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Clinical Trial Results:
A Randomized (1:1), Double-blind, Multi-center, Placebo Controlled Study Evaluating Intensive Chemotherapy With or Without Glasdegib (Pf-04449913) or Azacitidine (AZA) With or Without Glasdegib in Patients With Previously Untreated Acute Myeloid Leukemia

Summary
EudraCT number	2017-002822-19
Trial protocol	FR GB CZ SE BE PL ES DE IT RO
Global end of trial date	02 Dec 2022

Results information
Results version number	v2(current)
This version publication date	17 Dec 2023
First version publication date	04 Aug 2021
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

B1371019

ISRCTN number

US NCT number

NCT03416179

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Dec 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Dec 2022

Was the trial ended prematurely?

Main objective of the trial

To demonstrate that glasdegib is superior to placebo in combination with azacitidine (non-intensive study) or cytarabine and daunorubicin (intensive study) in prolonging overall survival (OS) in subjects with untreated acute myeloid leukemia (AML). To monitor the safety and tolerability of the investigational drugs in participants continuing study intervention from this study and participants originating from Study B1371012.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Apr 2018

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 21

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

Canada: 11

Country: Number of subjects enrolled

China: 72

Country: Number of subjects enrolled

Czechia: 61

Country: Number of subjects enrolled

France: 30

Country: Number of subjects enrolled

Germany: 16

Country: Number of subjects enrolled

Hungary: 37

Country: Number of subjects enrolled

Israel: 8

Country: Number of subjects enrolled

Italy: 22

Country: Number of subjects enrolled

Japan: 86

Country: Number of subjects enrolled

Korea, Republic of: 29

Country: Number of subjects enrolled

Poland: 25

Country: Number of subjects enrolled

Romania: 8

Country: Number of subjects enrolled

Russian Federation: 33

Country: Number of subjects enrolled

Spain: 73

Country: Number of subjects enrolled

Sweden: 4

Country: Number of subjects enrolled

Taiwan: 19

Country: Number of subjects enrolled

United Kingdom: 22

Country: Number of subjects enrolled

United States: 143

Country: Number of subjects enrolled

Austria: 16

Country: Number of subjects enrolled

Mexico: 4

Worldwide total number of subjects

743

EEA total number of subjects

295

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

318

From 65 to 84 years

410

85 years and over

Subject disposition

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Recruitment details

Study evaluated glasdegib in intensive(INT)&non-intensive(NINT)chemotherapy patients.INT study: Glasdegib in combination with cytarabine & daunorubicin for treating adults with previously untreated AML. Eligible NINT cohort subjects enrolled in B1371019(NCT03416179) &B1371012(NCT02367456) study were included in an open-label continuation study.

Screening details

NI study:Glasdegib in combination with azacitidine for treatment of adults with previously untreated AML who were not candidates for intensive induction chemotherapy.Open-label extension study:Eligible NINT cohort subjects enrolled in B1371019(NCT03416179)& B1371012(NCT02367456)study eligible subjects were included in an open-label extension study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Intensive Study: Glasdegib + Cytarabine + Daunorubicin

Arm description

Subjects received 28 days induction therapy: Cytarabine 100 milligram per square meter (mg/m^2) intravenous (IV) daily for 7 days + daunorubicin 60 mg/m^2 daily IV for 3 days. Depending on bone marrow blast or investigator judgement subjects had second induction to receive either same therapy or cytarabine 100 mg/m^2 IV daily for 5 days + daunorubicin 60 mg/m^2 IV daily for 2 days. Subjects with less than (<) 5 percentage (%) bone marrow blasts entered consolation phase: treated with either or both of: 1) Cytarabine 1 to 3 gm/m^2 IV for adults greater than or equal to (>=) 60 to <60 years twice daily on Days 1, 3, 5 for 4 cycle (1 cycle=28 days) or cytarabine per local prescribing information. 2) Received HSCT per local standard of care. Subjects received Glasdegib 100 mg tablet per oral (PO) once a day (QD) from Day 1 up to 28 days in both induction and until 2 consecutive CR MRD-negative, whichever came first.

Arm type

Experimental

Investigational medicinal product name

Glasdegib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received Glasdegib 100 mg tablet orally (PO) once daily (QD) from Day 1 of chemotherapy up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive (complete remission) CR MRD-negative central laboratory results, whichever came first.

Investigational medicinal product name

Daunorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received daunorubicin 60 mg/m^2 daily IV for 3 days. If >=5% bone marrow blast or investigator judgement for < 5% bone marrow blasts then received daunorubicin 60 mg/m^2 IV daily for 2 days or daunorubicin 60 mg/m^2 IV daily for 3 days.

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Cytarabine 100 mg/m^2 daily by IV infusion for 7 days. If greater than or equals to (>=) 5 percent (%) bone marrow blast or investigator judgement for less than (<) 5% bone marrow blasts then subjects received either option 1: cytarabine 100 mg/m^2 IV daily for 5 days or option 2: cytarabine 100 mg/m^2 IV daily for 7 days.

Intensive Study: Placebo + Cytarabine + Daunorubicin

Arm description

Subjects received 28 days induction therapy: Cytarabine 100 mg/m^2 IV daily for 7 days + daunorubicin 60 mg/m^2 daily IV for 3 days. Depending on bone marrow blast or investigator judgement subjects had second induction to receive either same therapy or cytarabine 100 mg/m^2 IV daily for 5 days + daunorubicin 60 mg/m^2 IV daily for 2 days. Subjects with <5% bone marrow blasts entered consolation phase: treated with either or both of: 1) Cytarabine 1 to 3 gm/m^2 IV for adults >= 60 to <60 years twice daily on Days 1, 3, 5 for 4 cycle (1 cycle=28 days) or cytarabine per local prescribing information. 2) Received HSCT per local standard of care. Subjects received Glasdegib matched placebo tablet PO QD from Day 1 up to 28 days in both induction and until 2 consecutive CR MRD-negative, whichever came first.

Arm type

Placebo

Investigational medicinal product name

Glasdegib matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received Glasdegib 100 mg matching placebo tablet PO QD from Day 1 of chemotherapy up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive CR MRD-negative central laboratory results, whichever came first.

Investigational medicinal product name

Daunorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Cytarabine 100 mg/m^2 daily by IV infusion for 7 days. If >=5% bone marrow blast or investigator judgement for <5% bone marrow blasts then subjects received either option 1: cytarabine 100 mg/m^2 IV daily for 5 days or option 2: cytarabine 100 mg/m^2 IV daily for 7 days.

Non-intensive Study: Glasdegib + Azacitidine

Arm description

Subjects received chemotherapy with azacitidine 75 mg/m^2 subcutaneous (SC) injection or IV infusion from Day 1 up to Day 7 of each cycle (28 day) and continued for at least 6 cycles or until unacceptable toxicity, subject refusal or death, whichever occurred first. Subjects also received glasdegib 100 mg PO QD from Day 1 of chemotherapy until clinical benefit or disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first. Eligible subjects underwent hematopoietic stem cell transplantation (HSCT) per local standard of care and received glasdegib unless 2 consecutive negative minimal residual disease (MRD) assessments.

Arm type

Experimental

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Glasdegib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received glasdegib 100 mg PO QD from Day 1 of chemotherapy and continued if subject’s demonstrated reasonable evidence of clinical benefit or until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first.

Non-intensive Study: Placebo + Azacitidine

Arm description

Subjects received chemotherapy with azacitidine 75 mg/m^2 SC injection or IV infusion from Day 1 up to Day 7 of each cycle (28 day) and continued for at least 6 cycles or until unacceptable toxicity, subjects refusal or death, whichever occurred first. Subjects also received glasdegib 100 mg tablet matching placebo PO QD from Day 1 of chemotherapy until clinical benefit or disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first. Eligible subjects underwent HSCT per local standard of care and glasdegib matching placebo unless 2 consecutive negative MRD assessments.

Arm type

Placebo

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Glasdegib matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received glasdegib 100 mg matching placebo PO QD from Day 1 of chemotherapy and continued if subject’s demonstrated reasonable evidence of clinical benefit or until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first.

Open Label Extension: Glasdegib + Azacitidine

Arm description

Subjects received glasdegib 100 mg tablet PO QD in combination with azacitidine 75 mg/ m^2/day as SC injection or IV infusion for 7 days every 28 days. Treatment continued until objective disease progression or relapse, death, unacceptable toxicity, or participant refusal, whichever occurred first. Participants were followed up for 28 days after end of study treatment.

Arm type

Experimental

Investigational medicinal product name

Azactidine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Glasdegib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Open Label Extension: Placebo + Azacitidine

Arm description

Subjects received placebo matched to Glasdegib in combination with azacitidine 75mg/m^2/day SC or IV for 7 days every 28 days. Treatment continued until objective disease progression or relapse, death, unacceptable toxicity, or participant refusal, whichever occurred first. Participants were followed up for 28 days after end of study treatment.

Arm type

Placebo

Investigational medicinal product name

Azactidine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Glasdegib matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine	Open Label Extension: Glasdegib + Azacitidine	Open Label Extension: Placebo + Azacitidine
Started	201	203	163	162	9	5
Completed	0	0	0	0	4	1
Not completed	201	203	163	162	5	4
Adverse event, serious fatal	67	60	96	88	-	-
Consent withdrawn by subject	13	19	5	6	-	-
Death	-	-	-	-	1	-
Ongoing	121	123	62	66	-	-
Unspecified	-	1	-	-	4	4
Lost to follow-up	-	-	-	2	-	-

Baseline characteristics

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Reporting group title

Intensive Study: Glasdegib + Cytarabine + Daunorubicin

Reporting group description

Reporting group title

Intensive Study: Placebo + Cytarabine + Daunorubicin

Reporting group description

Reporting group title

Non-intensive Study: Glasdegib + Azacitidine

Reporting group description

Reporting group title

Non-intensive Study: Placebo + Azacitidine

Reporting group description

Reporting group title

Open Label Extension: Glasdegib + Azacitidine

Reporting group description

Reporting group title

Open Label Extension: Placebo + Azacitidine

Reporting group description

Reporting group values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine	Open Label Extension: Glasdegib + Azacitidine	Open Label Extension: Placebo + Azacitidine	Total
Number of subjects	201	203	163	162	9	5	743
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	144	141	16	17	0	0	318
From 65-84 years	57	61	142	136	9	5	410
85 years and over	0	1	5	9	0	0	15
Age Continuous
Units: years
arithmetic mean (standard deviation)	56.55 ( 12.60 )	55.38 ( 13.61 )	73.19 ( 7.17 )	73.14 ( 6.82 )	72.33 ( 3.94 )	76.80 ( 5.26 )	-
Sex: Female, Male
Units: subjects
Female	71	97	97	89	3	3	360
Male	130	106	66	73	6	2	383
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	1	0	0	0	0	0	1
Asian	66	57	51	44	1	0	219
Black or African American	3	3	1	7	0	1	15
White	110	123	97	99	5	4	438
More than one race	1	0	0	0	0	0	1
Unknown or Not Reported	20	20	14	12	3	0	69
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	19	12	12	16	1	1	61
Not Hispanic or Latino	166	171	140	139	7	4	627
Unknown or Not Reported	16	20	11	7	1	0	55

End points

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Reporting group title

Intensive Study: Glasdegib + Cytarabine + Daunorubicin

Reporting group description

Reporting group title

Intensive Study: Placebo + Cytarabine + Daunorubicin

Reporting group description

Reporting group title

Non-intensive Study: Glasdegib + Azacitidine

Reporting group description

Reporting group title

Non-intensive Study: Placebo + Azacitidine

Reporting group description

Reporting group title

Open Label Extension: Glasdegib + Azacitidine

Reporting group description

Reporting group title

Open Label Extension: Placebo + Azacitidine

Reporting group description

Primary: Non-intensive Study: OS

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End point title

Non-intensive Study: OS ^[1]

End point description

OS was defined as the time from date of first study treatment to date of death from any cause. Subject's last known to be alive were to be censored at the date of last contact. FA set included all randomised subjects.

End point type

Primary

End point timeframe

Baseline up to 25 months

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	163	162
Units: Months
median (confidence interval 95%)	10.3 (7.7 to 12.4)	10.6 (8.4 to 13.3)

Glasdegib Vs Placebo

Statistical analysis description

Hazard ratio based on Cox proportional hazards model; under proportional hazards, hazard ratio < 1 indicates a reduction in hazard rate in favor of Glasdegib 100 mg PO QD + Azacitidine compared to Placebo + Azacitidine

Comparison groups

Non-intensive Study: Glasdegib + Azacitidine v Non-intensive Study: Placebo + Azacitidine

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5955

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.775

upper limit

1.388

Primary: Intensive Study: Overall Survival (OS)

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End point title

Intensive Study: Overall Survival (OS) ^[2]

End point description

OS was defined as the time from the date of randomisation to the date of death due to any cause. Subjects last known to be alive were to be censored at the date of last contact. Full Analysis (FA) set included all randomised subjects. Here, '99999 =Upper limit of 95 % CI was not estimable due to low number of subjects with events.'

End point type

Primary

End point timeframe

Baseline up to 25 months

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	201	203
Units: Months
median (confidence interval 95%)	17.3 (15.2 to 18.5)	20.4 (17.6 to 99999)

Glasdegib Vs Placebo

Statistical analysis description

Hazard ratio based on Cox proportional hazards model; under proportional hazards, hazard ratio less than (<) 1 indicated a reduction in hazard rate in favor of Glasdegib 100 mg PO + Cytarabine 100 mg/m^2 IV + Daunorubicin 60 mg/m^2 compared to Placebo + Cytarabine 100 mg/m^2 IV + Daunorubicin 60 mg/m^2.

Comparison groups

Intensive Study: Glasdegib + Cytarabine + Daunorubicin v Intensive Study: Placebo + Cytarabine + Daunorubicin

Number of subjects included in analysis

404

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6579

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.755

upper limit

1.532

Primary: Open Label Extension: Number of Subjects With Treatment Emergent Adverse Event (AE) and Treatment Related AE

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End point title

Open Label Extension: Number of Subjects With Treatment Emergent Adverse Event (AE) and Treatment Related AE ^[3] ^[4]

End point description

An AE was any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if the event occurred during the on-treatment period (regardless of if it was seen prior to the start of treatment). An AE was considered treatment related as assigned by the investigator.

