27 
6.3 
Study Periods .........................................................................................................27 
6.4 
Data Derivations and Definitions ...........................................................................28 
7 
STUDY POPULATION ..................................................................................................31 
7.1 
Patient Disposition .................................................................................................31 
7.2 
Demographic Characteristics .................................................................................31 
7.3 
Prior and Concomitant Medications ......................................................................32 
7.4 
Medical History and physical examination............................................................32 
7.5 
Inclusion/Exclusion Criteria ..................................................................................33 
7.6 
Protocol Deviations ................................................................................................33 
7.7 
Unblinding of treatment information .....................................................................33 
7.8 
Censoring rules for time to event analyses ............................................................33 
8 
EFFICACY ANALYSES ................................................................................................34 
8.1 
Primary Efficacy Analysis .....................................................................................34 
8.1.1 
Interim Analysis ...........................................................................................35 
8.1.2 
Final Analysis ..............................................................................................35 
8.2 
Secondary Endpoint Analyses ...............................................................................36 
8.3 
Exploratory Endpoint Analyses .............................................................................39 
8.4 
Quality of life .........................................................................................................42 
8.5 
Compliance to study treatment ..............................................................................42 
9 
SAFETY ..........................................................................................................................43 
9.1 
Exposure to Study TREATMENT .........................................................................43 
9.2 
Adverse Events ......................................................................................................44 
9.2.1 
Pre- and post-study adverse events ..............................................................44 
9.2.2 
Treatment emergent adverse events (TEAEs) .............................................45 
9.2.3 
Adverse events leading to dose modification and/or to discontinuation 
of study treatment ........................................................................................46 
9.2.4 
Serious adverse events .................................................................................46 
9.2.5 
Deaths ..........................................................................................................46 
9.2.6 
Unblinding of treatment information ...........................................................47 
9.2.7 
Adverse events by treatment cycle ..............................................................47 
9.3 
Subgroup Analyses ................................................................................................47 
9.4 
Clinical Laboratory Evaluation analyses ...............................................................48 
9.5 
Vital Signs analyses ...............................................................................................49 
9.6 
ElectroCardioGram analyses .................................................................................49 


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9.7 
Physical Examinations ...........................................................................................49 
10 PHARMACOKINETIC ANALYSIS ..............................................................................49 
11 CHANGES TO THE PLANNED ANALYSES IN THE PROTOCOL ..........................50 
12 REFERENCES ................................................................................................................50 
13 SUMMARY OF PLANNED EFFICACY ANALYSES .................................................51 
14 SORTING OF LISTINGS ...............................................................................................53 
15 GRADES ASSIGNED TO LABORATORY DATA ......................................................56 
 


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LIST OF ABBREVIATIONS 
Abbreviation  Definition  
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
AST 
Asparate Aminotransferase 
ATC 
Anatomical Therapeutical Chemical 
AZA 
AZAcitidine 
BDRM 
Blind Data Review Meeting 
BMI  
Body Mass Index  
BR 
Best Response  
BSA  
Body Surface Area  
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
cCR  
Composite Complete Remission  
CI  
Confidence Interval  
CR  
(Morphologic) Complete Remission  
CRc 
Cytogenetic Complete Remission 
CRi  
Morphologic Complete Remission with incomplete blood count recovery  
CR MRD-  
Complete Remission without Minimal Residual Disease 
CRO  
Contract Research Organization  
CTCAE  
Common Terminology Criteria for Adverse Events  
ECG  
ElectroCardioGram  
ECOG  
Eastern Cooperative Oncology Group  
eCRF  
electronic Case Report Form  
EE 
e.g. 
Efficacy Evaluable 
For example 
EORTC 
European Organization for Research and Treatment of Cancer 
FISH 
Flourescence In Situ Hybridazation 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HR  
Hazard Ratio  
IDMC 
Indipendent Data Monitoring Committee  
INR 
International Normalized Ratio 
ITT 
Intent To Treat 
IV 
IntraVenous  
IWG 
International Working Group 
KM 
Kaplan Meier 
LDH 
Lactate DeHydrogenase 
LS 
Least Squares 
MedDRA  
Medical Dictionary for Drug Regulatory Activities  
MLFS  
Morphologic Leukemia Free State  
MRD 
NCI 
Minimal Residual Disease 
National Cancer Institute 
OS  
Overall Survival  
 


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PD  
Progressive Disease  
PFS 
Progression Free Survival  
PH  
Proportional Hazards  
PK  
PharmacoKinetic  
PK/PD  
PharmacoKinetic/Pharmacodynamic  
PLT 
Platelet 
PP  
Per Protocol  
PT 
(MedDRA) Preferred Term 
PTT 
Prothrombin Time 
QoL 
Quality of Life 
QTc  
QT interval corrected  
RBC  
Red Blood Cell 
RFS 
Relapse Free Survival 
SAE  
Serious Adverse Event  
SAF 
Safety (Analysis Set) 
SAP  
Statistical Analysis Plan  
SC  
SubCutaneous  
SD  
Stable Disease  
SE 
Standard Error 
SOC  
(MedDRA) System Organ Class  
SWOG 
South West Oncology Group 
TEAE  
Treatment-Emergent Adverse Event  
vs.  
Versus  
WBC 
White Blood Cell 
WHO  
World Health Organisation  
 


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1 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the 
summary and analysis of safety and efficacy of pracinostat vs. placebo with azacitidine 
(AZA) as background therapy in patients ≥ 18 years of age with newly diagnosed acute 
myeloid leukemia (AML), excluding acute promyelocytic leukemia and cytogenetic low-risk 
AML, who are unfit to receive intensive remission induction chemotherapy due to age ≥ 75 
years or comorbidities. Main efficacy objective is the comparison of the overall survival of 
the patients in the two treatment groups. An interim analysis for the main efficacy variable 
overall survival (OS) is planned after occurrence of 260 events (death due to any cause) is 
reported. In addition to evaluation of the pharmacokinetics of pracinostat and its metabolites 
managed in the main study, there will be a substudy to investigate the possible interaction of 
pracinosat on the pharmacokinetics of Azacitidine . 
Background information is provided for the overall study design and objectives.  The reader 
is referred to the study protocol and case report forms (CRFs) for details of study conduct 
and data collection. 
2 
STUDY OBJECTIVES, TREATMENTS, AND ENDPOINTS 
2.1 
STUDY OBJECTIVES 
2.1.1 
Primary Objective 
The primary efficacy objective of the study is to show superiority in terms of overall survival 
(OS) of treatment with pracinostat (Group A – experimental group) versus placebo (Group B 
– control group) in patients treated with AZA as background therapy. 
2.1.2 
Secondary Objectives 
Secondary objectives of this study are:  
• to describe the efficacy of pracinostat by the evaluating additional efficacy variables  
• to assess the safety and tolerability  
• to evaluate the pharmacokinetics of pracinostat and its main metabolites  
• to assess the possible drug interaction of pracinostat on the PK of azacitidine  
• To perform a health-economic evaluation of treatment and control group 
The pharmacokinetics analyses of pracinostat and the possible drug interaction of pracinostat 
on the PK of azacytidine will not be described in this statistical plan.  
2.2 
TREATMENT GROUPS 
The trial has two treatment groups 
Group A (experimental): pracinostat + background therapy  
Pracinostat: one 60 mg capsule orally, once a day, 3 times a week (e.g., Monday, 
Wednesday, and Friday) for 3 weeks, followed by 1 week of rest during each 28-day cycle.  


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Group B (control): placebo + background therapy  
Placebo: 1 capsule orally, once a day, 3 times a week (e.g., Monday, Wednesday, and Friday) 
for 3 weeks, followed by 1 week of rest during each 28-day cycle.  
Background therapy : 
Azacitidine (AZA), will be administered to both treatment groups at a dose of 75 mg/m2 by 
SC or IV injection daily for 7 days of each 28-day cycle.  
2.3 
STUDY ENDPOINTS 
2.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the overall survival (OS), as measured from the time of 
randomization until death from any cause.  
2.3.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints are: 
• Morphologic Complete Remission (CR) rate 
• Transfusion independence  
• Complete Remission without Minimal Residual Disease (CRMRD-) rate  
• Cytogenetic Complete Remission (CRc) rate  
2.3.3 
Exploratory Endpoints 
Exploratory endpoints are: 
• Composite Complete Remission (cCR) rate  
• Relapse Free Survival (RFS)  
• Progression Free Survival (PFS) 
• Duration of Morphologic Complete Remission (CR) 
• Duration of Composite Complete Remission (cCR) 
• Time to CR 
• Morphologic CR within 6 cycles rate 
• Quality of Life  
2.3.4 
PK Endpoints 
PK endpoints are: 
• To characterize the pharmacokinetics (PK) of pracinostat and its main metabolites in 
AML patients by a population pharmacokinetic approach  
• To characterize demographic, physiopathological and therapeutic covariates that may 
influence pracinostat PK parameters and their interindividual variability  


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• To characterize the pracinostat exposure-response relationship for safety and efficacy 
endpoints (PK/PD)  
• To assess the possible drug interaction of pracinostat on the PK of AZA in AML 
patients by comparing the descriptive statistics of PK parameters of azacitidine in the 
two groups  
3 
STUDY DESIGN 
3.1 
OVERALL STUDY DESIGN 
This is a phase III, multicenter, double-blind, randomized study of pracinostat vs. placebo 
with azacitidine (AZA) as background therapy in patients ≥ 18 years of age with newly 
diagnosed acute myeloid leukemia (AML), excluding acute promyelocytic leukemia and 
cytogenetic favorable-risk AML, who are unfit to receive intensive remission induction 
chemotherapy due to age ≥ 75 years or comorbidities.  
 
Patients will be randomized in a 1:1 ratio to one of two groups: Group A (experimental 
group) to receive pracinostat plus AZA and Group B (control group) to receive placebo plus 
AZA. Randomization will be stratified by cytogenetic risk category (intermediate vs. 
unfavorable-risk, according to SWOG Cytogenetic Risk Category Definitions, Appendix B 
of the protocol) and ECOG performance status (0-1 vs. 2, Appendix C of the protocol).  
Treatments will be administered based on 28-day cycles, with pracinostat/placebo 
administered orally once every other day, 3 times a week for 3 weeks, followed by one week 
of no treatment and AZA administered for 7 days of each cycle.  
Study treatment, defined as the treatment with pracinostat/placebo (study drug) in addition to 
the background therapy (AZA), should continue until there is documented disease 
progression, relapse from complete remission (CR), or non-manageable toxicity. A minimum 
of 6 cycles may be required to achieve a complete remission.  
 
Once permanently discontinued from study treatment, patients will enter the Long-term 
Follow-up phase (also called ‘in-study long-term follow-up’) of the study and will be 
followed for assessment of disease progression, if applicable, and survival every 3 months 
(±1 month) until death.  
 
The end of this study is defined when 390 events (deaths) have occurred. Patients who are 
receiving study treatment at the end of the study may have the opportunity to continue to 
receive the study drug to which they were randomized to (Post-Study Observation Period), 
until the Sponsor informs the Investigators of the appropriate course of action based on the 
study results.  
The Post-Study Observation Period is defined as the period starting from the end of the study 
for a maximum of 24 months.  
 
An interim analysis at 67% (2/3) of information (260 over 390 events (deaths), being the 
study event-driven) will be performed for both futility (non-binding) and superiority.  
.


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3.2 
SCHEDULE OF ASSESSMENTS 
Assessments 
ScreeningA 
Study Treatment Cycles (28 days)B 
End 
of 
Treatment 
Visit 
In- 
study 
Long-
Term 
Follow-
UpV 
Study Day 
Day -28 
to -1 
Day -8 
to -1 
Day1 
Day2 
Day3 
Day4 
Day5 
Day6 
Day7 
Day8 
Day9 
Day15 
Day 
21-26 
30 Days (±2) 
after last 
study drug 
intake 
 
Obtain Informed 
ConsentC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization via 
IWRS 
 
 
[X]D 
C1 Only 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, 
demographics 
X 
 
[X]D 
Only C1 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow 
aspirate/biopsy and 
classic cytogenetic 
testing E 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
even 
cycles 
 
 
Smoking status F 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs G 
X 
 
X 
 
 
 
 
 
 
 
 
[X] 
X 
Only 
C2 
X 
 
Physical 
examinationH 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
Performance 
Status I 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Transfusion 
of RBC or 
platelets J 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
even 
Cycles 
 
 
Quality of Life 
Questionnaire K 
 
 
X 
odd 
cycles 
 
 
 
 
 
 
 
 
 
 
X 
 
12 Lead ECG L 
X 
 
X 
X 
X 
 
 
 
 
 
 
[X] 
X 
 
 


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CBC, Serum 
Chemistry, 
coagulation, serum 
pregnancy test M 
 
X 
X 
C2 
only 
 
 
 
 
 
 
 
 
[X] 
C1 
only 
X 
X 
 
HIV, HBV and 
HCV serology N 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick 
pregnancy test O 
 
 
[X] 
 
 
 
 
 
 
 
 
 
 
 
 
Pracinostat Pop PK 
Sampling P 
 
 
[X] 
[X] 
[X] 
 
 
 
 
 
 
[X] 
 
 
 
Pracinostat/ 
placebo 
Administration Q 
 
 
3 times a week/x3 weeks 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
Azacitidine 
Administration 
(Days 1-7) R 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Azacitidine 
Administration 
(Days 5-2-2) S 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
 
Study Drug 
accountability/ 
dispensation T 
 
 
X 
 
 
 
 
 
 
 
 
[X] 
complian
ce 
 
X 
 
Adverse 
events/toxicity 
assessment U 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
[X] 
X 
X 
 
Concomitant 
medication 
review U 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
[X] 
X 
X 
 
Sub-study 
pracinostat/AZA 
PK sampling 
(ONLY IN 
SELECTED SITES)W 
 
 
[X] 
[X] 
[X] 
 
 
 
 
 
 
[X] 
 
 
 
Biomarker 
Analysis Z 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Even 
cycle
s 
X 
 