End point type

Primary

End point timeframe

From initiation of study treatment to study completion from 17-May-2021 to 02-Dec-2022 (approximately 565 days)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Open Label Extension: Glasdegib + Azacitidine	Open Label Extension: Placebo + Azacitidine
Number of subjects analysed	9	5
Units: Subjects
Treatment emergent AE	7	4
Treatment related AE	5	4

No statistical analyses for this end point

Primary: Open Label Extension: Number of Subjects With Treatment Emergent Serious Adverse Events (SAE) and Treatment Related SAEs

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End point title

Open Label Extension: Number of Subjects With Treatment Emergent Serious Adverse Events (SAE) and Treatment Related SAEs ^[5] ^[6]

End point description

A SAE was defined as any untoward medical occurrence that, at any dose that resulted in death; was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or other medical events as per investigator’s judgement. A SAE was considered treatment emergent if the event occurred during the on-treatment period (regardless of if it was seen prior to the start of treatment). A SAE was considered treatment related as assigned by the investigator.

End point type

Primary

End point timeframe

From initiation of study treatment to study completed from 17-May-2021 to 02-Dec-2022 (approximately 565 days)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Open Label Extension: Glasdegib + Azacitidine	Open Label Extension: Placebo + Azacitidine
Number of subjects analysed	9	5
Units: Subjects
Treatment emergent SAEs	2	1
Treatment related SAEs	1	1

No statistical analyses for this end point

Secondary: Non-intensive Study: Percentage of Subjects who Improved in Fatigue Score Measured by the MDASI-AML/MDS Questionnaire at Week 12

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End point title

Non-intensive Study: Percentage of Subjects who Improved in Fatigue Score Measured by the MDASI-AML/MDS Questionnaire at Week 12 ^[7]

End point description

MDASI-AML/MDS: consists of 23 items, 13-item core cancer symptoms (pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, problem remembering, lack of appetite, drowsiness, dry mouth, sadness, vomiting, and numbness), 4-item AML/MDS specific symptoms (malaise, diarrhea, muscle weakness, and skin problems), and 6 areas of interference (general activity, mood, work, walking, relations with other people, and enjoyment of life). “Fatigue” was measured at the subjects’ worst level in last 24 hours by asking subjects to respond to each item on an 0-10 numeric rating scale (NRS), where 0 = “not present” and 10 = “as bad as you can imagine”. Percentage of subjects who had improvement in "fatigue" symptoms reported in this end point. Full analysis set included all randomised subjects.

End point type

Secondary

End point timeframe

Post-baseline up to Week 12

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	163	162
Units: Units on a scale
number (confidence interval 95%)	11.66 (6.73 to 16.58)	15.43 (9.87 to 21.00)

Glasdegib vs Placebo

Comparison groups

Non-intensive Study: Glasdegib + Azacitidine v Non-intensive Study: Placebo + Azacitidine

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.8359

Method

Mantel-Haenszel

Confidence interval

Secondary: Percentage of Subjects who Improved in Fatigue Score Measured by the MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Questionnaire

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End point title

Percentage of Subjects who Improved in Fatigue Score Measured by the MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Questionnaire ^[8]

End point description

End point type

Secondary

End point timeframe

Post-baseline up to Week 8

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	201	203
Units: Percentage of participants
number (confidence interval 95%)	17.41 (12.17 to 22.66)	17.24 (12.05 to 22.44)

Glasdegib vs Placebo

Comparison groups

Intensive Study: Glasdegib + Cytarabine + Daunorubicin v Intensive Study: Placebo + Cytarabine + Daunorubicin

Number of subjects included in analysis

404

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5095

Method

Mantel-Haenszel

Confidence interval

Secondary: Non-intensive Study: Percentage of Subjects With CR Including CRMRD-neg

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End point title

Non-intensive Study: Percentage of Subjects With CR Including CRMRD-neg ^[9]

End point description

CR was defined based on 2017 ELN recommendations. CR: Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC >=1.0*10^9/L; platelet count >=100*10^9/L. CRMRDneg: CR with negativity for a genetic marker by RT-qPCR, or CR with negativity by MFC. Full analysis set included all randomised subjects.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	163	162
Units: Percentage of subjects
number (confidence interval 95%)	19.6 (13.8 to 26.6)	13.0 (8.2 to 19.1)

No statistical analyses for this end point

Secondary: Intensive Study: Percentage of Subjects With CR Including CRMRD-neg

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End point title

Intensive Study: Percentage of Subjects With CR Including CRMRD-neg ^[10]

End point description

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	201	203
Units: Percentage of subjects
number (confidence interval 95%)	49.3 (42.1 to 56.4)	47.3 (40.3 to 54.4)

No statistical analyses for this end point

Secondary: Non-intensive Study: Percentage of Subjects With CRMRD-neg

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End point title

Non-intensive Study: Percentage of Subjects With CRMRD-neg ^[11]

End point description

CR was defined based on 2017 ELN recommendations. CR: Bone marrow blasts <5 %; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC >= 1.0*10^9/L; platelet count >=100*10^9/L. CRMRD-neg: CR with negativity for a genetic marker by RT-qPCR, or CR with negativity by MFC. Full analysis set included all randomised subjects. Full analysis set included all randomised subjects.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	163	162
Units: Percentage of subjects
number (confidence interval 95%)	1.8 (0.4 to 5.3)	0.6 (0.0 to 3.4)

No statistical analyses for this end point

Secondary: Intensive Study: Percentage of Subjects With Complete Remission With Incomplete Hematologic Recovery (CRi)

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End point title

Intensive Study: Percentage of Subjects With Complete Remission With Incomplete Hematologic Recovery (CRi) ^[12]

End point description

CR was defined based on 2017 ELN recommendations. CR: MRD (positive or unknown), bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC less than (<) 1.0*10^9/L; platelet count <100 × 10^9/L. CRi (included CR [includes CRMRD-neg]): not qualifying for CR, neutropenia <1.0*10^9/L or platelets <100*10^9, absence of extramedullary disease, and absence of blasts with Auer rods. Full analysis set included all randomised subjects.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	201	203
Units: Percentage of subjects
number (confidence interval 95%)	1.5 (0.3 to 4.3)	5.4 (2.7 to 9.5)

No statistical analyses for this end point

Secondary: Intensive Study: Percentage of Subjects With Complete Remission Without Negative Minimal Residual Disease (CRMRD-neg)

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End point title

Intensive Study: Percentage of Subjects With Complete Remission Without Negative Minimal Residual Disease (CRMRD-neg) ^[13]

End point description

Complete remission (CR) was defined based on 2017 European LeukemiaNet (ELN) recommendations. CR: Bone marrow blasts <5 percentage (%); absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) greater than equal to (>=) 1.0*10^9/Liter (L); platelet count >=100*10^9/L. CRMRD-neg: CR with negativity for a genetic marker by reverse transcription quantitative polymerase chain reaction (RT-qPCR), or CR with negativity by Multiparameter Flow Cytometry (MFC). Full analysis set included all randomised subjects.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	201	203
Units: Percentage of subjects
number (confidence interval 95%)	5.0 (2.4 to 9.0)	5.4 (2.7 to 9.5)

No statistical analyses for this end point

Secondary: Non-intensive Study: Percentage of Subjects With CRi

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End point title

Non-intensive Study: Percentage of Subjects With CRi ^[14]

End point description

CR was defined based on 2017 ELN recommendations. CR: MRD (positive or unknown), bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC <1.0*10^9/L; platelet count <100*10^9/L. CRi (included CR [includes CRMRD-neg]): not qualifying for CR, neutrophil <0.5*10^9/L or platelets <50*10^9/L, absence of extramedullary disease, and absence of blasts with Auer rods. Full analysis set included all randomised subjects.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	163	162
Units: Percentage of subjects
number (confidence interval 95%)	2.5 (0.7 to 6.2)	4.9 (2.2 to 9.5)

No statistical analyses for this end point

Secondary: Intensive Study: Percentage of Subjects With Morphologic Leukemia-free State (MLFS)

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End point title

Intensive Study: Percentage of Subjects With Morphologic Leukemia-free State (MLFS) ^[15]

End point description

MLFS was defined based on 2017 ELN recommendations. MLFS: MRD (positive or unknown), bone marrow blasts <5%, no hematologic recovery required, marrow should not be aplastic, at least 200 cells enumerated or cellularity absence of extramedullary disease >=10%, and absence of blasts with Auer rods. Full analysis set included all randomised subjects.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	201	203
Units: Percentage of subjects
number (confidence interval 95%)	1.5 (0.3 to 4.3)	2.0 (0.5 to 5.0)

No statistical analyses for this end point

Secondary: Intensive Study: Percentage of Subjects With Partial Remission (PR)

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End point title

Intensive Study: Percentage of Subjects With Partial Remission (PR) ^[16]

End point description

PR was defined based on 2017 ELN recommendations. PR: MRD (positive or unknown); bone marrow blasts – decrease to 5-25% and decrease of pre-treatment bone marrow blast percentage by at least 50%; neutrophil count >=1.0*10^9/L; and platelets count >=100*10^9/L. Full analysis set included all randomised subjects.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	201	203
Units: Percentage of subjects
number (confidence interval 95%)	5.0 (2.4 to 9.0)	4.4 (2.0 to 8.2)

No statistical analyses for this end point

Secondary: Non-intensive Study: Percentage of Subjects With MLFS

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End point title

Non-intensive Study: Percentage of Subjects With MLFS ^[17]

End point description

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	163	162
Units: Percentage of subjects
number (confidence interval 95%)	3.1 (1.0 to 7.0)	0.6 (0.0 to 3.4)

No statistical analyses for this end point

Secondary: Non-intensive Study: Percentage of Subjects With PR

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End point title

Non-intensive Study: Percentage of Subjects With PR ^[18]

End point description

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	163	162
Units: Percentage of subjects
number (confidence interval 95%)	2.5 (0.7 to 6.2)	4.9 (2.2 to 9.5)

No statistical analyses for this end point

Secondary: Non-intensive Study: Percentage of Subjects With Complete Remission With Partial Hematologic Recovery (CRh)

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End point title

Non-intensive Study: Percentage of Subjects With Complete Remission With Partial Hematologic Recovery (CRh) ^[19]

End point description

CRh: MRD (positive or unknown); bone marrow blasts <5%; assessed in non-intensive chemotherapy study only, not qualifying for CR, ie, both neutrophil >=0.5*10^9/L and platelets >=50*10^9/L must be met, but does not satisfy both Neutrophils >=1*10^9/L and Platelets >=100*10^9/L at the same time; absence of extramedullary disease; and absence of blasts with Auer rods. Full analysis set included all randomised subjects.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	163	162
Units: Percentage of subjects
number (confidence interval 95%)	3.1 (1.0 to 7.0)	3.1 (1.0 to 7.1)

No statistical analyses for this end point

Secondary: Intensive Study: Duration of Response (DoRi)

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End point title

Intensive Study: Duration of Response (DoRi) ^[20]

End point description

DoRi: only defined for subjects who have ever achieved CRi or better (included CR as well) on study as the time from date of first achieving CRi or better to the date of relapse after CRi or better or death due to any cause. CRi: not qualifying for CR, neutropenia (neutrophils <1.0*10^9/L) or platelets <100*10^9/L, absence of extramedullary disease, and absence of blasts with Auer rods. Subjects last known to be alive who were free from relapse after CRi or better were censored at the date of last disease assessment that verifies their status. DORi was not analysed as the intensive cohort ended in futility. Subjects ended study intervention early and were not followed for the remainder of the study.

End point type

Secondary

End point timeframe

From date of first achieving CRi or better to the date of relapse after CRi or better or death due to any cause (maximum up to 2 years)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	0 ^[21]	0 ^[22]
Units: Months
arithmetic mean (standard deviation)	( )	( )

Notes
[21] - DORi was not analysed as the intensive cohort ended in futility.
[22] - DORi was not analysed as the intensive cohort ended in futility.

No statistical analyses for this end point

Secondary: Non-intensive Study: DoRi

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End point title

Non-intensive Study: DoRi ^[23]

End point description

Dori: Subjects who ever achieved CRi or better (included CR,CRh) on study as time from date of first achieving CRi or better to date of relapse after CRi or better or death due to any cause. DoRh: Subjects ever achieved CRh or better (included CR) on study as time from date of first achieving CRh or better to date of disease progression, or relapse after CRh or better,or death due to any cause. CRi: not qualifying for CR,neutrophil(N)<0.5*10^9/L or platelets (P)<50*10^9, absence of extramedullary disease and blasts with Auer rods. CRh: MRD (positive or unknown); bone marrow blasts <5%; assessed in non-intensive chemotherapy study only, not qualifying for CR, ie, both N >=0.5*10^9/L, P >=50*10^9/L must be met, but does not satisfy both N >=1*10^9/L and P>=100*10^9/L at same time; absence of extramedullary disease and blasts with Auer rods. DORi not analysed as intensive cohort ended in futility. Subjects ended study intervention early and were not followed for remainder of study.

End point type

Secondary

End point timeframe

From date of first achieving CRi/CRh or better to the date of relapse/disease progression after CRi/CRh or better or death due to any cause (maximum up to 3 years)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	0 ^[24]	0 ^[25]
Units: Months
number (confidence interval 95%)	( to )	( to )

Notes
[24] - DORi was not analysed as the intensive cohort ended in futility.
[25] - DORi was not analysed as the intensive cohort ended in futility.

No statistical analyses for this end point

Secondary: Non-intensive Study: Time to Response

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End point title

Non-intensive Study: Time to Response ^[26]

End point description

TTRi: Subjects who achieved CRi or better, as the time from the date of randomisation to the first documentation of response (CRi or better). TTRh: Subjects who achieved CRh or better, as the time from the date of randomisation to the first documentation of response (CRh or better). CRi: not qualifying for CR, neutrophil <0.5*10^9/L or platelets <50*10^9/L, absence of extramedullary disease, and absence of blasts with Auer rods. CRh: MRD (positive or unknown); bone marrow blasts <5%; assessed in non-intensive chemotherapy study only, not qualifying for CR, ie, both neutrophil >=0.5*10^9/L and platelets >=50*10^9/L must be met, but does not satisfy both Neutrophils >=1*10^9/L and Platelets >=100*10^9/L at the same time; absence of extramedullary disease; and absence of blasts with Auer rods. Full analysis set included all randomised subjects.

End point type

Secondary

End point timeframe

From the date of randomisation to the first documentation of response (CRi/CRh or better) (maximum up to 3 years)

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	163	162
Units: Months
arithmetic mean (standard deviation)
TTRi	4.057 ( 1.9532 )	4.093 ( 2.1809 )
TTRh	4.334 ( 1.8853 )	4.146 ( 2.1540 )

No statistical analyses for this end point

Secondary: Intensive Study: Event-free Survival (EFS)

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End point title

Intensive Study: Event-free Survival (EFS) ^[27]

End point description

EFS: Time from the date of randomisation to the date of treatment failure (TF), relapse from CR, or death from any cause, whichever comes first. TF was defined as failure to achieve CR during the induction cycle (including the re-induction cycle if there is one) and the event date for TF is the day of randomisation. CR was defined based on 2017 ELN recommendations. CR: Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC >=1.0*10^9/L; platelet count >=100*10^9/L. Subjects ended study intervention early and were not followed for the remainder of the study.

End point type

Secondary

End point timeframe

From the date of randomisation to the date of TF, relapse from CR, or death from any cause, whichever comes first (maximum up to 2 years)

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	0 ^[28]	0 ^[29]
Units: Months
number (confidence interval 95%)	( to )	( to )

Notes
[28] - EFS was not analysed as the intensive cohort ended in futility.
[29] - EFS was not analysed as the intensive cohort ended in futility.

No statistical analyses for this end point

Secondary: Intensive Study: MDASI-AML/MDS Score

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End point title

Intensive Study: MDASI-AML/MDS Score ^[30]

End point description

MDASI-AML/MDS: consists of 23 items,13-item core cancer symptoms(pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, problem remembering, lack of appetite, drowsiness, dry mouth, sadness, vomiting, numbness), 4-item AML/MDS specific symptoms(malaise, diarrhea, muscle weakness,skin problems), and 6 areas of interference (general activity, mood, work, walking, relations with other people, enjoyment of life). The 13 core symptoms and 6 core interference items had highest frequency and/or severity in subjects with various cancers and treatment types. It was measured at severity of symptoms and related interference at their worst level in last 24 hours by asking subjects to respond to each item on an 0-10 NRS,where 0 = “not present” or “did not interfere” and 10 = “worst” or “interfered completely”. MDASI-AML/MDS score was not analysed as intensive cohort terminated because of futility. Subjects ended study intervention early and were not followed up as planned.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	0 ^[31]	0 ^[32]
Units: Units on a scale
number (confidence interval 95%)	( to )	( to )

Notes
[31] - MDASI-AML/MDS score was not analysed as intensive cohort terminated because of futility.
[32] - MDASI-AML/MDS score was not analysed as intensive cohort terminated because of futility.

No statistical analyses for this end point

Secondary: Non-intensive Study: EFS

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End point title

Non-intensive Study: EFS ^[33]

End point description

EFS: Time from the date of randomisation to the date of TF, relapse from CR, or death from any cause, whichever comes first. TF was defined as failure to achieve CR during the induction cycle (including the re-induction cycle if there is one) and the event date for TF is the day of randomisation. CR was defined based on 2017 ELN recommendations. CR: Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC >=1.0*10^9/L; platelet count >=100*10^9/L. Subjects ended study intervention early and were not followed for the remainder of the study.

End point type

Secondary

End point timeframe

From the date of randomisation to the date of TF, relapse from CR, or death from any cause, whichever comes first (maximum up to 3 years)

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	0 ^[34]	0 ^[35]
Units: Months
number (confidence interval 95%)	( to )	( to )

Notes
[34] - EFS was not analysed as the non-intensive cohort ended in futility.
[35] - EFS was not analysed as the non-intensive cohort ended in futility.

No statistical analyses for this end point

Secondary: Non-intensive Study: MDASI-AML/MDS Score

Top of page

End point title

Non-intensive Study: MDASI-AML/MDS Score ^[36]

End point description

MDASI-AML/MDS: consists of 23 items, 13-item core cancer symptoms (pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, problem remembering, lack of appetite, drowsiness, dry mouth, sadness, vomiting,numbness), 4-item AML/MDS specific symptoms (malaise, diarrhea, muscle weakness,skin problems), and 6 areas of interference (general activity, mood, work, walking, relations with other people, enjoyment of life). The 13 core symptoms and 6 core interference items had highest frequency and/or severity in subjects with various cancers and treatment types. It was measured at severity of symptoms and related interference at their worst level in last 24 hours by asking subjects to respond to each item on an 0-10 NRS,where 0 = “not present” or “did not interfere” and 10 = “worst” or “interfered completely”. MDASI-AML/MDS score was not analysed as non-intensive cohort terminated because of futility. Subjects ended study intervention early and were not followed up as planned.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	0 ^[37]	0 ^[38]
Units: Units on a scale
number (confidence interval 95%)	( to )	( to )

Notes
[37] - MDASI-AML/MDS score was not analysed as non-intensive cohort terminated because of futility.
[38] - MDASI-AML/MDS score was not analysed as non-intensive cohort terminated because of futility.

No statistical analyses for this end point

Secondary: Intensive Study: EQ-5D-5L Score

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End point title

Intensive Study: EQ-5D-5L Score ^[39]

End point description

EQ-5D-5L:brief,self-administered,validated,reliable generic health status instrument developed by EuroQoL(EQ)Group.Consists of EQ-5D descriptive system and visual analogue scale(VAS),EQ-VAS.EQ-5D:Measures subject’s health state on 5-dimensions(mobility,self-care,usual activities,pain/discomfort,anxiety/depression).Health state indicated by rating each dimension on 5-level scale(1=no problem,5=extreme problem).Rating resulted in1-digit number expressing level selected for that dimension.Digits for 5 dimensions were combined in 5-digit number describing subject's health state. EQ-5D index scores ranges=0 (worst health state) to 1(perfect health). EQ-5D-5L score not analysed as intensive cohort ended in futility. Subjects ended study intervention early and not followed for remainder of study. EQ-5D-5L score was not analysed as intensive cohort terminated because of futility. Subjects ended study intervention early and were not followed up as planned.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	0 ^[40]	0 ^[41]
Units: Units on a scale
number (confidence interval 95%)	( to )	( to )

Notes
[40] - EQ-5D-5L score was not analysed as intensive cohort terminated because of futility.
[41] - EQ-5D-5L score was not analysed as intensive cohort terminated because of futility.

No statistical analyses for this end point

Secondary: Intensive Study: Patients Global Impression of Symptoms (PGIS)

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End point title

Intensive Study: Patients Global Impression of Symptoms (PGIS) ^[42]

End point description

PGIS: is a single 1-item questionnaire designed to assess subject’s overall impression of disease severity at a given point in time. It uses a 4-point Likert scale as follows: In the last 24 hours, my leukemia symptoms are: 1-“absent (no symptoms)”, 2-“mild”, 3-“ moderate”, 4=”severe”. PGIS was not analysed as intensive cohort terminated because of futility. Subjects ended study intervention early and were not followed up as planned.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	0 ^[43]	0 ^[44]
Units: Units on a scale
number (confidence interval 95%)	( to )	( to )

Notes
[43] - PGIS was not analysed as intensive cohort terminated because of futility.
[44] - PGIS was not analysed as intensive cohort terminated because of futility.

No statistical analyses for this end point

Secondary: Non-intensive Study: EQ-VAS

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End point title

Non-intensive Study: EQ-VAS ^[45]

End point description

EQ-5D-5L: brief, self-administered, validated, reliable generic health status instrument developed by EuroQoL group. It consists of EQ-5D descriptive system and a VAS, EQ-VAS. EQ VAS records respondent’s self-rated health on a 20-cm vertical, VAS from 0 (worst imaginable health state) to 100 (best imaginable health state). EQ-VAS was not analysed as non-intensive cohort terminated because of futility. Subjects ended study intervention early and were not followed up as planned.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	0 ^[46]	0 ^[47]
Units: Units on a scale
number (confidence interval 95%)	( to )	( to )

Notes
[46] - EQ-VAS was not analysed as non-intensive cohort terminated because of futility.
[47] - EQ-VAS was not analysed as non-intensive cohort terminated because of futility.

No statistical analyses for this end point

Secondary: Intensive Study: EuroQoL Visual Analogue Scale (EQ-VAS)

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End point title

Intensive Study: EuroQoL Visual Analogue Scale (EQ-VAS) ^[48]

End point description

EQ-5D-5L: brief, self-administered, validated, reliable generic health status instrument developed by EuroQoL group. It consists of EQ-5D descriptive system and a VAS, EQ-VAS. EQ VAS records respondent’s self-rated health on a 20-cm vertical, VAS from 0 (worst imaginable health state) to 100 (best imaginable health state). EQ-VAS was not analysed as intensive cohort terminated because of futility. Subjects ended study intervention early and were not followed up as planned.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	0 ^[49]	0 ^[50]
Units: Units on a scale
number (confidence interval 95%)	( to )	( to )

Notes
[49] - EQ-VAS was not analysed as intensive cohort terminated because of futility.
[50] - EQ-VAS was not analysed as intensive cohort terminated because of futility.

No statistical analyses for this end point

Secondary: Non-intensive Study: EQ-5D-5L Score

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End point title

Non-intensive Study: EQ-5D-5L Score ^[51]

End point description

EQ-5D-5L: brief, self-administered, validated, reliable generic health status instrument developed by EuroQoL Group. Consists of EQ-5D descriptive system and VAS, EuroQoL (EQ)-VAS. EQ-5D: descriptive system measures subject’s health state on 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Subject to indicate his/her health state by rating each dimension on 5-level scale (1=no problem, 5=extreme problem). Rating resulted in 1-digit number expressing level selected for that dimension. Digits for 5 dimensions were combined in 5-digit number describing respondent’s health state. EQ-5D index scores ranges= 0 (worst health state) to1 (perfect health). EQ-5D-5L score was not analysed as non-intensive cohort terminated because of futility. Subjects ended study intervention early and were not followed up as planned.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	0 ^[52]	0 ^[53]
Units: Units on a scale
number (confidence interval 95%)	( to )	( to )

Notes
[52] - EQ-5D-5L score was not analysed as non-intensive cohort terminated because of futility.
[53] - EQ-5D-5L score was not analysed as non-intensive cohort terminated because of futility.

No statistical analyses for this end point

Secondary: Non-intensive Study: PGIS

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End point title

Non-intensive Study: PGIS ^[54]

End point description

PGIS: is a single 1-item questionnaire designed to assess subject's overall impression of disease severity at a given point in time. It uses a 4-point Likert scale as follows: In the last 24 hours, symptoms are: 1-"absent (no symptoms)", 2-"mild", 3-" moderate", 4="severe". The non-intensive cohort was terminated because of futility. Subjects ended study intervention early and were not followed up as planned. Hence, PGIS was not collected, analyzed and reported.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	0 ^[55]	0 ^[56]
Units: Percentage of participants
number (confidence interval 95%)	( to )	( to )

Notes
[55] - PGIS was not analysed as non-intensive cohort terminated because of futility.
[56] - PGIS was not analysed as non-intensive cohort terminated because of futility.

No statistical analyses for this end point

Secondary: Intensive Study: Participants Global Impression of Change (PGIC)

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End point title

Intensive Study: Participants Global Impression of Change (PGIC) ^[57]

End point description

PGIC: a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change since starting treatment as rated on a 7-point Likert scale anchored by (1) 'very much improved' to (7) 'very much worse', with (4) =' no change'. The PGIC is a measure of "participant rating of global improvement and satisfaction with treatment". The intensive cohort was terminated because of futility. Subjects ended study intervention early and were not followed up as planned. Hence, PGIC was not collected, analysed and reported.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	0 ^[58]	0 ^[59]
Units: Percentage of Participants
number (confidence interval 95%)	( to )	( to )

Notes
[58] - PGIC was not analysed as intensive cohort terminated because of futility.
[59] - PGIC was not analysed as intensive cohort terminated because of futility.

No statistical analyses for this end point

Secondary: Non-intensive Study: PGIC

Top of page

End point title

Non-intensive Study: PGIC ^[60]

End point description

PGIC: a single-item questionnaire designed to assess the subject’s overall sense of whether there has been a change since starting treatment as rated on a 7-point Likert scale anchored by (1) ‘very much improved’ to (7) ‘very much worse’, with (4) =’ no change’. The PGIC is a measure of “subject rating of global improvement and satisfaction with treatment”. PGIC was not analysed as non-intensive cohort terminated because of futility. Subjects ended study intervention early and were not followed up as planned.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	0 ^[61]	0 ^[62]
Units: Units on a scale
number (confidence interval 95%)	( to )	( to )

Notes
[61] - PGIC was not analysed as non-intensive cohort terminated because of futility.
[62] - PGIC was not analysed as non-intensive cohort terminated because of futility.