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SCHEDULE OF EVENTS (CONTINUED) 
Assessments noted with [X] are to be done during Cycle 1 only. All other assessments are to be done during all cycles including Cycle 1,  
unless otherwise specified.  
A  Screening Visit should occur ≤ 28 days before commencement of Cycle 1 Day 1.  
B There is ± 4 days window allowable between each clinic visit Day 1 Cycle.  
C Written informed consent must be obtained prior to initiation of study related procedures  
D Inclusion/exclusion criteria must be met prior to randomization. Patients <75 years of age must have at least 1 co-morbidity, per inclusion criterion 2. 
Eligibility criteria, including co-morbidities, must be reviewed by Medical Monitor prior to randomization.  
E 
Bone marrow aspirate/biopsy samples will be collected and evaluated for:  
- Morphologic evaluation: at Screening (Section 6.1.1 of study protocol) to confirm AML diagnosis (local evaluation) and at the end of every even 
cycle, between Day 21 and Day 26, to evaluate the disease response to therapy at the Day 1 of each odd cycle (local evaluation). A morphologic 
evaluation of bone marrow already performed within 30 days prior to the ICF signature will be accepted as screening evaluation. Morphologic response 
assessment is required until a complete response is achieved and confirmed after 2 further cycles of treatment. At subsequent cycles, a bone marrow 
evaluation is no longer required, unless there is a suspicion of disease progression or relapse from CR. A bone marrow biopsy is only required in case of 
dry tap for the pathology interpretation of response, including bone marrow blasts.  
- Classical cytogenetics (karyotyping), with analysis of preferably 20 metaphases (central evaluation): at screening and at each subsequent bone marrow 
assessment, only if screening cytogenetic is abnormal, until the patient achieves a cytogenetic complete remission.  
- MRD evaluation by MFC: at screening and after 2 cycles from first CR  
- Biobanking for mutational analysis (mandatory in all patients)  
- If no bone marrow blood can be aspirated at screening (“dry tap”, even at repeated attempts) the patient will be considered a screen failure  
Peripheral blood and bone marrow fluorescence in situ hybridization (FISH) analysis for cytogenetic study and molecular analysis are not required. However 
if FISH testing or molecular analysis are part of the institution’s standard of care, the results will be recorded in the Case Report Forms.  
F Smoking status will be collected at screening.  
G Vital signs assessments will include: pulse rate, systolic and diastolic blood pressures (after the patient has been in the sitting or in semi-supine position for at 
least 5 minutes), body temperature, body weight.  
Height will be only taken at screening.  
Pulse rate, systolic and diastolic blood pressures will be measured:  
(1) at screening  
(2) pre-dose on Day 1 of Cycle 1 and Day 1 of Cycle 2  
(3) at 90 minutes (±30minutes) post pracinostat/placebo administration on Day 1 of all Cycles and at Day 15 of Cycle 1 
(4) at any time during the visit between Day 21 and Day 26 of Cycle 2 
(5) at any time during EoT visit 
Body temperature will be measured:  
(1) at screening  
(2) on Day 1 of all Cycles (pre-dose)  
(3) on Day 15 of Cycle 1 only  


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(4) at any time during EoT visit  
Body weight will be measured:  
(1) at screening  
(2) on Day 1 all Cycles 
(3) at any time during EoT visit 
H Complete physical examination will be performed at Screening.This evaluation will include an examination of general appearance, head, eyes, ears, nose, 
throat, skin, neck, lungs, cardiovascular, breast, lymph nodes, abdomen, musculoskeletal and neurological. 
Limited physical examination, covering general appearance, cardiovascular, lungs and abdomen body systems, will be performed at Day 1 of each cycle to 
assess any changes that may have occurred since the last examination.  
I  ECOG performance status will be evaluated at screening and on Day 1 of each Cycle and EoT visit  
J Information on transfusion of RBC or platelets (including date and type of transfusion) will be collected: at Day 1 of Cycle 1 (Section 5.1.2 of study protocol) 
and between Day 21 and Day 26 of Cycle 2 and all subsequent even cycles. 
K Quality of Life Questionnaire to be administered on Day 1 Cycle 1 and on each Day 1 of odd Cycles and EoT visit. 
L Triplicate 12-lead ECGs will be recorded (after the patient has been in sitting or in semi-supine position for at least 5 minutes):  
(1) at screening  
(2) on Day 1 of Cycle 1(predose; at 90 minutes ±30minutes and 6 hours ±30minutes post pracinostat/placebo administration), on Day 2 of Cycle 1 (at 24 
hours ±1hours post pracinostat/placebo administration), on Day 3 of Cycle 1 (at 48 hours ±1hours post pracinostat/placebo administration), on Day 15 of 
Cycle 1(at 90 minutes ±30minutes post pracinostat/placebo administration), 
(3) on Day 1 of Cycle 2 (predose; at 90 minutes ±30minutes post pracinostat/placebo administration), 
(4) during the visit from Day 21 to Day 26 of Cycle 2 (any time) 
Single 12-lead ECGs will be collected 90 ±30 minutes post pracinostat/placebo administration on Day 1 of each subsequent Odd cycle (i.e., Cycles 3, 5, 7, 9). 
M Laboratory tests will be performed at a central laboratory. Samples for CBC, serum chemistry and coagulation are to be collected:  
(1) at screening within 8 days prior to Day1 of Cycle 1  
(2) at Day 15 of Cycle 1 only  
(3) at Day 1 of Cycle 2 only  
(4) between Day 21 and Day 26 starting from Cycle 2 and for all the subsequent Cycles  
(5) at any time during EoT visit 
Hematology panel: complete blood count (CBC): hematocrit, hemoglobin, erythrocytes (RBC), platelets, leukocytes (WBC) with differential (neutrophils,  
lymphocytes, basophils, eosinophils, monocytes and blasts).  
Blood chemistry panel: glucose, blood urea nitrogen/urea, creatinine, creatinine clearance (derived from blood creatinine value by Cockcroft formula), 
sodium, potassium, chloride, calcium, phosphorus, magnesium, bicarbonate/carbon dioxide (CO2), alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), totalbilirubin, total protein, uric acid, albumin, and lactic acid dehydrogenase (LDH).  
Coagulation panel: PT, INR, PTT, fibrinogen, D dimer  
Serum beta-hCG pregnancy tests: will be performed only of women childbearing potential at the Screening visit, on Day 1 of Cycle 2,  
between Day 21 and Day 26 of Cycle 2 and subsequent Cycles and EoT visit. 
N HBV serology (HBsAg, antibody to HBsAg [anti-HBs], anti-HBc and HCV serology (anti-HCV) will be evaluated centrally only at screening. HIV will be 
performed based on local regulation at local laboratory at screening only. HIV test already performed within 30 days prior to the ICF signature will be 
accepted as screening evaluation.  


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O Urine dipstick pregnancy test will be performed locally at predose on Day 1 of Cycle 1 only for women of childbearing potential. 
P Pracinostat Population Pharmacokinetic (PK) samples will be collected on Cycle 1: 30 minutes (±15minutes), 3 hours (±30minutes) and 6 hours 
(±30minutes); 24 hours (±1 hour) before AZA administration; 48 hours (±2 hours) before next pracinostat/placebo dose; Day 15 any time within 24 hours 
after pracinostat/placebo dosing for the day.  
Q Pracinostat/placebo will be dispensed at the beginning of each cycle. The capsules are to be taken 3 times a week (e.g., Monday, Wednesday, and Friday) for 
3 weeks, followed by 1 week of rest; this scheme will be repeated every 28-day cycle. Following Cycle 1, study medication compliance will also be assessed 
on Day 1 of each cycle. Pracinostat/Placebo oral administration is to be taken before SC or IV injection of AZA. 
R- S The Investigator must ensure azacitidine administration information is collected for the study, including dose changes and administration route. AZA 
administration: 75 mg/m2 via SC injection or as IV infusion on the first 7 days of every 28-day cycle. If unable to accommodate the Days 1-7 schedule, then 
the 5-2-2 schedule may be followed. Switch between Schedule 1 and Schedule 2 during the study period is acceptable.  
T Pracinostat/placebo will be dispensed at Day 1 of each cycle and study drug compliance will be checked. At cycle 1, compliance will be checked on Day 15 
as well.  
U AEs and concomitant medications: assessed from the signature of ICF (concomitant medications from 21 days prior to Day 1 of Cycle 1) until 30 days from 
last study drug administration or until initiation of new AML treatment, whichever occurs first. 
V In-study long-term Follow-up: After patients permanently discontinue study treatment, they will be followed every 3 months (±1 month) from the date when 
study drug was last administered. Patients may be contacted during outpatient visits or by telephone. The following information will be obtained during these 
Follow-up contacts:  
•Collect any new AML treatment 
•Collect any evidence of disease progression 
•Assess overall survival 
•When there is a suspicion of disease progression, a bone marrow evaluation is required to confirm disease progression  
 
W (IN SELECTED SITES ONLY) Sub-study pracinostat/AZA Pharmacokinetic (PK) samples will be collected on Cycle 1: 15 minutes (± 2 minute), 30 
minutes (± 2 minute), 1 hour (± 5 minutes), 2 hours (± 5 minutes), 3 hours (± 5 minutes), 4 hours (± 5 minutes), 6 hours (± 30 minutes), 8 hours (± 30 minutes 
– optional sampling) after start of AZA administration; 24 hours (±1 hour) before AZA administration; 48 hours (±2 hours) before next pracinostat/placebo 
dose; Day 15 any time within 24 hours after pracinostat/placebo dosing for the day.  
Z Biomarker Analysis (if consent obtained by patient): Peripheral blood samples and/or aspirate bone marrow samples will be collected and stored for potential 
molecular studies at screening and between day 21 and day 26 of every even cycle and at EoT visit (Section 6.4 of study protocol). 
 
 


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3.3 
SAMPLE SIZE CONSIDERATIONS 
This is an event-driven study. Sample size was computed for a group-sequential design with 
stopping rules for both futility and superiority (study-wise one-sided alpha level=0.025, 
power 0.90) with one interim analysis at 67% (2/3) of information and a final analysis. The 
alpha error spending function is from the O’Brien Fleming function for superiority and the 
Gamma family (with γ=-5.4695, more conservative than O’Brien Fleming) for futility (non-
binding). Proportionality of hazards is assumed. Assuming that median OS is 10.0 months in 
the Group B (placebo + AZA) the aim is to detect, by means of the log-rank test or 
equivalent, an increase to 14.0 months in Group A (pracinostat + AZA), i.e. a HR of 
0.714286. A total of 390 events (deaths) allows to meet a power requirement of at least 90% 
(actually 90.87%; it was 90% with the original function used in v1 protocol; further 
calculations kept fixed the number of events needed) at a study-wise one-sided significance 
level of 0.025.  


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4 
ANALYSIS SETS 
The following set definitions will be used in study summaries and analyses: All Randomized 
(ITT), ITT-2, Safety (SAF), Efficacy Evaluable 1 and 2 (EE-1 and EE-2), and Per Protocol 
(PP), and Pharmacokinetics (PK). 
Data listings will present all the collected information per patient and will be based on all 
screened patients in the study. 
4.1 
ALL RANDOMIZED (INTENTION TO TREAT; ITT) 
This set will comprise all randomized patients, regardless if the patient was administered 
study drug. Patients will be assigned to treatment groups based on the randomized study drug 
assignment. This set will be the primary set analyzed for the primary efficacy endpoint (OS) 
and the efficacy endpoint RFS, and will be also used for the analysis of durations of response 
(limited to patients with response), transfusion independence and for analysis of the efficacy 
endpoints CR rate, CRMRD- rate and for the exploratory endpoints.  
 
Summary tables of baseline and demographic data will be calculated for the All randomized 
set. 
 
A specific ITT set is also defined: ITT-2. This set will comprise patients in the ITT set with 
abnormal cytogenetics at enrollment. This will be the primary set used for the analysis of the 
efficacy endpoint CRc rate. 
4.2 
SAFETY (SAF) 
This set will comprise all patients who received at least one dose of pracinostat/placebo. 
Patients will be assigned to treatment groups based on the actual drug received. This set will 
be the primary set analyzed for safety and some baseline characteristics.  
4.3 
EFFICACY EVALUABLE (EE) 
4.3.1 
EE-1 
The Efficacy Evaluable Set will include all patients in the ITT who had a complete disease 
response assessment. A complete disease response assessment was defined as at least 1 post-
baseline peripheral blood count determined and 1 post-baseline bone marrow assessment 
performed, with an Investigator response reported. A peripheral blood count was defined as 
an assessment of absolute neutrophil count (ANC), platelets and peripheral blasts. In 
addition, patients who discontinued due to progressive disease per the Study Discontinuation 
form without a complete disease response assessment will also be included in this Efficacy 
Evaluable Set. This will be the secondary set used for the analysis of the efficacy endpoints 
CR rate,CRMRD- rate and cCR rate. 
4.3.2 
EE-2 
The Efficacy Evaluable Set will include all patients in the ITT-2 who had a complete disease 
response assessment. A complete disease response assessment was defined as at least 1 post-
baseline peripheral blood count determined and 1 post-baseline bone marrow assessment 


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performed, with an Investigator response reported. A peripheral blood count was defined as 
an assessment of absolute neutrophil count (ANC), platelets and peripheral blasts. In 
addition, patients who discontinued due to progressive disease per the Study Discontinuation 
form without a complete disease response assessment will also be included in this Efficacy 
Evaluable Set. This will be the secondary set used for the analysis of the efficacy endpoint 
CRc rate.  
4.4 
PER PROTOCOL (PP) 
This set will comprise patients who meet all eligibility criteria and receive randomized study 
treatment (i.e. study drug and AZA) without major deviations or violations. This set will be 
the secondary set analyzed for the efficacy endpoint OS.  
Membership in above defined sets, especially in the PP set, will be determined prior to 
unblinding.   
4.5 
PHARMACOKINETICS (PK) 
At least two sets will be defined for the PK analysis, the first set for analyzing the pracinostat 
data and the other set for analyzing the azacitidine data; this last set will be limited to the 
patients from selected sites included in the sub-study and who consented for the sampling for 
the PK of azacitidine. The possibility to participate into the PK AZA sub-study will be closed 
as soon as the requested number of patients is reached (set at present to at least 12 for each 
group); due to the blindness of the study, the unblinded statistician who takes care of the 
analysis for the IDMC will be responsible for checking the number of patients in each group. 
Detailed definitions of these sets and possible additional sets will be defined in the dedicated 
PK SAP. 
 
 


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5 
CONSIDERATIONS FOR DATA ANALYSIS 
5.1 
PROGRAMMING ENVIRONMENT 
All analyses will be conducted using SAS® version 9.4 or higher. 
5.2 
STRATA AND COVARIATES 
Patients will be randomized 1:1 to one of the two treatment groups, stratified based on the 
following two factors:  
• 
Cytogenetic risk category (intermediate vs. unfavorable-risk)  
• 
ECOG (0/1 vs. 2) at screening 
For the primary analysis the stratification used for the randomization will be used. 
The results from the central assessment of the cytogenetic risk category and the ECOG grade 
assessed on day 1 of cycle 1 will be used as a sensitivity analysis (in case of discrepancies 
between the local and the central result of the baseline cytogenetic analysis leading to 
different cytogenetic risk categories compared to those used in the randomization process, 
the patient will be included in the risk category determined by the central assessment. In case 
the central result should not be available, the local result will be used instead). 
The Kaplan-Meier estimates of the primary efficacy variable (Overall Survival) will be 
reported for the two treatment groups, overall and within the strata. 
Also descriptive statistics (i.e. absolute and relative frequency for rates and Kaplan Meier 
estimates for the RFS and duration of responses) will be produced overall and within strata 
for the secondary and exploratory efficacy endpoints. 
Other covariates with potential impact on the efficacy endpoints will be evaluated at the 
Blind Data Review Meeting (BDRM). 
For the PK analysis demographic, physiopathological and therapeutic covariates will be used 
to determine the influence of these variables on PK parameters and their interindividual 
variability. Details will be described in the PK SAP. 
Cases of randomized patients who performed a cycle with Azacitidine or Decitabine during 
the screening period will be evaluated at BDRM. 
5.3 
SUBGROUPS 
The primary endpoint of OS and the secondary endpoints of CR, transfusion independence, 
CRc, and CRMRD- will be also explored in each of the following subgroups: Intermediate 
Cyto risk (at randomitzation), unfavorable cyto risk (at randomization), ECOG 0-1 (at 
randomization), ECOG 2 (at randomization), ECOG 0-1 at Day 1 Cycle 1, ECOG 2 at Day 1 
Cycle 1. In addition OS and CR will be explored in subgroups by geographical area (i.e. OS 
and CR analysis comparing treatments within each geographical area). 
In each defined subgroup, the analysis will be carried out using the same type of 
methodology as described for the overall analysis of the corresponding endpoint. These 
results will be considered exploratory because of the multiplicity issue and also smaller 
sample sizes that cannot be pre-specified.  


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5.4 
MULTIPLE COMPARISONS AND MULTIPLICITY 
Secondary endpoints will be tested according to a fixed sequence method. If the primary 
endpoint is statistically significant, then the first secondary endpoint (according to the 
predefined list) will be tested, and so on for the other three secondary endpoints. When the 
sequence stops for a non-significant test the following tests will be downgraded to 
exploratory. 
The secondary efficacy outcome measures for this study are ordered as follows: 
• Morphologic CR rate  
• Transfusion independence 
• CRMRD- rate 
• CRc rate 
5.5 
SIGNIFICANCE LEVEL 
The overall significance level for the primary efficacy endpoint is 0.025 (one sided). As an 
interim analysis according to the O’Brien Fleming function for superiority and the Gamma 
family function (with γ=-5.4695 for non-binding futility)  will be done after 260 events (2/3 
of the total number of events), the respective significance levels are 0.00605 for the interim 
and 0.02314 for the final analysis. These significance levels will be re-computed at time of 
analysis based on the real fraction of information available. 
Calculations of significance levels and related thresholds were performed by means of SAS 
PROC SEQDESIGN. 
 
The following table shows probabilities to stop at interim analysis for futility or superiority 
with the null and alternative hypotheses for the primary endpoint: 
 
Table 1 
Probability to stop at Interim 
Analysis 
HA as Median OS 
10 months 
14 months 
Gamma spending function  
γ=-5.4695 for futility 
0.70094 
0.01442 
O’Brien Fleming for 
superiority 
0.00605 
0.58059 
 
The following table shows probabilities of significant results for the first secondary endpoint, 
according to the chosen hierarchical procedure and assuming no need to consider the 
correction for multiplicity as 100% of information would be collected (which was the 
assumption at time of SAP V1). The reference alternative hypothesis is that the difference 
between treatments in the CR rate is 0.13 (having 0.20 as the rate for the placebo group). 
Probabilities are corrected by unconditional probability of significant results for the primary 
endpoint as conditional probability assumes the correlation between endpoints to be known. 
The obtained results are conservative and represent the lower probability bound assuming no 
correlation. 
 


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Table 2 
Secondary endpoint(s) 
Assumption: 100% information for secondary endpoint at interim analysis is available 
probability of significant 
results 
0.13 rate difference 
Independent from primary 
endpoint (i.e. as it was the only 
endpoint in the study) 
Hierarchical procedure * 
at Interim Analysis 
0.91 
0.55 
Overall 
0.91 
0.82 
* rounded power for the primary endpoint is 0.90 overall and 0.60 at interim analysis, respectively (median OS = 14 months 
vs. 10 months) 
However, it is now assumed that not all the patients could be recruited at time of interim look 
or some of them could not be followed-up for enough time and considering that correlation 
between the primary endpoint and the secondary endpoints cannot be assumed to be null 
even if difficult to quantify (no correlation would have justified not correcting for 
multiplicity), a procedure that manages the multiplicity due to having planned for an interim 
analysis is needed. The Bonferroni correction (with 0.002 and 0.023 as the partition of the 
overall alpha level) will be adopted, regardless of the quantity of patients and the time of 
follow-up. Interpretation of p-values will be based on the hierarchy defined in section 5.4.  
The family-wise error rate of 0.025 will be adhered to [2, 3]. 
According to current recruitment rate, 85% of patients on average will have been recruited 
before the interim analysis time.  
The O’Brien Fleming bound for the primary endpoint and Bonferroni criterium for the 
secondary endpoint(s) will then be adopted, leading to the probability of significant results 
being as reported in the following table. 
Table 3 
Secondary endpoint(s) - probability of significant results at Interim/Final Analysis 
Assumptions: 85% of patients randomized and Bonferroni (0.002, 0.023) 
 
0.13 rate difference 
Independent from primary endpoint (i.e. 
as it was the only endpoint in the study) 
Overall 
Hierarchical 
procedure ** 
Probability of significant 
results at Interim Analysis 
0.56 
0.34 
Probability of significant 
results Overall 
0.82* 
0.74 
power for the primary endpoint is rounded to 0.90 overall and 0.60 at interim analysis (median OS = 14 months vs. 10 months) 
*assuming 0.6 as the probability to obtain significance at FA given failure at IA (as not all the 85% of patients will have been 
followed-up for more than 6 months) 
** performing test on secondary endpoint also at FA in the case the primary is significant at IA but secondary is not  
 
5.6 
STATISTICAL NOTATION AND METHODOLOGY 
Summary statistics for continuous variables will include the mean, standard deviation, 
minimum, first quartile (Q1), median, third quartile (Q3), and maximum. Categorical 


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variables will be presented as frequency counts and percentages, and time-to-event variables 
will be summarized using Kaplan-Meier estimates including median with 95% CI, number of 
events, number censored.  
 
In general, frequency tables will be presented by treatment group and overall except for 
efficacy analysis or otherwise specified. 
 
Data listings will be created to support each table and to present all data.  
 
Means, LS means, medians, and quartiles will be rounded to 1 decimal place greater than the 
precision of the original value, while standard deviations and SEs will be rounded to 2 
decimal places greater than the precision of the original value.  Percentages for summarizing 
categorical data will be rounded to one decimal place. 
P-values will be presented with 4 decimal places and values less than 0.0001 will be 
presented as < 0.0001. 
Unless otherwise noted, all data collected during the study will be included in data listings 
and will be sorted by treatment group, patient number and then by visit or event as relevant. 
Additional details and sorting order for each listing are presented in section 14.  
In case at least one parameter in a table has missing values, a row/column with the number of 
missing values will be added. In case no missing values are documented at all for a table, no 
missing rows/columns will be presented, even if missing rows/columns are foreseen in the 
respective table shell. 
In case more than one unscheduled visits fall in the same visit window (screening/cycle) 
without a value at the scheduled visit, the latest value will be included in summary tables 
based on cycle. 
 
The final decision whether the PP set is relevant to the study and if tables of baseline 
characteristics need to be produced for the PP set, will be made at the BDRM. 
5.7 
DOCUMENTATION OF CLINICAL RESPONSE 
Normally laboratory data needed for the assessment of clinical response are obtained from 
the central laboratory. In some cases, it is possible that data on peripheral blasts, neutrophil 
and platelet count needed for the assessment of response, are obtained from the site local 
laboratory when the central assessment is missing for any reason. These data will be 
collected in a specific form and separately listed only aimed to document response. 
 


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6 
DATA HANDLING METHODS 
6.1 
MISSING DATA 
6.1.1 
Date Values 
In cases of incomplete dates, the missing component(s) will be assumed as the most 
conservative value(s) possible.   
Actual data values as they appear in the original CRFs will be shown in the data listings. 
For the following dates specific imputation rules are defined: 
Imputation of time to event variable dates: 
Missing dates for time to event variables have to be avoided as far as possible.  
The difference between the start date and the event date is calculated as time to event for the 
main efficacy variable and for some of the secondary variables. 
Therefore the imputation of partial or complete missing event dates has to be handled using 
the most conservative approach. It is especially necessary to distinguish between active 
treatment and placebo group in this respect. As events analysed in this study are “negative” 
events, the following rules can be considered as conservative.  
Imputation rules for missing event date  
for patients who received active treatment (Pracinostat): 
• 
If “day” is the only missing field, impute the “day” as the first day of the month 
documented or the last visit date within the documented month, where the absence of 
the event is documented. 
• 
If “day” and “month” are missing, impute the “day” and “month” as 01 January of 
the year documented or the last visit date within the documented year, where the 
absence of the event is documented.  
• 
If “day”, “month”, and “year” are all missing, the date of event is imputed as the date 
of the last visit date where the absence of the event is documented.  
for patients who received Placebo: 
• 
If “day” is the only missing field, impute the “day” as the last day of the month 
documented or the last visit date within the documented month, where the absence of 
the event is documented. 
• 
If “day” and “month” are missing, impute the “day” and “month” as 31 December of 
the year documented or the last date within the documented year where the absence 
of the event is documented.  
• If “day”, “month”, and “year” are all missing, the date of event is imputed as the date 
of the last visit documented where the absence of the event is documented.  


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For missing start dates of duration of response, rules for placebo should be used for 
pracinostat and viceversa, to be conservative. 
 
Imputation of time of new AML therapies: 
Missing dates for new AML therapies (either those started after study treatment stop or 
concomitant to study treatment stop) have to be avoided as far as possible.  
The imputation of partial or complete missing start and end dates of new AML therapies have 
to be handled using the most conservative approach. It is especially necessary to distinguish 
between active treatment and placebo group in this respect. As events analysed in this study 
are “negative” events, the following rules can be considered as conservative.  
General rules for imputation are: 
• any imputed date should be before the date of death or the last day the patient was 
alive 
• the end date of the therapy should be greater or equal to the start date of the therapy 
If more than one new AML therapy is given to a patient during study period only the first 
start date of the new therapies is relevant for the censoring processes (selection of the first 
start date will be done after any imputations).  
Imputation rules for missing start date of the first new AML therapy  
for patients who received active treatment (Pracinostat): 
• 
If “day” is the only missing field, impute the “day” as the first day of the month 
documented. If month and year are equal to the start of the study treatment impute 
the date as the first treatment day. 
• 
If “day” and “month” are missing, impute the “day” and “month” as 01 January of 
the year documented or the start of the study treatment if the year is the same as for 
treatment start.  
• If “day”, “month”, and “year” are all missing, the date of the start of the new AML 
therapy is imputed as the date of the start of the study treatment. 
for patients who received Placebo: 
• 
If “day” is the only missing field, impute the “day” as the last day of the month 
documented.  
• 
If “day” and “month” are missing, impute the “day” and “month” as 31 December of 
the year documented or as 01 January if the year is the same as for treatment start. 
• If “day”, “month”, and “year” are all missing, the date of event is imputed as 01 
January of the year when the study treatment started.  
Imputation rules for missing end date of the first new AML therapy 
for patients who received active treatment (Pracinostat): 


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• 
If “day” is the only missing field, impute the “day” as the last day of the month 
documented. 
• 
If “day” and “month” are missing, impute the “day” and “month” as 31 December of 
the year documented.  
• If “day”, “month”, and “year” are all missing or if “ongoing” is documented, the date 
is imputed as the last date known alive . 
for patients who received Placebo: 
• 
If “day” is the only missing field, impute the “day” as the first day of the month 
documented. 
• 
If “day” and “month” are missing, impute the “day” and “month” as 01 January of 
the year. If the year documented is equal to the year of the start of the study 
treatment, the date of the end of the new AML treatment is imputed as the start date 
of the new AML treatment. 
• If “day”, “month”, and “year” are all missing or “ongoing” is documented, the date is 
imputed as the last date known alive.  
Imputation of Adverse Event dates: 
Missing AE dates will be queried as far as possible taking other information (eg, relatedness 
to study drug, first intake of study drug) into account.  
For missing AE start or end date, imputation rules follow the principle that the AE is 
regarded as treatment-emergent AE (TEAE) when a connection to the start and end of the 
treatment period could not be excluded (by the documented partial dates or other relevant 
information in the CRF). 
Imputations of adverse events are used for slotting events to the appropriate study time 
periods and for sorting in data listings. They will not be used to calculate duration of AEs. If 
an AE start or end date is missing, then the duration of the AE will be set to missing. 
Remaining missing dates will be imputed as follows: 
For AE start date, imputation rule is to conservatively capture AEs with missing start dates as 
treatment-emergent AEs (TEAEs): 
• 
If “day” is the only missing field, impute the “day” as the first dose date if their 
“month” are the same. Otherwise impute the “day” as the first day of the month 
documented. 
• 
If “day” and “month” are the only missing fields, impute the “day” and “month” as 
the first dose date if their “year” is the same. Otherwise impute the “day” and 
“month” as the first of January of the year documented. 
• 
If “day”, “month”, and “year” are all missing, to be conservative, the AE will be 
assumed to occur on the same day as the first dose was administered. 