No statistical analyses for this end point

Secondary: Intensive Study: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03

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End point title

Intensive Study: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03 ^[63]

End point description

AE: any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. SAE: any AE, regardless of dose, that led to death; was life-threatening; required hospitalisation or prolonged hospitalisation; led to persistent or significant incapacity or led to congenital anomaly or birth defect. AEs and SAEs based on NCI CTCAE v.4.03 has been reported in this endpoint. Grade 3=severe adverse event, Grade 4= life threatening consequences; urgent intervention indicated, Grade 5= death related to adverse event. Safety Analysis (SA) set included all subjects who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	198	201
Units: Subjects
AEs	196	198
SAEs	86	92
Grade 3 or 4 AE	161	149
Grade 5 AE	5	8

No statistical analyses for this end point

Secondary: Non-intensive Study: Number of Subjects With AEs and SAEs Graded by NCI CTCAE v.4.03

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End point title

Non-intensive Study: Number of Subjects With AEs and SAEs Graded by NCI CTCAE v.4.03 ^[64]

End point description

AE: any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. SAE: any AE, regardless of dose, that led to death; was life-threatening; required hospitalisation or prolonged hospitalisation; led to persistent or significant incapacity or led to congenital anomaly or birth defect. AEs and SAEs based on NCI CTCAE v.4.03 has been reported in this endpoint. Grade 3=severe adverse event, Grade 4= life threatening consequences; urgent intervention indicated, Grade 5= death related to adverse event. SA set included all subjects who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	162	160
Units: Subjects
AEs	161	158
SAEs	117	124
Grade 3 or 4 AE	106	100
Grade 5 AE	50	52

No statistical analyses for this end point

Secondary: Intensive Study: Number of Subjects With Treatment Related AEs and SAEs Graded by NCI CTCAE v.4.03

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End point title

Intensive Study: Number of Subjects With Treatment Related AEs and SAEs Graded by NCI CTCAE v.4.03 ^[65]

End point description

AE: any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. SAE: any AE, regardless of dose, that led to death; was life-threatening; required hospitalisation or prolonged hospitalisation; led to persistent or significant incapacity or led to congenital anomaly or birth defect. AEs and SAEs based on NCI CTCAE v.4.03 has been reported in this endpoint. Grade 3=severe adverse event, Grade 4= life threatening consequences; urgent intervention indicated, Grade 5= death related to adverse event. SA set included all subjects who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	198	201
Units: Subjects
Treatment related AEs	181	188
Treatment related SAEs	48	60
Grade 3 or 4 AE	161	149
Grade 5 AE	5	8

No statistical analyses for this end point

Secondary: Non-intensive Study: Number of Subjects With Treatment Related AEs and SAEs Graded by NCI CTCAE v.4.03

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End point title

Non-intensive Study: Number of Subjects With Treatment Related AEs and SAEs Graded by NCI CTCAE v.4.03 ^[66]

End point description

AE: any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. SAE: any AE, regardless of dose, that led to death; was life-threatening; required hospitalisation or prolonged hospitalisation; led to persistent or significant incapacity or led to congenital anomaly or birth defect. AEs and SAEs based on NCI CTCAE v.4.03 has been reported in this endpoint. Grade 3=severe adverse event, Grade 4= life threatening consequences; urgent intervention indicated, Grade 5= death related to adverse event. SA set included all subjects who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	162	160
Units: Subjects
Treatment related AEs	133	123
Treatment related SAEs	45	37
Grade 3 or 4 AE	97	72
Grade 5 AE	4	4

No statistical analyses for this end point

Secondary: Intensive Study: Number of Subjects With Shift From Baseline in Hematological Laboratory Abnormalities Graded by NCI CTCAE v.4.03

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End point title

Intensive Study: Number of Subjects With Shift From Baseline in Hematological Laboratory Abnormalities Graded by NCI CTCAE v.4.03 ^[67]

End point description

Hematology laboratory test included: anemia(A), hemoglobin(H) increased, international normalized ratio (INR) increased, lymphocyte(L) count decreased, lymphocyte count increased, neutrophil(N) count decreased, platelet(P) count decreased, and white blood cell(WBC) decreased. Laboratory results were categorically summarised according to the NCI-CTCAE criteria v4.03. Grade (G) 1= mild; G2= moderate; G 3= severe and G 4= life-threatening or disabling. Number of subjects with shift from baseline(B) for hematology laboratory test were assessed. Only those laboratory test parameters in which at least 1 subject had data were reported. SA set included all subjects who received at least one dose of study drug. Here, "Overall Number of Subjects Analyzed" signifies subjects evaluable for this endpoint and "Number Analyzed" signifies subjects evaluable for specified rows.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	196	197
Units: Subjects
A:Missing(B)toG3/4(CTCAEG)n=196,197	0	2
A:G<=2BtoG<=2(CTCAE G)n=196,197	27	14
A:G<=2 B to G3/4(CTCAE G)n=196,197	113	103
A:G3/4 B toG<=2(CTCAEG)n=196,197	4	5
A:G3/4 B toG3/4(CTCAE G)n=196,197	52	73
H inc:Missing B to G<=2 (CTCAE G),n=196,197	0	2
H inc:G<=2(B G to G<=2 (CTCAE G) n=196,197	194	194
H inc:G<=2 (B G)to G3/4 (CTCAE G)n=196,197	2	1
INR inc G<=2 (B G) to G<=2 (CTCAE G) n=3,1	3	1
Lcount dec Missing (BG) to G<=2CTCAE n=193,193	0	2
Lcount dec:Missing (B G) to G3/4 (CTCAEG)n=193,193	0	4
Lcount dec:G<=2(B) to G<=2(CTCAEG),n=193,193	21	26
Lcount dec:G<=2(B G) to G3/4(CTCAE G)n=193,193	160	152
Lcount dec:G3/4 (B G)to G<=2(CTCAEG)n=193,193	1	0
Lcount dec:G3/4(B G)to G3/4 (CTCAEG)n=193,193	11	9
Lcount inc:Missing(B G)toG <=2(CTCAEG)n=193,193	0	6
Lcount inc.G<=2(B G)toG<=2 (CTCAEG),n=193,193	185	180
Lcount dec:G<=2 (B G) to G3/4(CTCAEG) n=193,193	6	4
Lcount inc:G3/4(B G) toG<=2 (CTCAEG) n=193,193	1	3
Lcount inc G3/4 (B G)to G3/4 (CTCAEG) n=193,193	1	0
Ncount dec Missing (B G) toG3/4(CTCAEG) n=194,193	0	4
Ncount dec:G<=2(B G) toG<=2(CTCAE G) n=194,193	4	2
N count dec:G<=2 (B G) to G3/4 (CTCAEG) n=194,193	85	79
N count dec:G3/4 (B G) to G<=2 (CTCAEG) n=194,193	0	2
N count dec:G3/4 (B G) to G3/4 (CTCAEG) n=194,193	105	106
Pcount dec:Missing (BG)to G3/4 (CTCAEG)n=196,197	1	2
P count dec:G<=2 (B G) to G3/4 (CTCAE G) n=196,197	98	100
P count dec:G3/4 (B G) to G3/4 (CTCAE G) n=196,197	97	95
WBC dec: Missing (B G) to G 3/4(CTCAE G) n=196,197	1	4
WBC dec:G<=2 (B G) to G<=2 (CTCAE G) n=196,197	3	2
WBC dec G<=2(B G) to G 3/4(CTCAE G) n=196,197	155	156
WBC dec:G3/4(B G) to G3/4(CTCAE G) n=196,197	37	35

No statistical analyses for this end point

Secondary: Non-intensive Study: Number of Subjects With Shift From Baseline in Hematological Laboratory Abnormalities Graded by NCI CTCAE v.4.03

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End point title

Non-intensive Study: Number of Subjects With Shift From Baseline in Hematological Laboratory Abnormalities Graded by NCI CTCAE v.4.03 ^[68]

End point description

Hematology laboratory test included: anemia, hemoglobin increased, INR increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, and white blood cell decreased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Number of subjects with shift from baseline for hematology laboratory test were assessed. Only those laboratory test parameters in which at least 1 subject had data were reported. SA set included all participants who received at least one dose of study drug. Here, "Number of Subjects Analysed" signifies participants evaluable for this outcome measure and "Number Analyzed" signifies subjects evaluable for specified rows.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	162	160
Units: Subjects
Anemia:G<=2(BG)to G<=2(CTCAE G)n=160,160	29	41
A:G<=2 (B G) to G3/4 (CTCAE G) n=160,160	97	87
A:G3/4(BG)toG<=2(CTCAE G)n=160,160	5	1
Anemia:G3/4 (BG) to G3/4 (CTCAE G)n=160,160	29	31
H inc: G<=2 (BG) to G<=2 (CTCAEG)n=160,160	160	159
H inc: G<=2 (BG) to G3/4 (CTCAE G)n=160,160	0	1
L count dec:Missing(BG) to G<=2 (CTCAE G)n=159,160	2	0
L count dec:Missing(BG) to G3/4 (CTCAE G)n=159,160	1	0
L count dec:G<=2 (BG) to G<=2 (CTCAE G)n=159,160	96	89
L count dec:G<=2 (BG) to G3/4 (CTCAE G)n=159,160	51	54
L count dec:G3/4(BG) to G<=2 (CTCAE G)n=159,160	2	4
L count dec:G3/4 (BG) to G3/4 (CTCAE G)n=159,160	7	13
L count inc:Missing(BG) to G<=2 (CTCAE G)n=159,160	3	0
L count inc:G<=2 (BG) to G<=2 (CTCAE G)n=159,160	147	157
L count inc:G<=2 (BG) to G3/4 (CTCAE G)n=159,160	7	3
L count dec:G3/4 (BG) to G3/4 (CTCAEG)n=159,160	2	0
Ncount dec:Missing(BG)to G3/4 (CTCAE G)n=159,160	4	0
N count dec:G<=2 (BG) to G<=2 (CTCAE G)n=159,160	13	22
N count dec:G<=2 (BG) to G3/4 (CTCAE G) n=159,160	48	40
N count dec: G3/4 (BG) to G<=2 (CTCAE G) n=159,160	2	1
N count dec: G3/4 (BG) to G3/4 (CTCAE G)n=160,160	92	97
P count dec:G<=2 (BG) to G<=2 (CTCAE G)n=160,160	21	28
P count dec:G<=2 (BG) to G3/4 (CTCAE G)n=160,160	55	64
P count dec:G3/4 (BG) to G<=2 (CTCAE G)n=160,160	1	0
P count dec:G3/4 (BG) to G3/4 (CTCAE G)n=160,160	83	68
WBC dec:Missing (BG) to G<=2 (CTCAE G)n=160,159	1	0
WBC dec:Missing(BG) to G3/4 (CTCAE G) n=160,159	1	0
WBC dec:G<=2 (BG) to G<=2 (CTCAE G)n=160,159	43	48
WBC dec:G<=2 (BG) to G3/4 (CTCAE G)n=160,159	70	62
WBC dec:G3/4 (BG) to G<=2 (CTCAE G)n=160,159	0	1
WBC dec:G3/4 (BG) to G3/4 (CTCAE G)n=160,159	45	48

No statistical analyses for this end point

Secondary: Intensive Study: Number of Subjects With Shift From Baseline in Chemistry Laboratory Abnormalities Graded by NCI CTCAE v.4.03

Top of page

End point title

Intensive Study: Number of Subjects With Shift From Baseline in Chemistry Laboratory Abnormalities Graded by NCI CTCAE v.4.03 ^[69]

End point description

Chemistry laboratory test included:alanine aminotransferase(ALT)increased(inc),alkaline phosphatase(ALP)inc,aspartate aminotransferase(AST)inc,blood bilirubin(bil) inc,chronic kidney disease(CKD),creatine phosphokinase(CPK)inc,creatinine inc,gamma glutamyl transferase(GGT)inc,hypercalcemia, hyperglycemia,hyperkalemia,hypermagnesemia(hypermag),hypernatremia,hypoalbuminemia(hypoalb),hypocalcemia,hypoglycemia, hypokalemia,hypomagnesemia(hypomag),hyponatremia,hypophosphatemia(hypophos).Results were summarised according to NCI-CTCAE criteria v4.03.Grade1=mild;Grade2=moderate;Grade3=severe;Grade 4=life-threatening or disabling.Number of subjects with shift from baseline for chemistry laboratory test were assessed.Only those lab test parameters in which at least 1 subject had data is reported.SA set=subjects who received at least one dose of study drug.Here,''Number of Subjects Analysed"=subjects evaluable for this end point;"Number Analysed"=subjects evaluable for specific time points.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[69] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	196	198
Units: Subjects
ALT inc:Missing (BG) to G<=2 (CTCAE G)n=193,198	1	1
ALT inc:G<=2 (BG) to G<=2 (CTCAE G)n=193,198	175	184
ALT inc:G<=2 (BG) to G3/4 (CTCAE G)n=193,198	16	13
ALT inc:G3/4 (BG) to G<=2 (CTCAE G)n=193,198	1	0
ALP inc:Missing(BG) to G<=2 (CTCAE G)n=191,198	2	3
ALP inc:G<=2 (BG) to G<=2 (CTCAE G)n=191,198	187	192
ALP inc:G<=2 (BG) to G3/4 (CTCAE G)n=191,198	2	3
AST inc:Missing (BG) to G<=2 (CTCAE G)n=193,198	5	2
AST inc:Missing (BG) to G3/4 (CTCAE G)n=193,198	0	1
AST inc: G<=2 (BG) to G<=2 (CTCAE G)n=193,198	173	186
AST inc: G<=2 (BG) to G3/4 (CTCAE G)n=193,198	15	9
Blood Bil inc:Missing (BG)toG<=2(CTCAE G)n=192,198	0	3
Blood bil inc:G<=2(BG) to G<=2 (CTCAE G)n=192,198	184	189
Blood bil inc:G<=2(BG) to G3/4 (CTCAE G)n=192,198	8	5
Blood bil inc:G3/4 (BG) to G3/4 (CTCAE G)n=192,198	0	1
CKD: Missing (BG) to G<=2(CTCAE G)n=195,198	4	5
CKD:G<=2 (BG) to G<=2 (CTCAE G)n=195,198	182	188
CKD:G<=2 (BG) to G3/4 (CTCAE G)n=195,198	8	4
CKD:G3/4 (BG) to G<=2 (CTCAE G)n=195,198	1	0
CKD: G3/4 (BG) to G3/4 (CTCAE G)n=195,198	0	1
CPK inc:Missing(BG)toG<=2 (CTCAE G)n=183,185	20	19
CPK inc:G<=2(BG)to G<=2 (CTCAE G)n=183,185	161	166
CPK inc:G<=2 (BG) to G3/4 (CTCAE G)n=183,185	2	0
Creatinine inc:G<=2(BG)toG<=2 (CTCAE G)n=195,198	188	192
Creatinine inc:G<=2 (BG)toG3/4 (CTCAEG)n=195,198	7	6
GGT inc:Missing(BG) to G<=2 (CTCAEG)n=13,20	5	7
GGT inc:Missing (BG) to G3/4 (CTCAE G)n=13,20	8	11
GGT inc:G<=2 (BG) to G3/4 (CTCAE G)n=13,20	0	2
Hypercalcemia:Missing(BG)to G<=2 (CTCAEG)n=192,197	1	5
Hypercalcemia:G<=2(BG)toG<=2 (CTCAEG)n=192,197	191	192
Hyperglycemia:Missing(BG)toG<=2 (CTCAEG)n=194,198	1	3
Hyperglycemia:G<=2(BG)to G<=2 (CTCAEG)n=194,198	174	183
Hyperglycemia:G<=2(BG)toG3/4 (CTCAEG)n=194,198	15	10
Hyperglycemia:G3/4(BG) toG<=2 (CTCAEG)n=194,198	2	1
Hyperglycemia:G3/4(BG)toG3/4 (CTCAEG)n=194,198	2	1
Hyperkalemia:G<=2 (BG) to G<=2 (CTCAEG)n=196,198	194	194
Hyperkalemia:G<=2(BG)toG3/4 (CTCAEG)n=196,198	2	3
Hyperkalemia:G3/4(BG) to G<=2 (CTCAE G)n=196,198	0	1
Hypermag:Missing(BG)to G<=2(CTCAEG)n=193,192	2	4
Hypermag:Missing(BG) to G3/4 (CTCAEG)n=193,192	0	1
Hypernatremia:G<=2 (BG) to G<=2 (CTCAEG)n=193,192	190	184
Hypernatremia:G<=2(BG) to G3/4 (CTCAEG)n=193,192	1	2
Hypernatremia:G3/4(BG) to G<=2 (CTCAEG)n=193,192	0	1
Hypo alb:Missing(BG) to G<=2(CTCAEG)n=192,198	0	3
Hypo alb:Missing(BG)to G3/4(CTCAEG)n=192,198	1	1
Hypo alb:G<=2(BG)to G<=2 (CTCAEG)n=192,198	185	185
Hypo alb:G<=2(BG)to G3/4 (CTCAE G)n=192,198	5	8
Hypo alb:G3/4(BG) toG3/4 (CTCAEG)n=192,198	1	1
Hypocalcemia:Missing(BG)toG<=2 (CTCAEG)n=192,197	1	5
Hypocalcemia:G<=2(BG) to G<=2 (CTCAEG)n=192,197	190	189
Hypocalcemia:G<=2(BG)to G3/4 (CTCAEG)n=192,197	1	3
Hypoglycemia:Missing(BG) to G<=2 (CTCAEG)n=194,198	1	3
Hypoglycemia:G<=2(BG) to G<=2 (CTCAEG)n=194,198	193	194
Hypoglycemia:G<=2(BG)to G3/4 (CTCAEG)n=194,198	0	1
Hypokalemia:G<=2(BG) to G<=2 (CTCAEG)n=196,198	155	159
Hypokalemia:G<=2(BG) to G3/4 (CTCAEG)n=196,198	41	37
Hypokalemia:G3/4(BG)to G<=2 (CTCAEG)n=196,198	0	2
Hypomag:Missing(BG)to G<=2(CTCAEG)n=193,192	2	5
Hypomag:G<=2(BG) to G<=2 (CTCAEG)n=193,192	190	187
Hypomag:G<=2(BG) toG3/4 (CTCAEG)n=193,192	1	0
Hyponatremia:G<=2(BG)to G<=2(CTCAEG)n=196,198	177	188
Hyponatremia:G<=2(BG)to G3/4 (CTCAEG)n=196,198	17	8
Hyponatremia:G3/4(BG) to G<=2 (CTCAEG)n=196,198	1	1
Hyponatremia:G3/4(BG) to G3/4 (CTCAEG)n=196,198	1	1
Hypophos:Missing(BG)to G<=2(CTCAEG)n=193,193	3	3
Hypophos:Missing (BG) to G3/4 (CTCAEG)n=193,193	1	1
Hypophos:G<=2 (BG) toG<=2 (CTCAEG)n=193,193	153	153
Hypophos:G<=2 (BG) to G3/4 (CTCAEG)n=193,193	33	33
Hypophos:G3/4 (BG) to G<=2 (CTCAEG)n=193,193	0	2
Hypophos: G3/4 (BG) to G3/4 (CTCAEG)n=193,193	3	1

No statistical analyses for this end point

Secondary: Non-intensive Study: Number of Subjects With Shift From Baseline in Chemistry Laboratory Abnormalities Graded by NCI CTCAE v.4.03

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End point title

Non-intensive Study: Number of Subjects With Shift From Baseline in Chemistry Laboratory Abnormalities Graded by NCI CTCAE v.4.03 ^[70]

End point description

Chemistry laboratory test included: alanine ALT increased, ALP increased, AST increased, blood bilirubin increased, chronic kidney disease, CPK increased, creatinine increased, GGT increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia. Results were categorically summarised according to NCI-CTCAE criteria v4.03.Grade1=mild;Grade2=moderate;Grade3=severe;Grade 4=life-threatening or disabling.Number of subjects with shift from baseline for chemistry laboratory test were assessed.Only those lab test parameters in which at least 1 subject had data is reported.SA set=subjects who received at least one dose of study drug.Here,''Number of Subjects Analysed"=subjects evaluable for this end point;"Number Analysed"=subjects evaluable for specific time points.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	160	160
Units: Subjects
ALT inc:Missing (BG) to G<=2 (CTCAE G)n=160,160	2	0
ALT inc:G<=2 (BG) to G<=2 (CTCAE G)n=160,160	152	154
ALT inc:G<=2 (BG) to G3/4 (CTCAE G)n=160,160	6	6
ALT inc:G3/4 (BG) to G<=2 (CTCAE G)n=160,160	0	0
ALP inc:Missing(BG) to G<=2 (CTCAE G)n=159,159	0	1
ALP inc:G<=2 (BG) to G<=2 (CTCAE G)n=159,159	159	157
ALP inc:G<=2 (BG) to G3/4 (CTCAE G)n=159,159	0	1
AST inc:Missing (BG) to G<=2 (CTCAE G)n=159,160	3	0
AST inc: G<=2 (BG) to G<=2 (CTCAE G)n=159,160	152	156
AST inc: G<=2 (BG) to G3/4 (CTCAE G)n=159,160	4	4
Blood Bil inc:Missing (BG)toG<=2(CTCAE G)n=160,160	157	159
CKD: Missing (BG) to G<=2(CTCAE G)n=160,160	2	1
CKD:G<=2 (BG) to G<=2 (CTCAE G)n=160,160	130	134
CKD:G<=2 (BG) to G3/4 (CTCAE G)n=160,160	28	23
CKD: G3/4 (BG) to G3/4 (CTCAE G)n=160,160	0	2
CPK inc:Missing(BG)toG<=2 (CTCAE G)n=157,157	9	8
CPK inc:G<=2 (BG) to G3/4 (CTCAE G)n=157,157	1	2
Creatinine inc:G<=2(BG)toG<=2 (CTCAE G)n=160,160	153	155
Creatinine inc:G<=2 (BG)toG3/4 (CTCAEG)n=160,160	7	5
GGT inc:Missing(BG) to G<=2 (CTCAEG)n=8,8	3	5
GGT inc:Missing (BG) to G3/4 (CTCAE G)n=8,8	4	3
GGT inc:G<=2 (BG) to G3/4 (CTCAE G)n=8,8	1	0
Hypercalcemia:Missing(BG)to G<=2 (CTCAEG)n=158,160	2	2
Hypercalcemia:G<=2(BG)toG<=2 (CTCAEG)n=158,160	156	158
Hyperglycemia:Missing(BG)toG<=2 (CTCAEG)n=160,160	2	4
Hyperglycemia:G<=2(BG)to G<=2 (CTCAEG))n=160,160	147	136
Hyperglycemia:G<=2(BG)toG3/4 (CTCAEG)n=160,160	8	14
Hyperglycemia:G3/4(BG) toG<=2 (CTCAEG)n=160,160	2	2
Hyperkalemia:Missing(BG) to G<=2 (CTCAEG)n=159,160	2	0
Hyperkalemia:G<=2 (BG) to G<=2 (CTCAEG)n=159,160	155	157
Hyperkalemia:G<=2(BG)toG3/4 (CTCAEG)n=159,160	2	3
Hyperkalemia:G3/4(BG) to G<=2 (CTCAE G)n=159,160	0	0
Hyperkalemia:G3/4(BG)to G3/4 (CTCAEG)n=159,160	0	0
Hypermag:Missing(BG)to G<=2(CTCAEG)n=159,160	2	4
Hypermag:G<=2(BG) to G<=2 (CTCAEG)n=159,160	155	154
Hypermag:G<=2(BG) to G3/4 (CTCAEG)n=159,160	2	2
Hypernatremia:G<=2 (BG) to G<=2 (CTCAEG)n=160,160	158	159
Hypernatremia:G<=2(BG) to G3/4 (CTCAEG)n=160,160	2	1
Hypo alb:Missing(BG) to G<=2(CTCAEG)n= 159,160	2	0
Hypo alb:G<=2(BG)to G<=2 (CTCAEG)n=159,160	151	157
Hypo alb:G<=2(BG)to G3/4 (CTCAE G)n=159,160	6	3
Hypocalcemia:Missing(BG)toG<=2 (CTCAEG)n=158,160	2	2
Hypocalcemia:G<=2(BG) to G<=2 (CTCAEG)n=158,160	154	155
Hypocalcemia:G<=2(BG)to G3/4 (CTCAEG)n=158,160	1	3
Hypocalcemia:G3/4 (BG) to G3/4 (CTCAEG)n=158,160	0	0
Hypoglycemia:Missing(BG) to G<=2 (CTCAEG)n=160,160	2	4
Hypoglycemia:G<=2(BG) to G<=2 (CTCAEG)n=160,160	155	156
Hypoglycemia:G<=2(BG)to G3/4 (CTCAEG)n=160,160	3	0
Hypokalemia:Missing(BG) to G<=2 (CTCAEG)n=159,160	2	0
Hypokalemia:G<=2(BG) to G<=2 (CTCAEG)n=159,160	129	139
Hypokalemia:G<=2(BG) to G3/4 (CTCAEG)n=159,160	23	15
Hypokalemia:G3/4(BG)to G<=2 (CTCAEG)n=159,160	1	2
Hypokalemia:G3/4(BG) to G3/4 (CTCAEG)n=159,160	4	4
Hypomag:Missing(BG)to G<=2(CTCAEG)n=159,160	2	4
Hypomag:G<=2(BG) to G<=2 (CTCAEG)n=159,160	151	153
Hypomag:G<=2(BG) toG3/4 (CTCAEG)n=159,160	6	2
Hypomag:G3/4(BG) to G<=2 (CTCAEG)n=159,160	0	1
Hyponatremia:G<=2(BG)to G<=2(CTCAEG)n=160,160	135	142
Hyponatremia:G<=2(BG)to G3/4 (CTCAEG)n=160,160	24	15
Hyponatremia:G3/4(BG) to G<=2 (CTCAEG)n=160,160	0	1
Hyponatremia:G3/4(BG) to G3/4 (CTCAEG)n=160,160	1	2
Hypophos:Missing(BG)to G<=2(CTCAEG)n=158,160	3	2
Hypophos:Missing (BG) to G3/4 (CTCAEG)n=158,160	1	0
Hypophos:G<=2 (BG) toG<=2 (CTCAEG)n=158,160	141	138
Hypophos:G<=2 (BG) to G3/4 (CTCAEG)n=158,160	12	17
Hypophos:G3/4 (BG) to G<=2 (CTCAEG)n=158,160	0	1
Hypophos: G3/4 (BG) to G3/4 (CTCAEG)n=158,160	1	2
Blood bil inc:G<=2(BG)toG3/4 (CTCAEG),n=160,160	3	1
CPK inc:G<=2(BG)toG<=2(CTCAE G),n=157,157	147	147

No statistical analyses for this end point

Secondary: Intensive Study: Number of Subjects With Shift From Baseline in Coagulation Laboratory Abnormalities Graded by NCI CTCAE v.4.03

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End point title

Intensive Study: Number of Subjects With Shift From Baseline in Coagulation Laboratory Abnormalities Graded by NCI CTCAE v.4.03 ^[71]

End point description

Coagulation laboratory test included: activated partial thromboplastin time (APTT) prolonged, and INR increased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 0= no abnormality; Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Number of participants with shift from baseline for coagulation were assessed. Only those laboratory test parameters in which at least 1 subject had data were reported. SA set included all participants who received at least one dose of study drug. Here, "Overall Number of Subjects Analysed" signifies subjects evaluable for this end point and "Number Analysed" signifies subjects evaluable for specific time points.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[71] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	6	11
Units: Subjects
APTT prolonged: Missing (BG) to G0 (CTCAE G)n=4,9	1	0
APTT prolonged: Missing (BG) to G1 (CTCAEG)n=4,9	0	1
APTT prolonged:G0 (BG) to Grade 0 (CTCAEG)n=4,9	0	4
APTT prolonged:G0(BG) to G1 (CTCAEG)n=4,9	1	2
APTT prolonged:G0 (BG) to G2 (CTCAEG)n=4,9	0	1
APTT prolonged: G0 (BG) to G3 (CTCAEG)n=4,9	1	0
APTT prolonged:G1(BG) to G1 (CTCAEG)n=4,9	1	1
INR increased:Missing(BG) toG0 (CTCAEG)n=6,11	1	1
INR increased:Missing(BG) toG1(CTCAEG)n=6,11	0	1
INR increased:Missing(BG) to G2 (CTCAEG)n=6,11	1	0
INR increased: G0 (BG) to G0 (CTCAEG)n=6,11	0	2
INR increased: G0 (BG) to G1 (CTCAEG)n=6,11	1	0
INR increased: G0 (BG) to G2 (CTCAEG)n=6,11	1	1
INR increased: G0 (BG) to G3 (CTCAEG)n=6,11	0	1
INR increased: G1 (BG) to G0 (CTCAEG)n=6,11	0	1
INR increased: G1 (BG) to G1 (CTCAEG)n=6,11	0	3
INR increased: G1 (BG) to G2 (CTCAEG)n=6,11	1	1
INR increased: G1 (BG) to G3 (CTCAEG)n=6,11	1	0

No statistical analyses for this end point

Secondary: Non-intensive Study: Number of Subjects With Shift From Baseline in Coagulation Laboratory Abnormalities Graded by NCI CTCAE v.4.03

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End point title

Non-intensive Study: Number of Subjects With Shift From Baseline in Coagulation Laboratory Abnormalities Graded by NCI CTCAE v.4.03 ^[72]

End point description

Coagulation laboratory test included: APTT prolonged, and INR increased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 0= no abnormality; Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Number of participants with shift from baseline for coagulation were assessed. Only those laboratory test parameters in which at least 1 subject had data were reported. SA set included all participants who received at least one dose of study drug. Here, "Overall Number of Subjects Analysed" signifies subjects evaluable for this end point and "Number Analysed" signifies subjects evaluable for specific time points.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	17	13
Units: Subjects
APTT prolonged:Missing(BG) toG0 (CTCAEG)n=17,12	1	0
APTT prolonged:G0 (BG) to Grade 0 (CTCAEG)n=17,12	8	5
APTT prolonged:G0(BG) to G1 (CTCAEG)n=17,12	5	7
APTT prolonged: G1 (BG) to G0 (CTCAEG)n=17,12	1	0
APTT prolonged:G1(BG) to G1 (CTCAEG)n=17,12	1	0
APTT prolonged: G2 (BG) to G1 (CTCAEG)n=17,12	1	0
INR increased:Missing(BG) toG0 (CTCAEG)n=17,13	1	0
INR increased: G0 (BG) to G0 (CTCAEG)n=17,13	4	5
INR increased: G0 (BG) to G1 (CTCAEG)n=17,13	6	4
INR increased: G0 (BG) to G2 (CTCAEG)n=17,13	1	2
INR increased: G0 (BG) to G3 (CTCAEG)n=17,13	1	0
INR increased: G1 (BG) to G1 (CTCAEG)n=17,13	1	1
INR increased: G1 (BG) to G2 (CTCAEG)n=17,13	2	0
INR increased: G3 (BG) to G1 (CTCAEG)n=17,13	1	1

No statistical analyses for this end point

Secondary: Intensive Study: Plasma Trough Concentration (Ctrough) of Glasdegib

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End point title

Intensive Study: Plasma Trough Concentration (Ctrough) of Glasdegib ^[73]

End point description

Ctrough of Glasdegib was measured in nanogram per milliliter (ng/mL). Analysis population included all subjects who were treated and who had at least 1 value of analyte concentration of Glasdegib available. Here, "Overall Number of Subjects Analysed" signifies subjects evaluable for this end point and "Number Analysed" signifies subjects evaluable for specific time points.