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For AE end date, imputation rule is to conservatively capture AEs with missing end dates as 
treatment-emergent AEs (TEAEs): 
• 
If “day” is the only missing field, impute the “day” as the last day of the month 
documented if their “month” are the same.  
• 
If “day” and “month” are the only missing fields, impute the “day” and “month” as 
December 31 of the year, if the patient is alive at that date. Otherwise impute the date 
of death. 
• 
If “day”, “month”, and “year” are all missing, to be conservative, the AE will be 
assumed to be ongoing at the end of the study for the respective patient. 
Imputation of Concomitant Medication dates 
Impute start and end dates for use to derive the reference variables for concomitant 
medication start and end relative to treatment. The reference variables will be used to 
differentiate before, during and after treatment for the concomitant medication. 
For concomitant medication start date, imputation rules are as follows: 
• 
If “day” is the only missing field, impute the “day” as the first dose date if their 
“month” are the same and the reference variable will be set to “during treatment”. 
Otherwise impute the “day” as the first day of the month documented.  
• 
If “day” and “month” are the only missing fields, impute the “day” and “month” as 
the first dose date if their “year” is the same and the reference variable will be set to 
“during treatment”. Otherwise impute the “day” and “month” as the first of January 
of the year documented.  
• 
If “day”, “month”, and “year” are all missing, do not impute completely missing 
concomitant medication start dates; all values that depend on this date will be set to 
missing. The reference variable will be set to “during treatment”. 
For concomitant medication end date, provided that imputed date cannot be prior to start 
date, imputation rules are as follows: 
• 
If “day” is the only missing field, impute the “day” as the earliest of the last day of 
the month documented and the last safety assessment visit date in the documented 
month. The reference variable will be set to “during treatment” if the imputed date is 
not before first randomized study medication. 
• 
If “day” and “month” are the only missing fields, impute the “day” and “month” as 
the earliest of December 31 and the last safety assessment visit date in the 
documented year. The reference variable will be set to “during treatment” if the 
imputed date is not before first randomized study medication. 
• 
If “day”, “month”, and “year” are all missing, do not impute completely missing 
concomitant medication end dates; all values that depend on this date will be set to 
missing. The reference variable will be set to “during treatment” if the imputed date 
is not before first randomized study medication. 


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6.1.2 
Non-Date Values 
Quality of life 
Missing values will be managed according to EORTC QLQ-C30 version 3.0 manual (see 
reference 1 for further information). 
 
According to this manual, scores of scales involving missing items will be computed only if 
at least half of the items from the scale have been answered. The scale score will be 
calculated by using all the items that were completed (any items with missing values will be 
ignored). If more than half of the items are missing (or the missing item is a single question) 
than the scale score will be set to missing. This will be independently applied to the 
calculation of each scale score (global scale score, functional scale scores, symptom scale 
scores) 
 
As the analysis of the quality of life data are descriptive, no additional efforts are made to 
impute missing items. Especially completely missing forms will not be imputed. 
 
Transfusion independence 
In the case of missing transfusion dates no imputation will be done. However, the patient is 
counted as transfusion independent, if a duration of 56 days or more is calculated for two 
consecutive transfusions with non-missing dates. For the remaining patients with missing or 
incomplete transfusion dates the patient is regarded as not transfusion independent, but the 
final decision about transfusion independence will be taken at the BDRM, using a 
conservative approach. 
 
Other non-date values 
Other non-date values will not be inputed in any of the analysis. 
6.2 
VISIT WINDOWS 
Values will be presented for all scheduled study visits according to the nominal visit obtained 
from the CRF.  If an unscheduled visit falls in a visit window with an existing nominal visit 
assessment, the nominal assessment will be used for summary presentation.  All unscheduled 
assessments are to be assigned to the latest initiated cycle based on the date of the 
assessment.  
All visits will be included in the data listings. 
6.3 
STUDY PERIODS 
A patient is considered to have performed a cycle if during that cycle at least one dose of 
either AZA or PRAN/Placebo was administered to the patient, according to the Drug 
administration forms (Cycle x Day 1 drug administration /Pracinostat/placebo (for 
PRAN/PLAC) and drug administration – azacitidine forms (for azacitidine)). 
 


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A patient is to be considered entered in the long-term follow-up if: 
1. Has at least one long-term follow-up visit filled (including the visit of End of Long-
term Follow-up), 
OR 
2. Was discontinued from active treatment phase for reasons other than death, lost to 
follow-up, withdrawal by subject (*). 
 
(*) Withdrawal by subject will be considered a criterion for not entering long-term follow-up 
only when it is reported in the eCRF as the reason for stopping both  treatment and long-term 
follow-up phases and the dates of stop of treatment and long-term follow-up are equal. 
6.4 
DATA DERIVATIONS AND DEFINITIONS 
When reporting durations in months, divide the number of days by 30.4375; to report in 
weeks divide the number of days by 7; to report in years divide the number of days by 
365.25. These algorithms for durations / time to event return decimal numbers, and ignore 
the actual numbers of days in the months or years between start date and stop date. The 
"year" used in these algorithms is 365.25 days long, and the "month" is one twelfth of that 
year. 
Durations and time to events will be analyzed in days. 
Baseline is defined as measurement obtained at the most recent assessment prior to the date 
of the first study treatment dose.  Change from baseline will be calculated as the difference 
between the respective visit value and the baseline value. 
Age will be calculated from the date of birth to Screening date.  
For the calculation of exposure to study drug the Body Surface Area (BSA) is needed. If the 
baseline BSA is not documented, the next available documented BSA within the study period 
will be used for the calculation of the exposure. 
 
The following will define pre-treatment use versus concomitant medication use: 
• Prior use ending before receiving the first administration of study drug will be defined as 
“pre-treatment medications”. 
• Medications that started prior to the first administration of study drug, and continued pass 
through the first administered dose date as well as medication started after the first 
administered dose date will be defined as concomitant medications. 
 
In a similar way, prior and concomitant procedures will be defined as: 
• Prior procedures ending before receiving the first administration of study drug will be 
defined as “prior procedures”. 


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• Procedures that started prior to the first administration of study drug, and continued pass 
through the first administered dose date as well as procedures started after the first 
administered dose date will be defined as concomitant procedures. 
 
TEAEs will be considered as any event occurring, or a pre-existing event worsening, on or 
after receiving the first intake of pracinostat /placebo, and up to 30 days after receiving the 
last administration of study drug (date reported in the field Date of Last Pracinostat/Placebo 
Administration in the Subject Disposition page of the CRF will be used as the reference 
point). 
Each TEAE is collected in the eCRF by recording one initial record and one record for each 
change in seriousness and/or severity within the same occurrence of the event. A summary 
record will be derived aimed at being used for the production of the summary tables, while 
individual records will only be listed. 
 
The summary record will pick-up among the collected records relevant to the same event (it 
is allowed to collect one field from one record and another field from another record) the 
maximum seriousness and the maximum severity. Actions taken will be picked up from all 
the records in order to keep all the actions taken with the event. The outcome will be picked 
up from the last record in time-sequential order. The relationship will be reconciled during 
data cleaning, so it will be the same in all of the records related to the same event at time of 
analysis. 
 
As MRD (positive/negative) will be obtained together with the other data related to MRD 
analyses from the external lab, CRMRD- will be derived in the CDISC datasets from CR and 
MRD results. 
 
Adverse events of special interest (as described in the study protocol) will be retrieved 
according to the following rules reported in the table: 
 
AESI 
MedDRA SMQ (v.20.0) 
MedDRA PT (v. 20.0) 
Comments 
QTc prolongation  
Torsade de Pontes/QT 
prolongation (SMQ) -
NARROW 
n/a 
Supraventricular 
arrhythmias 
Supraventricular 
tachyarrhythmias (SMQ) - 
NARROW 
n/a 
Sepsis, septic shock, 
grade ≥3 lung 
infection 
(pneumonia), any 
infection leading to 
death 
Toxic-septic shock 
conditions (SMQ) - 
NARROW 
1.Any PT that includes 
the word sepsis 
2.Exact match to the PT  
pneumonia or lung 
infection 
Pneumonia only 
if grade ≥3 


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Grade ≥3 anemia, 
neutropenia, febrile 
neutropenia and 
thrombocytopenia 
n/a 
1.Any PT that includes 
the word anaemia. 
 
2.Exact match to any of 
the following PTs: 
 
Haemoglobin decreased 
Band neutrophil count 
decreased 
Band neutrophil 
percentage decreased 
Febrile neutropenia 
Granulocyte count 
decreased 
Granulocytopenia 
Neutropenia 
Neutropenic infection 
Neutropenic sepsis 
Neutropenic colitis 
Neutrophil count 
decreased 
Neutrophil percentage 
decreased 
Platelet count decreased 
Platelet production 
decreased 
Thrombocytopenia 
Febrile bone marrow 
aplasia 
All listed PTs 
only if grade ≥3 
Grade ≥3  
haemorrhage 
n/a 
Any PT that includes the 
word haemorrhage or 
haematoma or bleeding 
All listed PTs 
only if grade ≥3 


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7 
STUDY POPULATION 
7.1 
PATIENT DISPOSITION 
Patient disposition will be presented for all screened patients.  The composition of the 
analysis sets and strata and those who were screened, failed screening, were randomized, 
treated, randomized and not treated, are still ongoing, discontinued from the study treatment, 
entered in long-term follow-up and those who discontinued from the long-term follow-up 
will be summarized by treatment group and overall.  Reasons for discontinuation from study 
treatment will be presented with frequencies and percentages for all categories: adverse 
event, progressive disease, death, lost to follow-up, non-compliance by subject, physician 
decision, pregnancy, protocol deviation, withdrawal by patient, other. Reason for 
discontinuation will be also reported by cycle. Number of cycles performed by patients (by 
category or as median number) will be reported. 
Also reasons for discontinuation from long-term follow-up will be presented with 
frequencies and percentages for all relevant categories (lost to follow-up, death, withdrawal 
by patient, physician decision, study terminated by sponsor, other). 
Additionaly, the number of patients where randomization code was broken by investigator 
together with the reason for breaking the code will be provided. 
7.2 
DEMOGRAPHIC CHARACTERISTICS 
Demographic and baseline characteristic data will be summarized with descriptive statistics 
for age, gender, self-reported race/ethnicity, baseline height, baseline weight, cytogenetic risk 
category (central lab results and results used for randomization), and ECOG grade at baseline 
(used at randomization and at Cycle 1 Day 1), smoking status at baseline and descriptive 
statistics of numbers of cigarettes/cigars/pipes for patients who are current smokers.  
Additionally serology (HIV, HBV, HCV) examination at baseline will be presented. These 
summaries will be done for ITT, ITT-2 and SAF sets. 
Baseline AML Characteristics  
The following data will be summarized:  
• Bone marrow blast count at diagnosis/screening (≥20% and ≤30%; and >30% 
categories) 
• De-novo AML (defined as absence of antecedent hematological disorders and therapy-
related myeloid neoplasms) 
• WHO 2016 AML Classification: 
– AML with recurrent genetic abnormalities (Y/N) and types (absolute and relative 
frequencies) 
– AML with  myelodisplasia related changes (Y/N) 
– Therapy related myeloid neoplasms (Y/N) and types (absolute and relative 
frequencies) 
– AML not otherwise specified (Y/N) and types (absolute and relative frequencies) 
• Extramedullary disease 
• Classic cytogenetic analysis results 


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• Cytogenetic FISH results (if done) 
• Molecular analysis results (if done) 
• Prior hydroxyurea for cytoreduction (Y/N obtained from the prior/concomitant 
medication form by considering the ATC code L01XX (hydroxyurea)) 
• Prior cycle with hypometylating agents (Y/N obtained from the prior/concomitant 
medication form by considering the ATC code L01BC (azacitidine and decitabine)). 
 
These summaries will be done for ITT, ITT-2, and SAF sets. A listing of patients who 
received hydroxyurea and hypometylating agents, including details on the specific drugs, will 
be produced. 
7.3 
PRIOR AND CONCOMITANT MEDICATIONS 
Concomitant medications will be coded with the World Health Organization (WHO) drug 
dictionary (B3 Enhanced format dated 01 March 2018). Version used at the start of the study 
will be used until the end of the study.  Concomitant medications will be summarized with 
frequencies and percentages by drug Anatomical Therapeutic Chemical (ATC) Classification 
System (level 4), generic name, and treatment group. A data listing will be included that 
shows all medications by generic name and verbatim name. Prior anti-cancer therapies will 
be listed  by drug (ATC level 4), generic name, and treatment group. Pre-treatment 
medications will be excluded from the summary table but included in the listing of all 
prior/concomitant medications. New anticancer therapy started during or after treatment 
period will be reported in a summary table (ATC level 4 and generic name), and will be 
listed. These summaries will be based upon the ITT set. 
7.4 
MEDICAL HISTORY AND PHYSICAL EXAMINATION 
Medical history (non AML specific, coded with MedDRA version 20.0) will be summarized 
with descriptive statistics (frequencies and percentages) by medical history code and 
treatment group.  A comprehensive data listing will also be included. These summaries will 
be based upon the ITT set. 
AML history 
Specific hematological disorders prior to study start could be entered into the CRF. The 
frequency and percentage of any prior hematologic disorder, the type of the hematological 
disorder, time from initial diagnosis of antecedent hematologic disorder to initial diagnosis of 
AML (months), and anti-cancer therapies will be presented in a summary table for the ITT, 
ITT-2, and SAF sets. 
Physical examination 
Baseline examinations will be presented as summary table by treatment group. The baseline 
examination is defined as the examination done in the screening period. Examinations 
performed during study follow-up will be listed. These summaries will be based upon the 
ITT set. 


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7.5 
INCLUSION/EXCLUSION CRITERIA 
Inclusion and exclusion criteria failures will be summarized for the screened patients by 
treatment group and overall in a table and also shown in a data listing. 
7.6 
PROTOCOL DEVIATIONS 
Protocol deviations will be summarized by treatment group and category for the ITT set. 
Deviations will be classified as major or minor, with major deviations resulting in exclusion 
from the Per Protocol set.  Deviations referring to assessment of the disease might have 
impact also on the inclusion into the EE sets. The final decision whether a protocol deviation 
is major or minor and the assignment to the analysis sets is made at the BDRM.  
A listing of all deviations will also be included. Included in the listing will be those protocol 
deviations coming from the PD tracker generated during study by the CRAs and those 
protocol deviations coming from the specific listings generated for the BDRM by 
programming. 
For Covid19 related protocol deviations a separate listing will be provided. 
7.7 
UNBLINDING OF TREATMENT INFORMATION 
Patient’s treatment information can be unblinded by investigator or sponsor’s drug-safety 
department for regulatory communications. Data of patients unblinded by sponsor will be 
used as no impact on the conduct of the study is expected. Data obtained before the 
unblinding by investigator will be used in the analyses without restrictions. Overall survival 
data will be used without any restrictions for unblinded patients. Individual cases will be 
examined at the BDRM to evaluate whether a potential impact of unblinding on efficacy is to 
be considered. 
7.8 
CENSORING RULES FOR TIME TO EVENT ANALYSES 
The rules for censoring of time to event variables are described in the following. Incomplete 
dates for the new AML therapies which are used as censoring variable in some of the 
analyses will be imputed using the rules described in chapter 6.1.1 of the SAP. The 
imputations are done prior to the use of the new AML therapies as censoring variables, so 
that only complete dates are used for the censoring rules. 
Rules for the use of new AML therapies as censoring variable in time to event analyses: 
• Treatment with HDAC is regarded as new AML therapy 
• G-CSF is not regarded as new AML therapy and therefore the treatment with G-CSF 
is not regarded as censoring variable.  
• Treatment with decitabine, Azacitidine or hydroxyurea given only for up to 3 days are 
not regarded as new AML therapy and therefore not regarded as censoring variables 
• Treatment with Methotrexate for the treatment of Crohn’s disease is not regarded as 
new AML therapy and therefore not regarded as censoring variable. 
• A new AML therapy that started and ended before Day15 of Cycle1 of the treatment 
phase of the study are not regarded as censoring variable in the time to event 
analyses. 