End point type

Secondary

End point timeframe

Induction, Day 10 +/-1: pre-dose, 1, 4 hour; Consolidation phase, Day 1: pre-dose, 1, 4 hour

Notes
[73] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin
Number of subjects analysed	123
Units: ng/mL
geometric mean (geometric coefficient of variation)
Induction Day 10, n=81	413.54 ( 125 )
Consolidation 1, Day 1, n=33	245.48 ( 80 )
Consolidation 2, Day 1, n=41	259.79 ( 122 )

No statistical analyses for this end point

Secondary: Non-intensive Study: Ctrough of Glasdegib

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End point title

Non-intensive Study: Ctrough of Glasdegib ^[74]

End point description

Ctrough of Glasdegib was measured in ng/mL. Analysis population included all subjects who were treated and who had at least 1 value of analyte concentration of Glasdegib available. Here, "Overall Number of Subjects Analysed" signifies subjects evaluable for this end point and "Number Analysed" signifies subjects evaluable for specific time points. SA set included all participants who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Pre-dose: Cycle 1 Day 15 and Cycle 2 Day 1

Notes
[74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine
Number of subjects analysed	53
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 15, n=34	565.44 ( 126 )
Cycle 2 Day 1, n=37	472.42 ( 122 )

No statistical analyses for this end point

Secondary: Intensive Study: Number of Subjects With Shift From Baseline in Corrected QT (QTc) Interval

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End point title

Intensive Study: Number of Subjects With Shift From Baseline in Corrected QT (QTc) Interval ^[75]

End point description

Triplicate 12-lead Electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia’s formula (QTcF = QT divided by cube root of RR) and by Bazette’s formula (QTcB = QT divided by square root of RR). Participants with maximum increase from baseline of <=450 to >500 msec (post-baseline[PB]) were summarized. Number of participants with shift from baseline for QTc were assessed. Only those QTc parameters in which at least 1 subject had data were reported. Here, "Overall Number of Subjects Analysed" signifies subjects evaluable for this end point and "Number Analysed" signifies subjects evaluable for specific time points.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 2 years

Notes
[75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Intensive Study: Placebo + Cytarabine + Daunorubicin
Number of subjects analysed	188	189
Units: Subjects
QTcB:<=450ms(B) to <=450 msec(PB),n=188,188	51	71
QTcB:<=450ms(B)to >450-<=480 msec(PB),n=188,188	64	63
QTcB:<=450ms(B)to >480-<=500 msec(PB),n=188,188	18	11
QTcB:<=450ms(B)to >500msec (PB),n=188,188	11	6
QTcB:>450-<=480ms(B)to<=450ms(PB),n=188,188	2	3
QTcB:>450-<=480ms(B)to >450-<=480ms(PB),n=188,188	20	17
QTcB:>450-<=480ms(B)to >480-<=500ms(PB),n=188,188	16	10
QTcB:>450-<=480ms(B)to >500ms(PB),n=188,188	1	5
QTcB:>480-<=500ms(B)to >450-<=480ms(PB),n=188,188	1	0
QTcB:>480-<=500ms(B)to >480-<=500ms(PB), n=188,188	2	1
QTcB:>480-<=500ms(B)to >500 ms(PB),n=188,188	1	0
QTcB:>500ms(B)to >500ms(PB),n=188,188	1	1
QTcF:<=450ms(B)to <=450ms(PB), n=187,189	116	132
QTcF:<=450ms(B)to >450-<=480ms(PB),n=187,189	50	39
QTcF:<=450ms(B)to >480-<=500ms(PB),n=187,189	8	10
QTcF:<=450ms(B)to >500ms(PB),n=187,189	5	0
QTcF:>450-<=480ms(B)to <=450 ms(PB),n=187,189	2	1
QTcF:>450-<=480ms(B)to >450-<=480ms(PB),n=187,189	5	5
QTcF:>450-<=480ms(B)to >500 ms(PB),n=187,189	1	1
QTcF:>480-<=500ms(B)to >480-<=500ms(PB),n=187,189	0	1

No statistical analyses for this end point

Secondary: Non-intensive Study: Number of Subjects With Shift From Baseline in QTc Interval

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End point title

Non-intensive Study: Number of Subjects With Shift From Baseline in QTc Interval ^[76]

End point description

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia’s formula (QTcF = QT divided by cube root of RR) and by Bazette’s formula (QTcB = QT divided by square root of RR). Subjects with maximum increase from baseline of <=450 to >500 msec (post-baseline) were summarized. Number of subjects with shift from baseline for QTc were assessed. Only those QTc parameters in which at least 1 subjects had data were reported. SA set included all participants who received at least one dose of study drug. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure and "Number Analyzed" signifies participants evaluable for specific time points.

End point type

Secondary

End point timeframe

Day 1 up to maximum of 3 years

Notes
[76] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified

End point values	Non-intensive Study: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Number of subjects analysed	158	155
Units: Subjects
QTcB:<=450ms(B) to <=450 msec(PB),n=158,155	48	58
QTcB:<=450ms(B)to >450-<=480 msec(PB), n=158,155	53	43
QTcB:<=450ms(B)to >480-<=500 msec(PB),n=158,155	6	11
QTcB:<=450ms(B)to>500msec (PB),n=158,155	7	3
QTcB:>450-<=480ms(B)to<=450 ms(PB),n=158,155	0	1
QTcB:>450-<=480ms(B)to >450-<=480ms(PB),n=158,155	20	22
QTcB:>450-<=480ms(B)to>480-<=500ms(PB),n=158,155	13	8
QTcB:>450-<=480ms(B)to>500 ms(PB),n=158,155	5	3
QTcB:>480-<=500ms(B)to>450-<=480ms(PB),n=158,155	1	2
QTcB:>480-<=500ms(B)to>480-<=500ms(PB),n=158,155	3	1
QTcB:>480-<=500ms(B)to>500 ms(PB),n=158,155	2	3
QTcF:<=450ms(B)to <=450ms(PB),n=155,155	100	104
QTcF:<=450ms(B)to >450-<=480ms(PB),n=155,155	39	36
QTcF:<=450ms(B)to >480-<=500ms(PB),n=155,155	7	0
QTcF:<=450ms(B)to >500ms(PB),n=155,155	1	1
QTcF:>450ms(B)to <=480 ms(PB),n=155,155	0	1
QTcF:>480ms(B)to <500ms(post baseline), n=155,155	5	8
QTcF:>480ms(B)to <=500ms(PB),n=155,155	1	4
QTcF:>450ms(B)to >=480ms(PB),n=155,155	1	1
QTcF:>450ms(B)to<500ms(PB),n=155,155	1	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Intensive study: Day 1 up to maximum of 2 years; non-intensive study: Day 1 up to maximum of 3 years; Open-label extension (OLE) study: Up to approximately 565 days

Adverse event reporting additional description

Same event may appear as both an AE and SAE.However,what is presented are distinct events.Events may be serious in one subject and non-serious in other or both serious&non-serious in a subject.Safety analysis set included all subjects who received at least one dose of study drug.MedDRA23.1 was used for INT and NINT and 25.1 for OLE cohort.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Non-intensive Study: Glasdegib + Azacitidine

Reporting group description

Subjects received chemotherapy with azacitidine 75 mg/m^2 SC injection or IV infusion from Day 1 up to Day 7 of each cycle (28 day) and continued for at least 6 cycles or until unacceptable toxicity, subject refusal or death, whichever occurred first. Subjects also received glasdegib 100 mg orally PO QD from Day 1 of chemotherapy until clinical benefit or disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first. Eligible subjects underwent HSCT per local standard of care and received glasdegib up to 2 years following randomization unless 2 consecutive negative MRD assessments. Subjects were followed up for first 2 years from last dose of drug and had long term follow-up for survival for up to 5 years from randomization of last subject in study, or until death, or consent withdrawal.

Reporting group title

Intensive Study: Placebo + Cytarabine + Daunorubicin

Reporting group description

Subjects received 28 days induction therapy: Cytarabine 100 mg/m^2 IV daily for 7 days + daunorubicin 60 mg/m^2 daily IV for 3 days. Depending on bone marrow blast or investigator judgement subjects had second induction to receive either same therapy or cytarabine 100 mg/m^2 IV daily for 5 days + daunorubicin 60 mg/m^2 IV daily for 2 days. Subjects with <5% bone marrow blasts entered consolation phase: treated with either or both of: 1) Cytarabine 1 to 3 gm/m^2 IV for adults >= 60 to <60 years twice daily on Days 1, 3, 5 for 4 cycle (1 cycle=28 days) or cytarabine per local prescribing information. 2) Received HSCT per local standard of care. Subjects received Glasdegib matched placebo tablet PO QD from Day 1 up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive CR MRD-negative, whichever came first. FU was up to 2 years from last dose and long term survival FU from last subject randomized up to 5 years or until death or consent withdrawal.

Reporting group title

Intensive Study: Glasdegib + Cytarabine + Daunorubicin

Reporting group description

Subjects received 28 days induction therapy: Cytarabine 100 mg/m^2 IV daily for 7 days + daunorubicin 60 mg/m^2 daily IV for 3 days. Depending on bone marrow blast or investigator judgement subjects had second induction to receive either same therapy or cytarabine 100 mg/m^2 IV daily for 5 days + daunorubicin 60 mg/m^2 IV daily for 2 days. Subjects with <5% bone marrow blasts entered consolation phase: treated with either or both of: 1) Cytarabine 1 to 3 gm/m^2 IV for adults >= 60 to <60 years twice daily on Days 1, 3, 5 for 4 cycle (1 cycle=28 days) or cytarabine per local prescribing information. 2) Received HSCT per local standard of care. Subjects received Glasdegib 100 mg tablet PO QD from Day 1 up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive CR MRD-negative, whichever came first. FU was up to 2 years from last dose and long term survival FU from last subject randomized up to 5 years or until death or consent withdrawal.

Reporting group title

Open Label Extension: Placebo + Azacitidine

Reporting group description

Participants received placebo matched to Glasdegib in combination with azacitidine 75mg/m^2/day SC or IV for 7 days every 28 days. Treatment continued until objective disease progression or relapse, death, unacceptable toxicity, or participant refusal, whichever occurred first. Participants were followed up for 28 days after end of study treatment.

Reporting group title

Open Label Extension: Glasdegib + Azacitidine

Reporting group description

Participants received glasdegib 100 milligrams (mg) tablet per oral (PO) once a day (QD) in combination with azacitidine 75 mg per meter squared (m^2)/day as subcutaneous (SC) injection or intravenous (IV) infusion for 7 days every 28 days. Treatment continued until objective disease progression or relapse, death, unacceptable toxicity, or participant refusal, whichever occurred first. Participants were followed up for 28 days after end of study treatment.