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• If a new AML therapy started before Day15 of Cycle1 of the treatment phase of the 
study and ended at or after Day15 of Cycle1 then the censoring starts at Day15 of 
Cycle1. 
• If a new AML therapy started at or after Day15 of Cycle1 of the treatment phase of 
the study then the new AML start date is taken as censoring timepoint. 
• If more than one new AML therapies are documented for one patient then only the 
start of the first therapy is used as censoring timepoint. 
According to protocol only hydroxycarbamide (hydroxyurea) is allowed during the first 14 
days of cycle 1; the rule for this treatment was enlarged to 28 days, using a pragmatic 
approach. 
 
8 
EFFICACY ANALYSES 
In general, efficacy analyses will be performed on the ITT set (or the ITT-2 set). 
Interceding therapies are defined as new treatment for AML including salvage treatments and 
hematopoietic stem cell transplantation (HSCT). 
8.1 
PRIMARY EFFICACY ANALYSIS 
The primary efficacy endpoint is overall survival (OS) measured as the time from 
randomization until death from any cause. The primary set of analysis will be the ITT set. 
OS time for patients alive at their last assessment of survival status will be right censored 
• At the documented date of the last assessment during follow-up (which should finally 
correspond to the date reported in the end of long-term follow-up) in the CRF, in the case 
that the long-term follow-up is filled in, 
• At the last assessment of survival status available in the case that the long-term follow-up 
is not filled in. 
OS will not be censored at the time of subsequent interceding therapies, if the patient 
received any. Final analysis will take place after the required number of events (390 deaths) 
has occurred or after the decision to stop the trial because of futility or superiority at time of 
the interim analysis.  
Missing start or end dates for the calculation of OS will be imputed as described in section 
6.1.1. 
The primary OS analysis will be based on the log-rank test stratified by ECOG PS and 
cytogenetic risk (both ECOG PS and cytogenetic risk values used for the randomization) 
comparing the two survival functions of the active treatment group and placebo at the overall 
one-sided alpha = 0.025 level of significance (a group sequential design according to  
Gamma family spending function, adopting γ=-3.6 (similar to O’Brien Fleming) for 
superiority and γ=-5.5 (more conservative than O’Brien Fleming) for futility (non-binding)) 
is used).  


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Additionally, the duration of the follow-up will be calculated using a reverse KM analysis, 
considering an event in patients who are alive and censoring patients at their date of death. 
8.1.1 
Interim Analysis 
The efficacy analyses done for the interim analysis by the unblinded statistician at the CRO 
will be provided to the IDMC, which will provide a recommendation to Sponsor whether the 
study should proceed or stop due to efficacy or futility (non-binding). The efficacy criterion, 
which will be the basis for the IDMC recommendation together with the overall risk-benefit 
assessment is that the p-value of the stratified log-rank test is below the computed 
significance level of the interim analysis (p-value <0.00605). For the futility the significance 
level of 0.29906 is computed as the bound. In terms of HR, the following values are 
calculated: 0.73254 for the efficacy and 0.93671 for the futility evaluation, respectively.  
Significance levels and their counterpart in terms of HR will be re-computed at time of 
analysis based on the real fraction of information available. Conditional power of getting a 
significant result at the final analysis taking into account the results of the interim analysis 
will also be computed. In case of stopping of the study at the interim stage, correction to the 
estimation (median estimate and related CI) will be applied to reduce potential bias. 
Adequate SAS code will be used to produce the stratified log-rank test (PROC LIFETEST), 
save the test results and pass these results to the PROC SEQTEST together with the needed 
data from the PROC SEQDESIGN. Elaboration of data from PROC LIFETEST could be 
needed considering that the alternative hypothesis is one-sided. 
Boundaries at time of the Interim Analysis (IA) will be recomputed having as fraction of 
information the number of events at IA in the ITT set  / overall number of planned events 
(390). For calculations, the power of the test will be changed as needed to maintain the initial 
total number of events  (390). 
The proportionality of hazards will be exploratively evaluated plotting the log negative log 
survival distribution function for each of the treatment groups in each stratum against the log 
of survival days. 
Selected secondary endpoints could be analyzed to provide additional information to the 
IDMC, if requested .  
8.1.2 
Final Analysis 
The efficacy criterion, is that the p-value of the stratified log-rank test is below the computed 
significance level of the final analysis (p-value <0.02314). In terms of HR, the following 
value is calculated: 0.81723.  Significance levels and their counterpart in terms of HR will be 
re-computed at time of analysis based on the real fraction of information available. 
At the final stage the following analyses will be done (if the study is stopped at the interim 
analysis, all procedures/tests described below, as well as those related to the secondary 
endpoints, will be performed but considered only as exploratory; PROC SEQTEST will not 
be performed): 
Stratified log-rank test. The proportionality of hazards will be exploratively evaluated 
plotting the log negative log survival distribution function for each of the treatment groups in 
each stratum against the log of survival days.  


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Appropriate methods of estimation will be applied to take into account for the sequential 
design. PROC SEQTEST will be adopted with the input of relevant data from PROC 
LIFETEST and PROC SEQTEST run at IA. 
 
The following analysis will also be performed: 
• Stratified log-rank test maintaining patients in the cytogenetic risk category assessed by the 
central laboratory and the ECOG PS grade as documented at Day 1 as sensitivity analysis. 
• Unstratified log-rank test and Cox (PH) model including strata (cytogenetic risk factor 
and ECOG grade as randomized) as covariates in the model will be used as a sensitivity 
analysis to support evidence of efficacy. Ties will be handled using the “Efron method” 
in SAS. Interaction terms of the strata with the treatment groups will not be included in 
the model. 
The proportional hazards assumption will be exploratively evaluated by including the 
time dependent covariate Time x Treatment and by plotting for each covariate in the 
model the standardized score process of the actual data against simulated patterns based 
on the PH assumption (option ASSESS of SAS PROC PHREG) 
• Kaplan-Meier estimates of OS in each treatment group will be reported, both overall and 
within strata of patients. Estimates of median survival will be provided with two-sided 
95% confidence intervals, along with the first and third quartile (Q1 and Q3). 
• Estimation of the hazard ratio of the two treatments by means of the Cox PH model 
including stratification factors and treatment.  
• The number of surviving patients, the number of deaths and the number of patients with 
censored values will be displayed as well.  
• Censoring patterns will be examined between treatment groups. Therefore the censored 
and not censored observations in the two treatment groups will be analyzed over time in a 
scatterplot.  
• The effect of subsequent therapy on OS will be analyzed, including an analysis that 
compares OS in the treatment groups with censoring at the start date of the new 
interceding therapy, including those started during study treatment phase (concomitant 
therapy) and after stopping of study treatment as recorded in the new AML therapy eCRF 
page. Balance of such cases in the two treatment groups will be assessed to evaluate the 
appropriateness of this analysis method.  
• Other sensitivity analyses will be performed to assess the robustness of OS results, if 
relevant. These will be decided prior to unblinding (e.g. at BDRM) based on real data. 
• The primary OS analysis (stratified log-rank test) will be repeated for the PP set.  
• Impact on OS of other baseline/demographic factors (including those considered for the 
subgroup analysis (section 5.3), plus possible others), will not be evaluated by means of 
Cox PH model(s) as initially planned due to the evident lack of the PH assumption for the 
treatment group factor.  
8.2 
SECONDARY ENDPOINT ANALYSES 
The secondary efficacy outcome measures for this study are the following (the order is 
relevant to the sequence procedure for testing endpoints):  
• Morphologic Complete Remission (CR) rate  


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• Transfusion independence  
• CRMRD- rate  
• CRc rate  
A group-sequential procedure will be applied as described in section 5.5. 
 
Morphologic Complete Remission (CR) rate  
The rate of CR is defined as the proportion of patients who achieve a morphologic CR 
according to the IWG response criteria (Appendix F of the protocol) in the absence of 
interceding therapies, including salvage treatments and hematopoietic stem cell 
transplantation (HSCT), within the study period. Interceding therapies, salvage treatments, as 
well as HSCT are collected in the “New AML Treatment” eCRF page and in the concomitant 
medication page (if started before and continued into the treatment period or started during 
treatment period). The proportions in the two treatment groups will be compared using the 
Cochran-Mantel-Haenszel test stratified for cytogenetic risk and ECOG PS (values stated at 
randomization). 
The level of significance to be adopted is described in Section 5.5. 
In addition, the two-sided 95% CI for the difference between the responder proportions in the 
two treatment groups will be provided, using the stratified Newcombe method.  
The analysis will be primarily performed in the ITT set (patients for whom no efficacy 
assessment is available will be analyzed as not having CR) and then in the EE-1 set.  
Unstratified analysis will be done for sensitivity purpose by means of likelihood ratio Chi 
square test. 
Logistic regression models will be set up including also demographic characteristics 
(especially the AML history variables as described in section 7.2) and factors described in 
section 5.3 as covariates to explore the influence of these variables on CR rate (likelihood 
ratio test to compare different models and Wald test to evaluate covariates within a model). 
Transfusion Independence 
For the evaluation of transfusion independence (which is defined as achieving eight weeks or 
longer with neither red blood cell nor platelet transfusions during the study period), the 
following transfusions are regarded as “relevant” transfusions: 
• Red Blood Cell (RBC) transfusions 
• Platelet (PLT) infusions 
• Whole Blood infusions 
Transfusion independence rate is defined as the proportion of patients who achieve eight 
weeks or longer with no “relevant” transfusion during the study period. 
The period of transfusion independence will be calculated for each patient as the duration (in 
days) from baseline (Cycle 1 Day 1) to the first “relevant” transfusion during the study 
period, and then between each subsequent “relevant” transfusion up to the last visit where 
this information was collected.  


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If at least one of the durations calculated is greater or equal to 56 days, the patient is regarded 
as transfusion independent within study period.  
The proportion of patients who showed transfusion independence will be summarized by 
study treatment and transfusion dependence at baseline (patient received any kind of 
transfusion during the eight weeks prior to baseline).  
In addition, the transfusion independence will be calculated separately for each of the 
relevant transfusions specified above. The porportion of patients who showed transfusion 
independence from RBC, PLT (whole blood transfusions are included in both categories for 
the calculations)will be also summarized by treatment. 
The proportion of patients who are transfusion independent during study will be compared 
between the two treatment groups using the same methods as those used for the CR rate 
analysis including only treatment and stratification factor values documented at 
randomization. The analysis set will be the ITT set. 
All transfusions will be listed. 
Complete Remission without Minimal Residual Disease (CRMRD-) rate 
The CR MRD- rate is the proportion of patients who achieve a CR with MRD negativity by 
multi-color flow cytometry, according to the IWG response criteria (Appendix F of the 
protocol) within the study period. Absence of interceding therapies is requested for 
considering the response in the analysis (for both CR and MRD negativity). 
CR MRD- rate will be analyzed on the ITT and EE-1 sets, using the same methods as those 
used for the CR rate analysis including only treatment and stratification factors (values stated 
at randomization). Patients for whom no assessment with multi-color flow cytometry is 
available at the planned timepoints will be analyzed as not having reached CR MRD-. However 
patients from sites for which no assessment of MRD was possible due to logistic reasons will 
be excluded from the ITT/EE-1 sets.  
The current definition of the endpoint is applicable also to the patients assessed according to 
the scheduling given in previous protocol version. 
The following rules will be applied. 
• A CR should be reported in the Response form. 
• A MRD negativity should be reported with a collection date (for blood) greater 
than or equal to collection date of BM used for declaring CR. 
• No progression/relapse/PR/SD should be reported between the above dates of 
collection. 
 
Cytogenetic Complete Remission (CRc) rate 
The rate of Cytogenetic Complete Remission (CRc) is defined as the proportion of patients 
who achieve a reversion to normal karyotype at CR  according to the IWG response criteria 
(Appendix F of the protocol)  within the study period. Absence of interceding therapies is 
requested for considering the response in the analysis. 
CRc rate will be analyzed on the ITT-2 set (as this endpoint applies only to patients with 
abnormal cytogenetics at enrollment). CRc rate will be analyzed using the same methods as 


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those used for the CR rate analysis including only treatment and randomization factors. The 
endpoint will also be analyzed in EE-2 set. 
8.3 
EXPLORATORY ENDPOINT ANALYSES 
The exploratory efficacy outcome measures for this study are the following:  
• 
cCR rate  
• 
Relapse Free Survival (RFS)  
• 
Progression Free Survival (PFS) 
• 
Duration of Responses (CR, cCR) 
• 
Time to CR 
• 
CR within 6 cycles 
Additonal to the exploratory endpoints a summary table will be generated for the best 
response reached during study course by each subject. 
 
Quality of life is described in section 8.4. 
Composite Complete Remission (cCR) rate 
Composite complete remission (cCR) rate is defined as the proportion of patients who 
achieve either a disease response of CR,  CRi (Morphologic Complete Remission with 
incomplete blood count recovery; see Appendix F of the protocol for further information) or 
MLFS (Morphologic Leukemia Free State; see Appendix F of the protocol for further 
information) (ie, cCR = CR + CRi + MLFS) within the study period, according to the IWG 
Criteria (Appendix F of the protocol). Absence of interceding therapies is requested for 
considering the response in the analysis. 
Composite CR rate will be analyzed on the ITT and the EE-1 sets. Composite CR rate will be 
analyzed using the same methods as those used for the CR rate analysis, limiting to the 
stratified analysis. Patients for whom no efficacy assessment is available will be analyzed as 
not having cCR when considering the ITT set.  
Relapse-free Survival (RFS) 
RFS is defined as the time from the date of achievement of CR or CRi until the date of  relapse 
(progression) or  death from any cause, whichever occurs first.  
The analysis set will be the ITT set limited to patients who achieve a CR/CRi in absence of 
interceding therapies.  
Censoring rules are:  
• Time to relapse (progression) will be censored at the date of the last assessment of patient 
status that excluded relapse (progression). Current disease status field in the CRF page of 
long-term follow-up visits is to be considered as adequate information. 
• In case of no disease assessments after CR, censoring will be at the date of CR/CRi.  
 
RFS will be analyzed  using the same methods as those used for OS (Kaplan Meier estimates 
and stratified log-rank test).  


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In addition, the influence of additional censoring criteria on RFS in the two treatment groups 
will be analyzed, namely censoring at the start date of a new cancer therapy instead of 
censoring at the date of the last assessment in the study.  
Progression-Free Survival (PFS) 
PFS is defined as the time from the date of randomization until the date of relapse (progression) 
or death from any cause, whichever occurs first.  
The analysis set will be the ITT set. 
Censoring rules are:  
• Time to relapse (progression) will be censored at the date of the last assessment of patient 
status that excluded relapse (progression).  Current disease status field in the CRF page of 
long-term follow-up visits is to be considered as adequate information. 
• In case of no disease assessments, censoring will be at the date of randomization.  
 
PFS will be analyzed using the same methods as those used for OS (Kaplan Meier estimates 
and stratified log-rank test).  
In addition, the influence of additional censoring criteria on PFS in the two treatment groups 
will be analyzed, namely censoring at the start date of a new cancer therapy instead of 
censoring at the date of the last assessment in the study.  
Duration of Morphologic Complete Remission (CR) 
Duration of CR is defined as the time from the date of achievement of CR until the date of 
relapse (progression). Kaplan-Meier methods will be used to estimate duration of response in 
each treatment group. Duration of CR will be analyzed  using the same methods as those 
used for OS (Kaplan Meier estimates and stratified log-rank test). 
Censoring rules will include the following:  
• Time will be censored at the date of the last adequate assessment of patient status that 
excluded relapse (progression). In case of no disease assessments after CR, censoring will 
be at the date of CR.  
• Time will be censored at the start of interceding therapies 
The analysis set will be the ITT set limited to patients who achieve a CR in absence of 
interceding therapies.  
Duration of Composite Complete Remission (cCR) 
Duration of cCR response is defined as the time from the date of achievement of either CR, 
CRi or MLFS until the date of relapse (progression) and will be analyzed as the duration of 
CR response.  
Censoring rules will include the following:  
• Time will be censored at the date of the last assessment of patient status excluding 
relapse. In case of no disease assessments after cCR, censoring will be at the date of cCR.  
• Time will be censored at the start of interceding therapies 


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The analysis set will be the ITT set limited to patients who achieve a cCR in absence of 
interceding therapies. 
Time to Morphologic Complete Remission (CR) 
Time to CR is defined as the time from the date of randomization until the date of first CR in 
the absence of interceding therapies. 
The analysis set will be the ITT set. 
Time to CR will be censored at the date of the last assessment of patient status excluding CR 
in the case no CR occurred by time of analysis. In case of interceding therapies, PD or death,  
time to CR will be censored to the start date of the interceding therapy, PD assessment date 
or death date respectively. Cumulative Incidence Function (CIF) will be computed as 1-
Kaplan Meier curve and treatment groups will be compared by the stratified (cytogenetic risk 
and ECOG PS at randomization) log-rank test. 
Morphologic Complete Remission (CR) within 6 cycles rate 
Morphologic complete remission (CR) within the first 6 cycles rate is defined as the 
proportion of patients who achieve CR in the absence of interceding therapies within 6 
treatment cycles (i.e. during treatment phase up to Day 1 of Cycle 7 included). Analysis will 
be performed in the ITT set. 
CR within 6 cycles  rate will be analyzed using the same methods as those used for the CR 
rate analysis, limited to the stratified analysis. Patients for whom no efficacy assessment is 
available will be analyzed as not having CR.  
Best Response 
A summary table including the best response obtained during study course will also be 
presented (number of patients and related percentage).  
For each patient the response assessment will be classified as best response using the 
following criteria:  
• Morphologic Complete Remission (CR) as highest level,  
o Cytogenetic Complete Remission (CRc) 
followed by  
• Morphologic complete remission with incomplete blood count recovery (CRi),  
• Morphologic leukemia free state (MLFS) 
• Partial Remission (PR),  
• Stable disease (SD) 
• Progression  
and the two summary response classifications: 
• Composite Complete Response (patients with at least MLFS) 
• Overall Response (patients with CR or CRi or MLFS or PR) 
The criteria used for the single responses will be adequately used also for the two summary 
classifications. 
The analysis sets will be the ITT and the EE-1 set. The corresponding ITT-2 and EE-2 sets 
will be the basis for the analysis of CRc. 


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8.4 
QUALITY OF LIFE 
Quality of life will be evaluated using the EORTC QLQ-C30 questionnaire.  
The following scores will be analyzed by treatment group presenting absolute score value 
and change from baseline for the different visits where the questionnaire was to be filled in: 
• Global Health Status / QoL (questions 29, 30) 
• Functional Scale “Physical Functioning” (questions 1 to 5) 
• Functional Scale “Role Functioning” (questions 6,7) 
• Symptom Scale / Item “Fatique” (questions 10, 12, 18) 
• Symptom Scale / Item “Nausea and Vomiting” (questions 14, 15) 
• Symptom Scale / Item “Appetite Loss” (question 13)  
 
All other functional and symptom scale scores will be computed and listed. These are 
• Functional Scale “Cognitive Functioning” (questions 20, 25) 
• Functional Scale “Emotional Functioning” (questions 21 to 24) 
• Functional Scale “Social Functioning” (questions 26, 27) 
• Symptom Scale / Item “Pain” (questions 9, 19) 
• Symptom Scale / Item “Dyspnoea” (question 8)  
• Symptom Scale / Item “Insomnia” (question 11) 
• Symptom Scale / Item “Constipation” (question 16) 
• Symptom Scale / Item “Diarrhoea” (question 17) 
• Symptom Scale / Item “Financial Difficulties” (question 28). 
 
The analysis set will be the ITT set. 
8.5 
COMPLIANCE TO STUDY TREATMENT 
During each cycle (defined from the day of current visit to the day before the next visit), a 
patient will be considered to be compliant with therapy if s/he takes at least 8 of the 9 
capsules of study drug provided in the clinical study medication kit and at least 6 of the 7 
AZA administrations (as a consequence, cycles with interruptions due to AEs are not 
included).  
Compliance with therapy (number of patients compliant/non-compliant; percentage of 
compliant patients) will be summarized by cycle and by treatment group for pracinostat / 
placebo and for AZA. 
Compliance over the whole study period will also be summarized.  
A patient is regarded as compliant with therapy overall, if the ratio between the total number 
of capsules of study drug (pracinostat/placebo) taken and the total number of capsules 
expected for all the cycles performed (excluding drug-holiday period and interruptions due to 
AEs) for this patient is ≥8/9 and the ratio between the total number of administrations of 
AZA and the total number of administrations expected for all the cycles performed 


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(excluding drug-holiday period and interruptions due to AEs) for this patient is ≥6/7.  Overall 
compliance will also be presented split by study drug and AZA. 
The analysis set will be the ITT set. 
All compliance data will be provided in data listings.   
9 
SAFETY 
The SAF set will be used for all the analyses of safety data. 
9.1 
EXPOSURE TO STUDY TREATMENT  
Exposure and drug dosing compliance will be summarized with descriptive statistics by 
treatment group.  All exposure data will be provided in data listings.  Exposure will be 
calculated for the overall study separately for pracinostat/placebo and AZA and analyzed by 
means of descriptive statistics: 
- 
As treatment period duration: the end of the treatment period within one cycle is not 
documented in the CRF, the period duration for patients still on study treatment is 
therefore calculated as the scheduled last dose date minus the first dose date plus 1. 
For patients who already finished the treatment period, the duration of the whole 
study period is calculated as date of last treatment dose (pracinostat/placebo as 
documented in the subject disposition page of the CRF) minus the date of the first 
treatment (pracinostat/placebo) plus 1. 
- 
As cumulative administered dose (summing up all the actual doses in mg). If 
computation is to be performed when information on current cycle is still not 
available (as the respective data are collected at start of the next cycle), the dose for 
the actual cycle will be estimated based on planned scheduling. 
- 
As percent relative cumulative administered dose (cumulative administered dose (mg) 
/ expected cumulative administered dose (mg) x 100). Expected dose will be based on 
the dose to be administered (i.e. 60 mg for pracinostat/placebo and 75mg/m2 BSA for 
AZA) independently from any reduction or modification that occurred (however, 
drug holiday will not be included). The BSA used for the calculations will be the one 
measured at start of each cycle, according to protocol scheduling. 
- 
As cumulative number of administrations. 
- 
As cumulative number of cycles with treatment (either partial or complete). 
Description by categories might also be considered at time of BDRM. 
- 
As absolute and relative frequency (percentage) of patients who reduced the dose 
(two possible reductions for AZA), of patients who had permanent discontinuation of  
treatment and of patients who interrupted treatment temporarily (overall and by 
reason of interruption) and patients who had drug-holiday. 
AZA administration route will also be reported according to the following classification: 
- 
IV infusion for entire study  


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- 
SC injection for entire study  
- 
Switched between IV infusion and SC injection 1 time during study  
- 
Switched route more than 1 time during study 
 
Scheduling will also be categorized, based on actual administration dates, as follows: 
- 
Number of patients on Azacitidine schedule 1 (consecutive 1-7 days) entire study 
- 
Number of  patients on Azacitidine schedule 2 (5-2-2) entire study 
- 
Number of  patients switching between 1-7 and  5-2-2  or viceversa during study 
- 
Alternative schedules 
 
In order to classify patients, first each cycle will be categorized as above described, then 
patients will be classified after exclusion of cycles with a number of administrations less than 
7. 
Data collected for the possible cases of drug-holiday will be listed.  
9.2 
ADVERSE EVENTS 
The analyses of safety will be performed on the SAF set.  
Adverse events will be coded to the Preferred Term (PT) level using the Medical Dictionary 
for Regulatory Activities. Version used at the start of the study will be the most recent one 
published (current version 20.0), and will be used until the end of the study.  
The NCI CTCAE grade for each adverse event will be documented by the treating physician 
in the eCRF. 
A by-patient AE (including treatment-emergent, pre-treatment and post-treatment (if any)) 
data listing including verbatim term, PT, SOC, NCI CTCAE grade, and relationship to study 
treatment (AZA and Pracinostat/placebo) will be provided.  
Deaths, SAEs, including those leading to death, and adverse events leading to 
discontinuation of study treatment or of special interest will be listed.  
All AEs regardless of when they were reported will be listed. 
9.2.1 
Pre- and post-study adverse events 
Pre-treatment AEs and post-treatment AEs (if any) will be listed.  
Pre-treatment AEs are defined as adverse events starting before the first dose of 
pracinostat/placebo is given, and which did not worsen during treatment period. 
Post-treatment AEs are defined as adverse events starting after the end of the observation 
period, which is defined as 30 days after the last dose of pracinostat/placebo, or start of a new 
therapy for AML, whichever occurs first. 
However, to avoid missing important AEs, also AEs started within 30 days after last dose of 
pracinostat/placebo after start of a new therapy for AML will be considered as post-treatment 
events but will be flagged within the related listing. 


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9.2.2 
Treatment emergent adverse events (TEAEs) 
Treatment-emergent AEs (TEAEs) are defined as AEs with onset date/time at or after the 
start date/time of the first intake of pracinostat /placebo, or AEs with onset date/time prior to 
start date/time of the first intake of pracinostat/placebo that worsen in severity after the start 
date/time of the first intake of pracinostat /placebo, up to the end of the observation period. 
The observation period is defined as 30 days after the last dose of pracinostat/placebo or start 
of a new therapy for AML, whichever occurs first. TEAEs will be summarized by treatment 
group. 
Where dates and/or times are missing or partially missing, AEs will be considered treatment 
emergent, unless there is clear evidence (through comparison of partial dates and/or times) to 
suggest that the AE started prior or after the study period.  
The following tables will be produced: 
• An overview summary of TEAEs by treatment group, including counts and 
percentages of patients as well as the number of events. The summary includes the 
following kinds of AEs:  
• 
any TEAE;  
• 
TEAEs by worst NCI CTCAE grade (only number of patients and %)  
• 
TEAEs by NCI CTCAE grade 
• 
TEAEs causally related to study drug / AZA / study drug or AZA (i.e either 
component of the study treatment);  
• 
TEAEs leading to permanent discontinuation of study treatment;  
• 
TEAEs leading to interruption of study treatment (separately for study drug and 
AZA) 
• 
TEAEs leading to dose reduction 
• 
SAEs;  
• 
SAEs causally related to study drug / AZA / study drug or AZA;  
• 
fatal SAEs;  
• 
fatal SAEs causally related to study drug / AZA / study drug or AZA 
• 
TEAEs of special interest 
• 
TEAEs of special interest related to study drug 
• The number and percentage of patients reporting TEAEs will be provided by 
treatment group, System Organ Class (SOC), Preferred Term (PT), worst NCI 
CTCAE grade, and total. TEAEs will be sorted by SOC and PT in alphabetical order 
(SOC and PT within SOC). 
• The number and percentage of patients reporting TEAEs together with the number of 
AEs,  will be provided by treatment group, SOC, PT , and total. Similar table will be 
provided including only ≥3 worst NCI CTCAE grade. TEAEs will be sorted by 
frequency (based on column Total of all AEs)  of a SOC and the PTs within a SOC. 
• The number and percentage of patients reporting study drug (pracinostat / placebo) 
related (as classified by investigator) TEAEs will be provided as described for “all 


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TEAEs” in previous bullett. Missing relationship to study drug will be regarded as 
related. The number and percentage of patients reporting AZA related (as classified 
by investigator) TEAEs will be provided as described for “all TEAEs” in previous 
bullet. Missing relationship to AZA will be regarded as related. 
• The number and percentage of patients reporting TEAEs either study drug 
(pracinostat / placebo) or AZA related (as classified by investigator) will be provided 
as described for “all TEAEs” in previous bullet. Missing relationship to at least one of 
the two components of treatment (study drug or AZA) will be regarded as related.  
• The number and percentage of patients reporting TEAEs of special interest (AESIs) 
will be provided by treatment group, type of  AESIs, PT, worst NCI CTCAE grade, 
and total. TEAEs will be sorted by type of  AESI and PT in alphabetical order (AESI 
and PT within AESI). The same summary table will be provided including only 
TEAEs related to study drug (pracinostat / placebo). Missing relationship to study 
treatment will be regarded as related. 
• The number and percentage of patients reporting TEAEs of special interest together 
with the number of AEs,  will be provided by treatment group, type of  AESIs, PT, 
and total. Similar table will be provided including only ≥3 worst NCI CTCAE grade. 
TEAEs will be sorted by frequency (based on column Total of all AEs) of a AESI and 
the PTs within a AESI. The same summary table will be provided including only 
TEAEs related to study drug. Missing relationship to study drug will be regarded as 
related.  
9.2.3 
Adverse events leading to dose modification and/or to 
discontinuation of study treatment 
The number and percentage of patients reporting TEAEs leading to dose reductions, dose 
interruptions, and permanent discontinuation of study treatment will be tabulated in separate 
tables as described for “all TEAEs” in section 9.2.2. Tables related to dose reductions and 
dose interruptions will be additionally separated for pracinostat/placebo and AZA. 
9.2.4 
Serious adverse events 
The number and percentage of patients reporting treatment-emergent SAEs and drug-related 
SAEs (study drug, AZA and either study drug or AZA) will be tabulated as described for “all 
TEAEs” in section 9.2.2. 
9.2.5 
Deaths 
The number and percentage of deaths will be summarized by treatment and cause. All deaths 
will be additionally listed together with treatment group, dosing parameters, death date, 
primary cause of death and autopsy values. 
Patients who died within 30 days, 60 day and 90 days from randomization will be 
additionally summarized. 
 