Reporting group title

Non-intensive Study: Placebo + Azacitidine

Reporting group description

Serious adverse events	Non-intensive Study: Glasdegib + Azacitidine	Intensive Study: Placebo + Cytarabine + Daunorubicin	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Open Label Extension: Placebo + Azacitidine	Open Label Extension: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Total subjects affected by serious adverse events
subjects affected / exposed	110 / 162 (67.90%)	91 / 201 (45.27%)	85 / 198 (42.93%)	1 / 5 (20.00%)	2 / 9 (22.22%)	118 / 160 (73.75%)
number of deaths (all causes)	96	60	67	0	0	88
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Differentiation syndrome
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal neoplasm
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Neoplasm prostate
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasm progression
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
Vascular disorders
Deep vein thrombosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 1	1 / 1	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Orthostatic hypotension
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aneurysm ruptured
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Axillary vein thrombosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis superficial
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypovolaemic shock
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Circulatory collapse
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	9 / 162 (5.56%)	6 / 201 (2.99%)	4 / 198 (2.02%)	0 / 5 (0.00%)	0 / 9 (0.00%)	11 / 160 (6.88%)
occurrences causally related to treatment / all	3 / 10	3 / 6	1 / 4	0 / 0	0 / 0	3 / 14
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	14 / 162 (8.64%)	4 / 201 (1.99%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	22 / 160 (13.75%)
occurrences causally related to treatment / all	0 / 15	0 / 4	0 / 2	0 / 0	0 / 0	0 / 22
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chills
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	3 / 160 (1.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Death
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	4 / 162 (2.47%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
Asthenia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue inflammation
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Graft versus host disease in skin
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Graft versus host disease in gastrointestinal tract
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Graft versus host disease
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cytokine release syndrome
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	3 / 162 (1.85%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	4 / 201 (1.99%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	2 / 201 (1.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infiltration
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	3 / 201 (1.49%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory distress syndrome
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Pulmonary alveolar haemorrhage
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary haemorrhage
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Pulmonary oedema
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	3 / 160 (1.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal pain
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adjustment disorder with depressed mood
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hallucination
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood creatinine increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrocardiogram QT prolonged
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	5 / 162 (3.09%)	8 / 201 (3.98%)	13 / 198 (6.57%)	0 / 5 (0.00%)	0 / 9 (0.00%)	3 / 160 (1.88%)
occurrences causally related to treatment / all	3 / 5	8 / 10	9 / 15	0 / 0	0 / 0	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood alkaline phosphatase increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	2 / 201 (1.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	2 / 201 (1.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	3 / 201 (1.49%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 4	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood lactate dehydrogenase increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SARS-CoV-2 test positive
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Electroencephalogram abnormal
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Creatinine renal clearance decreased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
C-reactive protein increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal fracture
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenic rupture
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural complication
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haemorrhage
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tooth fracture
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transfusion reaction
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure acute
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac arrest
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
Atrial fibrillation
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	3 / 198 (1.52%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 1	4 / 4	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocarditis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intracardiac mass
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiomyopathy
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular dysfunction
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Cardiorenal syndrome
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiopulmonary failure
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Epilepsy
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	2 / 201 (1.00%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 1	1 / 2	2 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
Syncope
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Seizure
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Central nervous system lesion
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial aneurysm
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic encephalopathy
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Partial seizures
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	24 / 162 (14.81%)	17 / 201 (8.46%)	18 / 198 (9.09%)	1 / 5 (20.00%)	1 / 9 (11.11%)	18 / 160 (11.25%)
occurrences causally related to treatment / all	14 / 33	22 / 23	20 / 26	0 / 1	0 / 1	6 / 27
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Anaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	5 / 162 (3.09%)	1 / 201 (0.50%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	5 / 160 (3.13%)
occurrences causally related to treatment / all	1 / 6	1 / 1	2 / 2	0 / 0	0 / 0	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	3 / 201 (1.49%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 4	28 / 28	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenic necrosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Vision blurred
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	4 / 162 (2.47%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	1 / 5	1 / 1	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	3 / 162 (1.85%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 1	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Gastrointestinal haemorrhage
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	0 / 201 (0.00%)	3 / 198 (1.52%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 3	0 / 0	1 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Haematemesis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal haemorrhage
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic colitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal fistula
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intussusception
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Proctalgia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal haemorrhage
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal distension
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal fissure
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intra-abdominal haematoma
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mechanical ileus
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal perforation
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glossitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids thrombosed
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stone
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis acute
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erythema
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis exfoliative generalised
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug eruption
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	3 / 201 (1.49%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Myalgia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Synovitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue necrosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Clostridium difficile colitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterobacter bacteraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopulmonary aspergillosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	3 / 162 (1.85%)	2 / 201 (1.00%)	4 / 198 (2.02%)	0 / 5 (0.00%)	0 / 9 (0.00%)	4 / 160 (2.50%)
occurrences causally related to treatment / all	1 / 4	0 / 2	5 / 6	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	7 / 160 (4.38%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 1	0 / 0	0 / 0	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis infective
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia bacteraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	3 / 198 (1.52%)	0 / 5 (0.00%)	0 / 9 (0.00%)	5 / 160 (3.13%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 3	0 / 0	0 / 0	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	3 / 162 (1.85%)	2 / 201 (1.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	5 / 160 (3.13%)
occurrences causally related to treatment / all	0 / 6	2 / 2	1 / 1	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
Pneumonia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	26 / 162 (16.05%)	11 / 201 (5.47%)	15 / 198 (7.58%)	0 / 5 (0.00%)	0 / 9 (0.00%)	35 / 160 (21.88%)
occurrences causally related to treatment / all	9 / 38	3 / 13	9 / 22	0 / 0	0 / 0	9 / 49
deaths causally related to treatment / all	0 / 9	0 / 1	0 / 5	0 / 0	0 / 0	1 / 9
Perirectal abscess
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	4 / 162 (2.47%)	4 / 201 (1.99%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	5 / 160 (3.13%)
occurrences causally related to treatment / all	3 / 7	4 / 4	1 / 2	0 / 0	0 / 0	7 / 9
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0	0 / 0	1 / 3
Sepsis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	13 / 162 (8.02%)	13 / 201 (6.47%)	15 / 198 (7.58%)	0 / 5 (0.00%)	0 / 9 (0.00%)	9 / 160 (5.63%)
occurrences causally related to treatment / all	5 / 18	10 / 14	12 / 26	0 / 0	0 / 0	3 / 13
deaths causally related to treatment / all	1 / 6	0 / 2	0 / 5	0 / 0	0 / 0	1 / 4
Pseudomembranous colitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia fungal
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	2 / 201 (1.00%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 2	3 / 3	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	3 / 160 (1.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	9 / 162 (5.56%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	4 / 160 (2.50%)
occurrences causally related to treatment / all	3 / 13	0 / 1	0 / 0	0 / 0	0 / 0	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anorectal infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial sepsis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain abscess
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium colitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Candida pneumonia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridial sepsis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium bacteraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related bacteraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated varicella zoster virus infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterococcal bacteraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	2 / 198 (1.01%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes ophthalmic
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Groin abscess
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fungal sepsis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Fungal infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal sepsis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomonal sepsis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomonal bacteraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	3 / 198 (1.52%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urethritis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	1 / 198 (0.51%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Catheter site infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Candida sepsis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes dermatitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infected skin ulcer
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection bacterial
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver abscess
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella bacteraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media acute
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Periodontitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal abscess
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 160 (1.25%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia staphylococcal
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdiaphragmatic abscess
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suspected COVID-19
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic mycosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	3 / 162 (1.85%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	3 / 3	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	1 / 201 (0.50%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperuricaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	3 / 160 (1.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Hyponatraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	2 / 162 (1.23%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypophosphataemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	1 / 162 (0.62%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Non-intensive Study: Glasdegib + Azacitidine	Intensive Study: Placebo + Cytarabine + Daunorubicin	Intensive Study: Glasdegib + Cytarabine + Daunorubicin	Open Label Extension: Placebo + Azacitidine	Open Label Extension: Glasdegib + Azacitidine	Non-intensive Study: Placebo + Azacitidine
Total subjects affected by non serious adverse events
subjects affected / exposed	153 / 162 (94.44%)	195 / 201 (97.01%)	194 / 198 (97.98%)	3 / 5 (60.00%)	6 / 9 (66.67%)	149 / 160 (93.13%)
Vascular disorders
Hypotension
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	17 / 201 (8.46%)	18 / 198 (9.09%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	23	19	0	0	0
Hypertension
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	25 / 201 (12.44%)	10 / 198 (5.05%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	39	15	0	0	0
General disorders and administration site conditions
Fatigue
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	13 / 162 (8.02%)	32 / 201 (15.92%)	31 / 198 (15.66%)	0 / 5 (0.00%)	0 / 9 (0.00%)	23 / 160 (14.38%)
occurrences all number	17	47	53	0	0	32
Oedema peripheral
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	11 / 162 (6.79%)	32 / 201 (15.92%)	25 / 198 (12.63%)	1 / 5 (20.00%)	0 / 9 (0.00%)	18 / 160 (11.25%)
occurrences all number	13	43	36	1	0	25
Pyrexia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	41 / 162 (25.31%)	84 / 201 (41.79%)	84 / 198 (42.42%)	0 / 5 (0.00%)	0 / 9 (0.00%)	39 / 160 (24.38%)
occurrences all number	68	169	194	0	0	65
Asthenia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	15 / 162 (9.26%)	11 / 201 (5.47%)	15 / 198 (7.58%)	0 / 5 (0.00%)	0 / 9 (0.00%)	18 / 160 (11.25%)
occurrences all number	24	14	21	0	0	40
Chills
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	11 / 201 (5.47%)	20 / 198 (10.10%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	17	25	0	0	0
Mucosal inflammation
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	7 / 201 (3.48%)	12 / 198 (6.06%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	9	16	0	0	0
Non-cardiac chest pain
Additional description: General disorders and administration site conditions
subjects affected / exposed	0 / 162 (0.00%)	8 / 201 (3.98%)	13 / 198 (6.57%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	10	16	0	0	0
Oedema
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	19 / 201 (9.45%)	9 / 198 (4.55%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	22	17	0	0	0
Injection site reaction
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	11 / 162 (6.79%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	7 / 160 (4.38%)
occurrences all number	42	0	0	0	0	19
Respiratory, thoracic and mediastinal disorders
Cough
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	10 / 162 (6.17%)	23 / 201 (11.44%)	23 / 198 (11.62%)	0 / 5 (0.00%)	0 / 9 (0.00%)	20 / 160 (12.50%)
occurrences all number	10	25	28	0	0	26
Dyspnoea
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	11 / 162 (6.79%)	23 / 201 (11.44%)	15 / 198 (7.58%)	0 / 5 (0.00%)	0 / 9 (0.00%)	18 / 160 (11.25%)
occurrences all number	11	25	18	0	0	25
Epistaxis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	8 / 162 (4.94%)	20 / 201 (9.95%)	19 / 198 (9.60%)	0 / 5 (0.00%)	0 / 9 (0.00%)	10 / 160 (6.25%)
occurrences all number	16	25	21	0	0	14
Oropharyngeal pain
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	19 / 201 (9.45%)	19 / 198 (9.60%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	21	23	0	0	0
Psychiatric disorders
Insomnia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	12 / 162 (7.41%)	30 / 201 (14.93%)	27 / 198 (13.64%)	0 / 5 (0.00%)	0 / 9 (0.00%)	8 / 160 (5.00%)
occurrences all number	15	37	29	0	0	13
Investigations
Alanine aminotransferase increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	13 / 162 (8.02%)	53 / 201 (26.37%)	39 / 198 (19.70%)	0 / 5 (0.00%)	0 / 9 (0.00%)	11 / 160 (6.88%)
occurrences all number	27	138	104	0	0	20
Aspartate aminotransferase increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	10 / 162 (6.17%)	41 / 201 (20.40%)	30 / 198 (15.15%)	0 / 5 (0.00%)	0 / 9 (0.00%)	9 / 160 (5.63%)
occurrences all number	17	83	51	0	0	20
Blood creatinine increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	20 / 162 (12.35%)	13 / 201 (6.47%)	18 / 198 (9.09%)	0 / 5 (0.00%)	0 / 9 (0.00%)	13 / 160 (8.13%)
occurrences all number	34	20	24	0	0	15
Electrocardiogram QT prolonged
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	20 / 162 (12.35%)	20 / 201 (9.95%)	21 / 198 (10.61%)	0 / 5 (0.00%)	0 / 9 (0.00%)	19 / 160 (11.88%)
occurrences all number	28	35	30	0	0	33
Neutrophil count decreased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	22 / 162 (13.58%)	49 / 201 (24.38%)	56 / 198 (28.28%)	0 / 5 (0.00%)	0 / 9 (0.00%)	22 / 160 (13.75%)
occurrences all number	129	317	308	0	0	153
Platelet count decreased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	30 / 162 (18.52%)	73 / 201 (36.32%)	77 / 198 (38.89%)	1 / 5 (20.00%)	0 / 9 (0.00%)	26 / 160 (16.25%)
occurrences all number	155	504	627	1	0	162
Weight decreased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	34 / 162 (20.99%)	22 / 201 (10.95%)	21 / 198 (10.61%)	0 / 5 (0.00%)	0 / 9 (0.00%)	19 / 160 (11.88%)
occurrences all number	63	32	37	0	0	36
White blood cell count decreased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	17 / 162 (10.49%)	53 / 201 (26.37%)	63 / 198 (31.82%)	0 / 5 (0.00%)	0 / 9 (0.00%)	18 / 160 (11.25%)
occurrences all number	114	495	454	0	0	143
Gamma-glutamyltransferase increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	10 / 162 (6.17%)	22 / 201 (10.95%)	12 / 198 (6.06%)	0 / 5 (0.00%)	0 / 9 (0.00%)	8 / 160 (5.00%)
occurrences all number	19	75	36	0	0	13
Blood bilirubin increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	13 / 201 (6.47%)	25 / 198 (12.63%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	34	62	0	0	0
Lymphocyte count decreased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	21 / 201 (10.45%)	19 / 198 (9.60%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	111	133	0	0	0
Blood alkaline phosphatase increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	13 / 201 (6.47%)	14 / 198 (7.07%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	21	26	0	0	0
C-reactive protein increased
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	7 / 162 (4.32%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	9 / 160 (5.63%)
occurrences all number	13	0	0	0	2	20
Injury, poisoning and procedural complications
Fall
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	10 / 162 (6.17%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	10 / 160 (6.25%)
occurrences all number	19	0	0	0	1	11
Cardiac disorders
Sinus tachycardia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	7 / 201 (3.48%)	11 / 198 (5.56%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	7	13	0	0	0
Nervous system disorders
Headache
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	4 / 162 (2.47%)	47 / 201 (23.38%)	39 / 198 (19.70%)	0 / 5 (0.00%)	0 / 9 (0.00%)	9 / 160 (5.63%)
occurrences all number	4	62	56	0	0	20
Dizziness
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	9 / 162 (5.56%)	18 / 201 (8.96%)	23 / 198 (11.62%)	0 / 5 (0.00%)	0 / 9 (0.00%)	14 / 160 (8.75%)
occurrences all number	9	26	32	0	0	24
Dysgeusia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	37 / 162 (22.84%)	20 / 201 (9.95%)	39 / 198 (19.70%)	0 / 5 (0.00%)	0 / 9 (0.00%)	8 / 160 (5.00%)
occurrences all number	41	21	48	0	0	8
Paraesthesia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	11 / 198 (5.56%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	0	11	0	0	0
Carotid arteriosclerosis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 160 (0.00%)
occurrences all number	0	0	0	0	1	0
Blood and lymphatic system disorders
Anaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	73 / 162 (45.06%)	97 / 201 (48.26%)	101 / 198 (51.01%)	0 / 5 (0.00%)	1 / 9 (11.11%)	70 / 160 (43.75%)
occurrences all number	217	530	553	0	2	335
Febrile neutropenia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	22 / 162 (13.58%)	96 / 201 (47.76%)	97 / 198 (48.99%)	0 / 5 (0.00%)	0 / 9 (0.00%)	20 / 160 (12.50%)
occurrences all number	32	152	134	0	0	37
Neutropenia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	35 / 162 (21.60%)	43 / 201 (21.39%)	41 / 198 (20.71%)	2 / 5 (40.00%)	4 / 9 (44.44%)	30 / 160 (18.75%)
occurrences all number	130	180	96	3	14	120
Thrombocytopenia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	37 / 162 (22.84%)	52 / 201 (25.87%)	52 / 198 (26.26%)	0 / 5 (0.00%)	1 / 9 (11.11%)	32 / 160 (20.00%)
occurrences all number	152	324	271	0	2	123
Leukopenia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	11 / 162 (6.79%)	13 / 201 (6.47%)	10 / 198 (5.05%)	0 / 5 (0.00%)	0 / 9 (0.00%)	4 / 160 (2.50%)
occurrences all number	52	65	34	0	0	10
Eye disorders
Retinal detachment
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 160 (0.00%)
occurrences all number	0	0	0	0	2	0
Gastrointestinal disorders
Abdominal pain
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	12 / 162 (7.41%)	29 / 201 (14.43%)	31 / 198 (15.66%)	0 / 5 (0.00%)	0 / 9 (0.00%)	10 / 160 (6.25%)
occurrences all number	13	38	37	0	0	12
Constipation
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	58 / 162 (35.80%)	61 / 201 (30.35%)	71 / 198 (35.86%)	0 / 5 (0.00%)	0 / 9 (0.00%)	50 / 160 (31.25%)
occurrences all number	90	87	96	0	0	69
Diarrhoea
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	36 / 162 (22.22%)	88 / 201 (43.78%)	96 / 198 (48.48%)	0 / 5 (0.00%)	1 / 9 (11.11%)	31 / 160 (19.38%)
occurrences all number	49	133	141	0	4	46
Haemorrhoids
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	8 / 162 (4.94%)	19 / 201 (9.45%)	13 / 198 (6.57%)	0 / 5 (0.00%)	0 / 9 (0.00%)	10 / 160 (6.25%)
occurrences all number	11	21	13	0	0	10
Nausea
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	55 / 162 (33.95%)	106 / 201 (52.74%)	110 / 198 (55.56%)	0 / 5 (0.00%)	0 / 9 (0.00%)	44 / 160 (27.50%)
occurrences all number	96	181	169	0	0	70
Vomiting
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	35 / 162 (21.60%)	40 / 201 (19.90%)	57 / 198 (28.79%)	0 / 5 (0.00%)	1 / 9 (11.11%)	32 / 160 (20.00%)
occurrences all number	47	57	77	0	1	44
Proctalgia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	6 / 201 (2.99%)	14 / 198 (7.07%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	7	15	0	0	0
Abdominal pain upper
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	9 / 201 (4.48%)	12 / 198 (6.06%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	12	12	0	0	0
Dyspepsia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	5 / 201 (2.49%)	12 / 198 (6.06%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	5	13	0	0	0
Stomatitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	41 / 201 (20.40%)	29 / 198 (14.65%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	55	45	0	0	0
Colitis
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 160 (0.00%)
occurrences all number	0	0	0	0	1	0
Colitis ulcerative
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 160 (0.00%)
occurrences all number	0	0	0	0	1	0
Inguinal hernia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 160 (0.00%)
occurrences all number	0	0	0	0	1	0
Hepatobiliary disorders
Hyperbilirubinaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	11 / 162 (6.79%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	18	0	0	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	20 / 162 (12.35%)	26 / 201 (12.94%)	22 / 198 (11.11%)	0 / 5 (0.00%)	1 / 9 (11.11%)	3 / 160 (1.88%)
occurrences all number	22	29	26	0	1	3
Rash
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	10 / 162 (6.17%)	51 / 201 (25.37%)	46 / 198 (23.23%)	0 / 5 (0.00%)	0 / 9 (0.00%)	13 / 160 (8.13%)
occurrences all number	12	80	70	0	0	16
Pruritus
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	8 / 162 (4.94%)	11 / 201 (5.47%)	12 / 198 (6.06%)	0 / 5 (0.00%)	0 / 9 (0.00%)	9 / 160 (5.63%)
occurrences all number	8	19	12	0	0	9
Dry skin
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	10 / 201 (4.98%)	13 / 198 (6.57%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	12	13	0	0	0
Petechiae
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	11 / 201 (5.47%)	8 / 198 (4.04%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	11	10	0	0	0
Rash maculo-papular
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	21 / 201 (10.45%)	21 / 198 (10.61%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	30	26	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	11 / 162 (6.79%)	14 / 201 (6.97%)	17 / 198 (8.59%)	0 / 5 (0.00%)	1 / 9 (11.11%)	11 / 160 (6.88%)
occurrences all number	13	16	23	0	1	20
Back pain
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	7 / 162 (4.32%)	17 / 201 (8.46%)	22 / 198 (11.11%)	1 / 5 (20.00%)	0 / 9 (0.00%)	12 / 160 (7.50%)
occurrences all number	8	18	24	1	0	15
Muscle spasms
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	28 / 162 (17.28%)	3 / 201 (1.49%)	20 / 198 (10.10%)	0 / 5 (0.00%)	0 / 9 (0.00%)	4 / 160 (2.50%)
occurrences all number	44	3	31	0	0	4
Myalgia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	11 / 201 (5.47%)	15 / 198 (7.58%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	12	27	0	0	0
Joint swelling
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 160 (0.00%)
occurrences all number	0	0	0	0	1	0
Infections and infestations
Urinary tract infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	16 / 162 (9.88%)	11 / 201 (5.47%)	5 / 198 (2.53%)	0 / 5 (0.00%)	0 / 9 (0.00%)	9 / 160 (5.63%)
occurrences all number	24	12	5	0	0	11
Pneumonia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	19 / 162 (11.73%)	33 / 201 (16.42%)	32 / 198 (16.16%)	0 / 5 (0.00%)	0 / 9 (0.00%)	15 / 160 (9.38%)
occurrences all number	27	53	44	0	0	19
Upper respiratory tract infection
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	12 / 162 (7.41%)	11 / 201 (5.47%)	9 / 198 (4.55%)	0 / 5 (0.00%)	0 / 9 (0.00%)	11 / 160 (6.88%)
occurrences all number	14	16	13	0	0	11
Bacteraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	11 / 201 (5.47%)	16 / 198 (8.08%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	14	20	0	0	0
Corynebacterium bacteraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 160 (0.00%)
occurrences all number	0	0	0	0	1	0
SARS-CoV-2 test positive
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 160 (0.00%)
occurrences all number	0	0	0	0	1	0
Epstein-Barr virus infection reactivation
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	0 / 201 (0.00%)	0 / 198 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 160 (0.00%)
occurrences all number	0	0	0	0	1	0
Metabolism and nutrition disorders
Decreased appetite
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	45 / 162 (27.78%)	41 / 201 (20.40%)	52 / 198 (26.26%)	0 / 5 (0.00%)	0 / 9 (0.00%)	21 / 160 (13.13%)
occurrences all number	55	68	67	0	0	32
Hyperglycaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	5 / 162 (3.09%)	10 / 201 (4.98%)	10 / 198 (5.05%)	0 / 5 (0.00%)	0 / 9 (0.00%)	9 / 160 (5.63%)
occurrences all number	5	17	12	0	0	19
Hypoalbuminaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	11 / 162 (6.79%)	30 / 201 (14.93%)	32 / 198 (16.16%)	0 / 5 (0.00%)	0 / 9 (0.00%)	13 / 160 (8.13%)
occurrences all number	28	57	78	0	0	28
Hypocalcaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	10 / 162 (6.17%)	17 / 201 (8.46%)	25 / 198 (12.63%)	0 / 5 (0.00%)	0 / 9 (0.00%)	13 / 160 (8.13%)
occurrences all number	25	37	41	0	0	32
Hypokalaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	35 / 162 (21.60%)	83 / 201 (41.29%)	76 / 198 (38.38%)	0 / 5 (0.00%)	0 / 9 (0.00%)	22 / 160 (13.75%)
occurrences all number	65	217	200	0	0	42
Hypomagnesaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	11 / 162 (6.79%)	24 / 201 (11.94%)	29 / 198 (14.65%)	0 / 5 (0.00%)	0 / 9 (0.00%)	5 / 160 (3.13%)
occurrences all number	17	49	52	0	0	6
Hyponatraemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	16 / 162 (9.88%)	15 / 201 (7.46%)	24 / 198 (12.12%)	0 / 5 (0.00%)	0 / 9 (0.00%)	9 / 160 (5.63%)
occurrences all number	21	23	34	0	0	19
Hypophosphataemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	10 / 162 (6.17%)	44 / 201 (21.89%)	42 / 198 (21.21%)	0 / 5 (0.00%)	0 / 9 (0.00%)	15 / 160 (9.38%)
occurrences all number	21	84	88	0	0	30
Hyperuricaemia
Additional description: MedDRA 25.1 was used for open label extension cohort.
subjects affected / exposed	0 / 162 (0.00%)	9 / 201 (4.48%)	13 / 198 (6.57%)	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 160 (0.00%)
occurrences all number	0	28	20	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

15 Nov 2017

In schedule of activities of Intenstive study, pregnancy testing added for Day 1 of each Consolidation Cycle with single-agent cytarabine and Day 1 of each cycle where single-agent glasdegib/placebo administered to ensure appropriate safety monitoring.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Inadvertently 1 subject was enrolled twice into the study resulting in enrollment number as 744. However, a total of 743 subject were randomized and received treatment in the study.

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Clinical trials

Clinical Trial Results: A Randomized (1:1), Double-blind, Multi-center, Placebo Controlled Study Evaluating Intensive Chemotherapy With or Without Glasdegib (Pf-04449913) or Azacitidine (AZA) With or Without Glasdegib in Patients With Previously Untreated Acute Myeloid Leukemia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Non-intensive Study: OS

Primary: Non-intensive Study: OS

Primary: Intensive Study: Overall Survival (OS)

Primary: Intensive Study: Overall Survival (OS)

Primary: Open Label Extension: Number of Subjects With Treatment Emergent Adverse Event (AE) and Treatment Related AE

Primary: Open Label Extension: Number of Subjects With Treatment Emergent Adverse Event (AE) and Treatment Related AE

Primary: Open Label Extension: Number of Subjects With Treatment Emergent Serious Adverse Events (SAE) and Treatment Related SAEs

Primary: Open Label Extension: Number of Subjects With Treatment Emergent Serious Adverse Events (SAE) and Treatment Related SAEs

Secondary: Non-intensive Study: Percentage of Subjects who Improved in Fatigue Score Measured by the MDASI-AML/MDS Questionnaire at Week 12

Secondary: Non-intensive Study: Percentage of Subjects who Improved in Fatigue Score Measured by the MDASI-AML/MDS Questionnaire at Week 12

Secondary: Percentage of Subjects who Improved in Fatigue Score Measured by the MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Questionnaire

Secondary: Percentage of Subjects who Improved in Fatigue Score Measured by the MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Questionnaire

Secondary: Non-intensive Study: Percentage of Subjects With CR Including CRMRD-neg

Secondary: Non-intensive Study: Percentage of Subjects With CR Including CRMRD-neg

Secondary: Intensive Study: Percentage of Subjects With CR Including CRMRD-neg

Secondary: Intensive Study: Percentage of Subjects With CR Including CRMRD-neg

Secondary: Non-intensive Study: Percentage of Subjects With CRMRD-neg

Secondary: Non-intensive Study: Percentage of Subjects With CRMRD-neg

Secondary: Intensive Study: Percentage of Subjects With Complete Remission With Incomplete Hematologic Recovery (CRi)

Secondary: Intensive Study: Percentage of Subjects With Complete Remission With Incomplete Hematologic Recovery (CRi)

Secondary: Intensive Study: Percentage of Subjects With Complete Remission Without Negative Minimal Residual Disease (CRMRD-neg)

Secondary: Intensive Study: Percentage of Subjects With Complete Remission Without Negative Minimal Residual Disease (CRMRD-neg)

Secondary: Non-intensive Study: Percentage of Subjects With CRi

Secondary: Non-intensive Study: Percentage of Subjects With CRi

Secondary: Intensive Study: Percentage of Subjects With Morphologic Leukemia-free State (MLFS)

Secondary: Intensive Study: Percentage of Subjects With Morphologic Leukemia-free State (MLFS)

Secondary: Intensive Study: Percentage of Subjects With Partial Remission (PR)

Secondary: Intensive Study: Percentage of Subjects With Partial Remission (PR)

Secondary: Non-intensive Study: Percentage of Subjects With MLFS

Secondary: Non-intensive Study: Percentage of Subjects With MLFS

Secondary: Non-intensive Study: Percentage of Subjects With PR

Secondary: Non-intensive Study: Percentage of Subjects With PR

Secondary: Non-intensive Study: Percentage of Subjects With Complete Remission With Partial Hematologic Recovery (CRh)

Secondary: Non-intensive Study: Percentage of Subjects With Complete Remission With Partial Hematologic Recovery (CRh)

Secondary: Intensive Study: Duration of Response (DoRi)

Secondary: Intensive Study: Duration of Response (DoRi)

Secondary: Non-intensive Study: DoRi

Secondary: Non-intensive Study: DoRi

Secondary: Non-intensive Study: Time to Response

Secondary: Non-intensive Study: Time to Response

Secondary: Intensive Study: Event-free Survival (EFS)

Secondary: Intensive Study: Event-free Survival (EFS)

Secondary: Intensive Study: MDASI-AML/MDS Score

Secondary: Intensive Study: MDASI-AML/MDS Score

Secondary: Non-intensive Study: EFS

Secondary: Non-intensive Study: EFS

Secondary: Non-intensive Study: MDASI-AML/MDS Score

Secondary: Non-intensive Study: MDASI-AML/MDS Score

Secondary: Intensive Study: EQ-5D-5L Score

Secondary: Intensive Study: EQ-5D-5L Score

Secondary: Intensive Study: Patients Global Impression of Symptoms (PGIS)

Secondary: Intensive Study: Patients Global Impression of Symptoms (PGIS)

Secondary: Non-intensive Study: EQ-VAS

Secondary: Non-intensive Study: EQ-VAS

Secondary: Intensive Study: EuroQoL Visual Analogue Scale (EQ-VAS)

Secondary: Intensive Study: EuroQoL Visual Analogue Scale (EQ-VAS)

Secondary: Non-intensive Study: EQ-5D-5L Score

Secondary: Non-intensive Study: EQ-5D-5L Score

Secondary: Non-intensive Study: PGIS

Secondary: Non-intensive Study: PGIS

Secondary: Intensive Study: Participants Global Impression of Change (PGIC)

Secondary: Intensive Study: Participants Global Impression of Change (PGIC)

Secondary: Non-intensive Study: PGIC

Secondary: Non-intensive Study: PGIC

Secondary: Intensive Study: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03

Secondary: Intensive Study: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03

Secondary: Non-intensive Study: Number of Subjects With AEs and SAEs Graded by NCI CTCAE v.4.03

Secondary: Non-intensive Study: Number of Subjects With AEs and SAEs Graded by NCI CTCAE v.4.03

Secondary: Intensive Study: Number of Subjects With Treatment Related AEs and SAEs Graded by NCI CTCAE v.4.03

Secondary: Intensive Study: Number of Subjects With Treatment Related AEs and SAEs Graded by NCI CTCAE v.4.03

Clinical Trial Results:
A Randomized (1:1), Double-blind, Multi-center, Placebo Controlled Study Evaluating Intensive Chemotherapy With or Without Glasdegib (Pf-04449913) or Azacitidine (AZA) With or Without Glasdegib in Patients With Previously Untreated Acute Myeloid Leukemia