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The number and percentage of patients reporting treatment-emergent SAEs resulting in death 
will be tabulated by treatment group, System Organ Class (SOC) and Preferred Term (PT) 
(sorting for SOC and PT in alphabetical order). 
9.2.6 
Unblinding of treatment information 
Patients where treatment information was unblinded by investigator will be listed together 
with treatment, date and time of unblinding. 
 
9.2.7 
Adverse events by treatment cycle 
The same summary tables for adverse events described in sections 9.2.2, 9.2.3, 9.2.4 and 
9.2.5 will be provided by cycle. Each AE will be assigned to only one cycle based on the date 
of  onset. The categories in the overview summary table (number of TEAEs, NCI CTCAE 
grading, relationship, etc.) will be presented by treatment group and cycle.  
For all the other summary tables the number and percentage of patients by treatment group, 
System Organ Class (SOC), Preferred Term (PT), worst NCI CTCAE grade, NCI CTCAE 
grade >=3, and total will be presented for each cycle. Sorting will be done as described in the 
relevant section. As the number of patients in higher cycle numbers may decrease, the 
analysis of these cycles may be not reasonable. During the BDRM it will be determined 
whether the analysis of cycles with a low number of patients will not be done or whether 
cycles will be pooled for the analysis.  
9.3 
SUBGROUP ANALYSES 
For the following subgroups additional analyses will be performed: 
• Age 
o <75 years of age at date of randomization 
o ≥75 years of age at date of randomization 
• ECOG grade 
o 0-1 at date of randomization 
o 2 at date of randomization 
• Renal impairment (Glomerular Filtration Rate (GFR)) at baseline, last value before 
first dose of pracinostat/placebo 
o Normal or high: ≥90 ml/mg/1.73m² 
o Mildly decreased: 60-89 ml/mg/1.73m² 
o Midly to moderately decreased: 45-59 ml/mg/1.73m² 
o Moderately to severely decreased: 30-44 ml/mg/1.73m² 
o Severely decreased: 15-29 ml/mg/1.73m² 
o Kidney failure <15 ml/mg/1.73m² 
 
The GFR value is calculated depending on the gender and serum creatinine values 
following the table below: 


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Gender 
Serum creatinine 
GFR equation 
Female 
≤0.7 mg/dl (≤62 mmol/l) 
144 𝑥 (𝑆𝐶𝑟
0.7 )
−0.329
𝑥 0.993𝐴𝑔𝑒[𝑥 1.159 𝑖𝑓 𝑏𝑙𝑎𝑐𝑘]  
Female 
>0.7 mg/dl (>62 mmol/l) 
144 𝑥 (𝑆𝐶𝑟
0.7 )
−1.209
𝑥 0.993𝐴𝑔𝑒[𝑥 1.159 𝑖𝑓 𝑏𝑙𝑎𝑐𝑘]  
Male 
≤0.9 mg/dl (≤80 mmol/l) 
141 𝑥 (𝑆𝐶𝑟
0.9 )
−0.411
𝑥 0.993𝐴𝑔𝑒[𝑥 1.159 𝑖𝑓 𝑏𝑙𝑎𝑐𝑘]  
Male 
>0.9 mg/dl (>80 mmol/l) 
141 𝑥 (𝑆𝐶𝑟
0.9 )
−1.209
𝑥 0.993𝐴𝑔𝑒[𝑥 1.159 𝑖𝑓 𝑏𝑙𝑎𝑐𝑘]  
In the case of missing demographic information (gender and/or race) the most 
conservative choice of parameters in the above formulas will be used  (i.e. in case of 
missing race, 1.159 multipler will not be used, while in case of missing gender, 
multiplier 141 will be used).  
The following analyses will be done for each of the subgroups: 
• Exposure to study drug and AZA  
• Treatment Emergent Adverse Events (TEAEs) 
o Summary of TEAEs  
o Related TEAEs  
o TEAEs leading to permanent treatment discontinuation  
o Serious TEAEs  
o Related serious TEAEs  
o Serious TEAEs leading to death  
o Summary of deaths  
9.4 
CLINICAL LABORATORY EVALUATION ANALYSES 
Clinical laboratory values (hematological panel, blood chemistry panel, and coagulation 
panel, as described in the clinical study protocol in section 6.2.4) will be analyzed. 
Descriptive statistics will be provided for the clinical laboratory results for the SAF set by 
treatment cycle, as well as for the change from baseline (leukocytes differential counts 
expressed as percentage on leukocytes will only be listed). The baseline value is defined as 
the last non-missing value before the initial administration of study treatment. In addition, 
change from baseline will be summarized for the maximum and minimum post-baseline 
values and the values at the “End of Treatment” visit (or the last value obtained under 
treatment).  
Abnormal clinical laboratory results will be graded according to NCI CTCAE version 4.03, if 
applicable, as graded by the Central Lab (table reported in Section 15) and the grade will be 
presented in the by-patient data listing. Abnormal clinical laboratory test results of NCI 
CTCAE grade ≥ 3 will be listed within the main laboratory data listings. 
The analysis of changes compared to baseline will be done as follows: 
• A shift table, presenting the 2-way frequency tabulation for baseline and the worst post-
treatment value according to the NCI CTCAE grade, will be provided for all clinical 
laboratory parameters where NCI CTCAE grading is available. 


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Results of serology (HIV, HBV, HCV) examination at screening will be summarized for the 
ITT set and will be provided together with the baseline characteristics in the analysis. 
9.5 
VITAL SIGNS ANALYSES 
Descriptive statistics will be provided for the vital signs measurements for the SAF set by 
treatment cycle, as well as for the change from baseline. The baseline value is defined as the 
last non-missing value before the initial administration of study treatment. In addition, mean 
change from baseline will be presented for the maximum and minimum post-baseline values 
and the values at the End of Treatment visit (or the last value obtained under treatment).  
A data listing will display all vital sign test results and findings. 
9.6 
ELECTROCARDIOGRAM ANALYSES 
Descriptive statistics will be provided for the central ECG measurements for the SAF set by 
scheduled measurement times, as well as for the change from baseline. The baseline value is 
defined as the last non-missing value before the initial administration of study treatment. For 
triplicate measurements the mean value will be used for analysis. Based on NCI-CTCAE 
criteria, the number and percentage of patients with QTcF interval values less than or equal 
to 450, between 451 and 480, between 481 and 500, as well as >500 ms will be tabulated and 
changes from baseline of  less than 30 ms, 30-60 ms and >60 ms, by treatment cycle and over 
all post treatment evaluations (worst value) will be summarized and described in relation to 
baseline values.  
Along with QTcF interval also JTcF interval will be assessed and will be reported by 
scheduled measurements times, as well as for the change from baseline. JTcF takes into 
account the physiologic shortening of the JT interval which occurs as the heart rate increases, 
permitting comparison of the JT interval across a range of rates. It is mathematically defined 
as:  
𝐽TcF (msec) =
JT
RR
1
3 (msec), 
where JT is defined as JT (msec) = QT - QRS (msec). JTcF will be derived from ECG 
parametes following the formula above. 
 
A data listing will display all ECG results and findings. 
9.7 
PHYSICAL EXAMINATIONS 
A data listing will display all physical examination results. 
10 PHARMACOKINETIC ANALYSIS 
The sparse concentration-time data collected for pracinostat and its metabolite will be 
analyzed by non-linear mixed effect modeling according to a population PK data analysis 
approach. The purpose of this analysis is to obtain exposure data in patients with AML, to 
characterize the PK parameters of pracinostat and its metabolite(s), and to identify relevant 
covariates affecting pracinostat exposure. In addition, exposure variables will be correlated to 
both efficacy and safety (AE) variables in a PK/PD analysis. The possible drug interaction of 


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Pracinostat on the PK of AZA will be evaluated by comparing the descriptive statistics of PK 
parameters of azacitidine in the two groups.  
Details on the PK/PD methods and analysis and of the PK set(s) are provided in a dedicated 
SAP. 
11 CHANGES TO THE PLANNED ANALYSES IN THE PROTOCOL 
Version 2 of SAP was based on protocol version 3. The version 3 of the SAP reflects changes 
due to study protocol version 5. Version 4 of the SAP reflects minor changes needed to be 
implemented after the first dry-run of the data (before the Interim Analysis) and tuning of the 
rules for the new AML therapy. Version 5 of the SAP reflects changes decided before and 
during the BDRM for Final Analysis (after unblinding of the results of the Interim Analysis). 
Due to FDA request the following changes were applied in the SAP, which are not reflected 
in the study protocol: 
1) Change of the function for performing the superiority test according to a group 
sequential design for the primary endpoint as requested by FDA 
2) Change of the parameter of the function for performing the futility test according to a 
group sequential design for the primary endpoint, in order to maintain the same 
probabilities to stop for true and wrong futility 
3) Change of the method to test for secondary endpoints to overcome some possible 
issues reported by FDA. The new proposal by Helsinn is under further review of FDA 
4) Details on the interceding therapies have been included 
5) Imputation rules for interceding therapies have been included 
 
12 REFERENCES 
1. Internet page where the questionnaire and the calculations in case of missing values is 
described: http://groups.eortc.be/qol/eortc-qlq-c30. 
2. Hierarchical testing of multiple endpoints in group-sequential trials, Ekkehard 
Glimm, Willi Maurer, Frank Bretz, Statistics in Medicine 2010, 29 219-228. 
3. A Gatekeeping Procedure to Test a Primary and a Secondary Endpoint in a Group 
Sequential Design with Multiple Interim Looks, Ajit C. Tamhane, Jiangtao Gou, 
Christopher Jennison, Cyrus R. Mehta, Teresa Curto, Biometrics 74, 40–48, March 
2018. 
4. Sylvain Thepot, American Journal of Hematology, Vol. 89, No. 4, April 2014, 410-
416. 


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13 SUMMARY OF PLANNED EFFICACY ANALYSES  
At the BDRM it might be decided not to perform any analyses for the PP set (depending on the number of patients to be excluded 
from the ITT set) and to add analyses for sensitivity and / or additional subgroups. 
Type of 
endpoint 
Endpoint 
Analysis 
set 
Stratification 
Test 
Other feature 
Relevance 
primary 
OS 
ITT 
ECOG, RISK 
(randomization) 
Log-rank 
none 
Primary analysis 
for this endpoint 
primary 
OS 
ITT 
ECOG (Day 1 Cycle 1), 
RISK (centralized) 
Log-rank 
none 
sensitivity 
primary 
OS 
ITT 
none 
Log-rank 
none 
sensitivity 
primary 
OS 
ITT 
ECOG, RISK 
(randomization) 
Cox PH 
none 
sensitivity 
primary 
OS 
ITT 
ECOG, RISK 
(randomization) 
Log-rank 
Censor at time 
of new therapy 
sensitivity 
primary 
OS 
PP 
ECOG, RISK 
(randomization) 
Log-rank 
none 
Secondary set 
primary 
OS 
ITT 
ECOG, RISK 
(randomization) + other 
factors 
Cox PH 
none 
Exploratory 
Factors and 
related levels to 
be decided at 
BDRM 
First secondary 
CR 
ITT 
ECOG, RISK 
(randomization) 
CMH 
none 
Primary analysis 
for this endpoint 
First secondary 
CR 
EE-1 
ECOG, RISK 
(randomization) 
CMH 
none 
Secondary set 
First secondary 
CR 
ITT 
none 
LRT 
none 
sensitivity 
First secondary 
CR 
EE-1 
none 
LRT 
none 
Sensitivity on 
secondary set 


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First secondary 
CR 
ITT 
ECOG, RISK 
(randomization) + other  
factors 
Logistic 
regression 
none 
Exploratory 
Factors and 
related levels to 
be decided at 
BDRM 
Second 
secondary 
Transfusion 
independence 
ITT 
ECOG, RISK 
(randomization) 
CMH 
none 
Primary analysis 
for this endpoint 
Third secondary 
CRMRD-  
ITT 
ECOG, RISK 
(randomization) 
CMH 
none 
Primary analysis 
for this endpoint 
Third secondary 
CRMRD-  
EE-1 
ECOG, RISK 
(randomization) 
CMH 
none 
Secondary set 
Fourth 
secondary 
CRc 
ITT-2 
ECOG, RISK 
(randomization) 
CMH 
none 
Primary analysis 
for this endpoint 
Fourth 
secondary 
CRc 
EE-2 
ECOG, RISK 
(randomization) 
CMH 
none 
Sensitivity on 
secondary set 
Explorative 
cCR 
ITT 
ECOG, RISK 
(randomization) 
CMH 
none 
Primary analysis 
for this endpoint 
Explorative 
cCR 
EE-1 
ECOG, RISK 
(randomization) 
CMH 
none 
Secondary set 
Explorative 
BR 
ITT 
none 
none 
none 
Primary analysis 
for this endpoint 
Explorative 
BR 
EE-1 
none 
none 
none 
Secondary 
analysis for this 
endpoint 
Explorative 
RFS 
ITT 
ECOG, RISK 
(randomization) 
Log-rank 
none 
Primary analysis 
for this endpoint 
Explorative 
RFS 
ITT 
ECOG, RISK 
(randomization) 
Log-rank 
Censor at time 
of new therapy 
sensitivity 
Explorative 
PFS 
ITT 
ECOG, RISK 
(randomization) 
Log-rank 
none 
Primary analysis 
for this endpoint 


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Explorative 
PFS 
ITT 
ECOG, RISK 
(randomization) 
Log-rank 
Censor at time 
of new therapy 
sensitivity 
Explorative 
Duration of CR 
ITT 
ECOG, RISK 
(randomization) 
Log-rank 
Censor at time 
of new therapy 
Primary analysis 
for this endpoint 
Explorative 
Duration of cCR 
ITT 
ECOG, RISK 
(randomization) 
Log-rank 
Censor at time 
of new therapy 
Primary analysis 
for this endpoint 
Explorative 
Time to CR 
ITT 
ECOG, RISK 
(randomization) 
Long-rank 
none 
Primary analysis 
for this endpoint 
Explorative 
CR within 6 
cycles 
ITT 
ECOG, RISK 
(randomization) 
CMH 
none 
Primary analysis 
for this endpoint 
Subgroups 
OS, CR, CRc 
CRMRD- 
Transfusion 
independence 
ITT as 
relevant 
(only the 
primary set) 
ECOG, RISK 
(randomization) if 
feasible 
Otherwise unstratified 
Log-rank 
or CMH or 
Logistic 
regression 
(as 
relevant) 
Features used in 
the main 
analysis of each 
endpoint 
Not Applicable 
14 SORTING OF LISTINGS  
General sorting will include strata (as randomized: cytogenetic risk Intermediate/Unfavorable, ECOG performance status 0-1/2), 
treatment group (Pracinostat+AZA / Placebo+AZA) and patient number. 
Sorting of unscheduled visits should be managed by properly assigning to one cycle (then sorting by date). 
Listings will be sorted as follows: 
Listing 
Sorted by 
Listing Shell A1 Disposition of patients 
GENERAL 
Listing Shell A2 All protocol deviations 
GENERAL 
Listing Shell A3 Stratification factors 
GENERAL 
Listing Shell B1 Demographic characteristics 
GENERAL 
Listing Shell B2 Current Cancer History 
GENERAL 


Statistical Analysis Plan 
 
Helsinn Healthcare SA 
Protocol number: PRAN-16-52 
 
11 November 2020 
 
 
 
 
 
 
  
 
CONFIDENTIAL 
Page 54 of 58 
 
Listing Shell B3 Prior Hematologic Disorder 
Antecedent to AML 
GENERAL 
Listing Shell B4 Left Ventricular Ejection Fraction 
(LVEF) 
GENERAL 
Listing Shell B5 Pulmunary Function Test 
GENERAL 
Listing Shell B6 Bone Marrow Aspirate/Biopsy 
GENERAL, Cycle 
Listing Shell B7 Classic Cytogenetics 
GENERAL, Cycle 
Listing Shell B8 Cytogenetics (FISH) (optional) 
GENERAL, Cycle 
Listing Shell B9 Molecular Analysis (optional) 
GENERAL, Cycle 
Listing Shell B10 Medical History (excluding 
AML specific terms) 
GENERAL, SOC, PT 
Listing Shell B11 Prior and Concomitant 
medication 
prior/concomitant, GENERAL,  PT, start date 
Listing Shell B12 Prior and Concomitant 
Procedures 
prior/concomitant, GENERAL,  procedure, 
start date 
Listing Shell B13 Therapy for Antecedent 
Hematological Disorder 
GENERAL,  medication, start date 
Listing Shell B14 New AML treatment 
GENERAL,  treatment, start date 
Listing Shell B15 Prior or Concomitant 
Medication regarded as New AML treatment 
GENERAL,  PT 
Listing Shell E1 Overall survival 
GENERAL 
Listing Shell E2 Overall survival – censoring due 
to new interceding therapies 
GENERAL 
Listing Shell E3 Relapse Free Survival 
GENERAL 
Listing Shell E4 Relapse Free Survival – censoring 
due to new interceding therapies 
GENERAL 
Listing Shell E5 Progression Free Survival 
GENERAL 
Listing Shell E6 Progression Free Survival – 
censoring due to new interceding therapies 
GENERAL 
Listing Shell E7 Morphologic Complete 
Remission 
GENERAL 


Statistical Analysis Plan 
 
Helsinn Healthcare SA 
Protocol number: PRAN-16-52 
 
11 November 2020 
 
 
 
 
 
 
  
 
CONFIDENTIAL 
Page 55 of 58 
 
Listing Shell E8 Composite Complete Remission 
(cCR) 
GENERAL 
Listing Shell E9 Cytogenic Complete Remission 
(CRc) only for subjects achieving CR 
GENERAL 
Listing Shell E10 MRD specific parameters 
GENERAL, Visit, Date 
Listing Shell E11 Duration of Morphologic 
Complete Remission 
GENERAL 
Listing Shell E12 Duration of Composite 
Complete Remission 
GENERAL 
Listing Shell E13 Transfusion Independence 
GENERAL, Visit, Date, kind of transfusion 
Listing Shell E14 Summary of efficacy results per 
patient and cycle 
GENERAL, cycle, date of assessment, date 
BM/Blood 
Listing Shell E15 EORTC QLQ C30  
GENERAL, Visit, Type of scale, Scale, 
Question 
Listing Shell E16 Compliance to Pracinostat/ 
Placebo  
GENERAL, Cycle, Date dose taken 
Listing Shell E17 Compliance to AZA  
GENERAL, Cycle, Date dose taken 
Listing Shell E18 Follow-up visits 
GENERAL, Visit date 
Listing Shell E19 Patients with drug holidays 
GENERAL 
Listing Shell F1 Exposure to Pracinostat/Placebo 
GENERAL, Cycle, Week, Day 
Listing Shell F2 Exposure to Azacitidine  
GENERAL, Cycle, Week, Day 
Listing Shell F3 Exposure to Study Drug – 
cumulative doses  
GENERAL 
Listing Shell F4 Exposure to Study Drug – 
cumulative number of administrations  
GENERAL, Cycle 
Listing Shell F5 Exposure to Study Drug – 
interruptions and discontinuations  
GENERAL, Cycle 
Listing Shell F6 Pre Treatment adverse events 
GENERAL, PT, Start date 
Listing Shell F7 Treatment emergent adverse 
events 
GENERAL, PT, Start date 
Listing Shell F8 Post treatment adverse events 
GENERAL, PT, Start date 


Statistical Analysis Plan 
 
Helsinn Healthcare SA 
Protocol number: PRAN-16-52 
 
11 November 2020 
 
 
 
 
 
 
  
 
CONFIDENTIAL 
Page 56 of 58 
 
Listing Shell F9 Adverse events – initial and 
follow-up records 
GENERAL, PT, Start date, Initial/Follow-up 
#1 to Last 
Listing Shell F10 Serious Adverse Events  
GENERAL, PT, Start date 
Listing Shell F11 Serious Adverse Events leading 
to death  
GENERAL, PT, Start date 
Listing Shell F12 Adverse Events leading to any 
study treatment discontinuation  
GENERAL, PT, Start date 
Listing Shell F13 Adverse Events of Special 
Interest  
GENERAL, PT, Start date 
Listing Shell F14 Deaths  
GENERAL 
Listing Shell F15 Vital Signs  
GENERAL, Visit, Parameter 
Listing Shell F16 Clinical safety laboratory – 
hematology panel (blood counts)  
GENERAL, Parameter, Visit 
Listing Shell F17 Clinical safety laboratory – 
hematology panel (serology and HIV) 
GENERAL, Parameter, Visit 
Listing Shell F18 Clinical safety laboratory - 
chemistry panel  
GENERAL, Parameter, Visit 
Listing Shell F19 Clinical safety laboratory - 
coagulation panel  
GENERAL, Parameter, Visit 
Listing Shell F20 ECG results  
GENERAL, Parameter, Visit 
Listing Shell F21 Physical exam  
GENERAL, Parameter, Visit 
Listing Shell F22 Unblinding by investigator 
GENERAL, Parameter, Visit 
15 GRADES ASSIGNED TO LABORATORY DATA  
The following table reports the grades assigned to selected laboratory parameters (according to NCI CTCAE version 4.03). 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Albumin decreased 
<LLN - 3 g/dL; <LLN - 
30 g/L 
<3 - 2 g/dL; <30 - 20 
g/L 
<2 g/dL; <20 g/L 
missing 
Alkaline Phosphatase 
increased 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 


Statistical Analysis Plan 
 
Helsinn Healthcare SA 
Protocol number: PRAN-16-52 
 
11 November 2020 
 
 
 
 
 
 
  
 
CONFIDENTIAL 
Page 57 of 58 
 
Alanine 
aminotransferase 
(ALT) increased  
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Activated partial 
thromboplastin 
time (APTT) prolonged 
>ULN - 1.5 x ULN 
>1.5 - 2.5 x ULN 
>2.5 x ULN 
missing 
Aspartate 
aminotransferase 
(AST) increased 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Calcium increased 
>ULN- 1.5 mmol/L 
>1.5 -1.6 mmol/L 
>1.6 -1.8 mmol/L 
>1.8 mmol/L 
Calcium decreased 
<LLN - 1.0 mmol/L 
<1.0 - 0.9 mmol/L 
<0.9 - 0.8 mmol/L 
<0.8 mmol/L 
Creatinine increased 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 6.0 x ULN 
>6.0 x ULN 
Creatinine clearance 
decreased 
<LLN – 60 
ml/min/1.73 m2 
59 – 30 ml/min/1.73 
m2 
29 – 15 ml/min/1.73 m2 
<15 ml/min/1.73 m2 
Fibrinogen decreased 
<1.0 - 0.75 x LLN 
<0.75 - 0.5 x LLN 
<0.5 - 0.25 x LLN 
<0.25 x LLN 
Glucose increased 
>ULN - 160 mg/dL 
(>ULN -8.9 mmol/L) 
>160 - 250 mg/dL 
(>8.9 - 13.9 mmol/L) 
>250 - 500 mg/dL 
(>13.9 - 27.8 
mmol/L) 
>500 mg/dL (>27.8 
mmol/L) 
Glucose decreased 
<LLN - 55 mg/dL 
(<LLN -3.0 
mmol/L) 
<55 - 40 mg/dL (<3.0 - 
2.2 
mmol/L) 
<40 - 30 mg/dL (<2.2 - 
1.7 
mmol/L) 
<30 mg/dL (<1.7 
mmol/L) 
Hemoglobin decreased 
<LLN - 10.0 
g/dL (<LLN - 
100 g/L) 
<10.0 - 8.0 g/dL ( <100 
- 80g/L) 
Hgb <8.0 g/dL (<80 
g/L) 
missing 
INR increased 
>1 - 1.5 x ULN 
>1.5 - 2.5 x ULN 
>2.5 x ULN 
missing 
Lymphocyte count 
decreased 
<LLN - 800/mm3 ( 
<LLN - 0.8 x 
10e9 /L) 
<800 - 500/mm3 ( <0.8 
- 0.5 x 
10e9 /L) 
<500 - 200/mm3 ( <0.5 
- 0.2 x 
10e9 /L) 
<200/mm3 ( <0.2 x 10e9 
/L) 
Lymphocyte count 
increased 
missing 
>4000/mm3 - 
20,000/mm3 
>20,000/mm3 
missing 


Statistical Analysis Plan 
 
Helsinn Healthcare SA 
Protocol number: PRAN-16-52 
 
11 November 2020 
 
 
 
 
 
 
  
 
CONFIDENTIAL 
Page 58 of 58 
 
Magnesium increased 
>ULN - 3.0 mg/dL ( 
>ULN - 1.23 mmol/L) 
missing 
>3.0 - 8.0 mg/dL (>1.23 
- 3.30 
mmol/L) 
>8.0 mg/dL ( >3.30 
mmol/L) 
Magnesium decreased 
<LLN - 1.2 mg/dL 
(<LLN - 0.5 
mmol/L) 
<1.2 - 0.9 mg/dL (<0.5 
- 0.4 
mmol/L) 
<0.9 - 0.7 mg/dL (<0.4 
- 0.3 
mmol/L) 
<0.7 mg/dL (<0.3 
mmol/L) 
Neutrophil count 
decreased 
<LLN - 1500/mm3 ( 
<LLN - 1.5 x 
10e9 /L) 
<1500 - 1000/mm3 ( 
<1.5 - 1.0 x 
10e9 /L) 
<1000 - 500/mm3 ( 
<1.0 - 0.5 x 
10e9 /L) 
 
<500/mm3 ( <0.5 
x 10e9 /L) 
Phosphorus decreased 
<LLN - 2.5 mg/dL 
(<LLN - 0.8 
mmol/L) 
<2.5 - 2.0 mg/dL ( <0.8 
- 0.6 
mmol/L) 
<2.0 - 1.0 mg/dL ( <0.6 
- 0.3 
mmol/L) 
<1.0 mg/dL ( <0.3 
mmol/L) 
 
 
Platelet count 
decreased 
 
<LLN - 
75,000/mm3 (<LLN -
75.0 x 10e9 /L) 
<75,000 - 50,000/mm3 
(<75.0-50.0 x 10e9 /L) 
<50,000 - 25,000/mm3 
(<50.0-25.0 x 10e9 /L) 
<25,000/mm3 (<25.0 x 
10e9 /L) 
Potassium increased 
>ULN - 5.5 mmol/L 
>5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L 
>7.0 mmol/L 
Potassium decreased 
<LLN - 3.0 mmol/L 
missing 
<3.0 - 2.5 mmol/L 
<2.5 mmol/L 
Sodium increased 
>ULN - 150 mmol/L 
>150 - 155 mmol/L 
>155 - 160 mmol/L 
>160 mmol/L 
Sodium decreased 
<LLN - 130 mmol/L 
missing 
<130 - 120 mmol/L 
<120 mmol/L 
Total bilirubin 
increased 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
Uric acid increased 
>ULN - 10 mg/dL 
(0.59 mmol/L) 
missing 
missing 
>10 mg/dL ( >0.59 
mmol/L) 
White blood cell 
decreased 
<LLN - 3000/mm3 ( 
<LLN - 3.0 x 
10e9 /L) 
<3000 - 2000/mm3 ( 
<3.0 - 2.0 x 
10e9 /L) 
<2000 - 1000/mm3 
(<2.0 - 1.0 x 
10e9 /L) 
<1000/mm3 (<1.0 x 
10e9 /L)