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Clinical Trial Results:
A Phase 1/2a Study Evaluating the Safety, Pharmacokinetics, and Efficacy of ABT-263 in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia.

Summary
EudraCT number	2007-002143-25
Trial protocol	GB DE
Global end of trial date	12 May 2022

Results information
Results version number	v1
This version publication date	03 May 2023
First version publication date	03 May 2023
Other versions	v2

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

M06-873

ISRCTN number

US NCT number

NCT00481091

WHO universal trial number (UTN)

Sponsor organisation name

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation address

AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United States, SL6 4UB

Public contact

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com

Scientific contact

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.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

12 May 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 May 2022

Was the trial ended prematurely?

Main objective of the trial

The objectives of the Phase 1 portion of the study include: ● Safety assessment ● Dose limiting toxicity (DLT) determination ● Maximum tolerated dose (MTD) determination ● Recommended Phase 2 Dose (RPTD) and schedule determination ● Pharmacokinetic profile evaluation The objectives of the Phase 2a portion of the study include: ● Safety assessment at the recommended Phase 2 dose (RPTD) and schedule determination ● Preliminary efficacy assessment including biomarker assessment ● Pharmacokinetic profile evaluation

Protection of trial subjects

The study will be conducted in accordance with the protocol, International Conference on Harmonization (ICH) GCP guidelines, applicable regulations and guidelines governing clinical study conduct and ethical principles that have their origin in the Declaration of Helsinki. Prior to the initiation of any screening or study-specific procedures, the investigator or his/her representative will explain the nature of the study to the subject and answer all questions regarding this study.

Background therapy

Evidence for comparator

Actual start date of recruitment

25 Jul 2007

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 8

Country: Number of subjects enrolled

Germany: 2

Country: Number of subjects enrolled

Australia: 28

Country: Number of subjects enrolled

United States: 22

Worldwide total number of subjects

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Subjects underwent screening procedures within 14 days prior to initial study drug administration (Lead-in Day 1/Cycle 1 Day 1). Adult male and female subjects with chronic lymphocytic leukemia (CLL) who met the inclusion criteria and who did not meet any of the exclusion criteria were eligible for enrollment into the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Navitoclax 14/21 Day Cycle: 10 mg

Arm description

Navitoclax 10 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Arm type

Experimental

Investigational medicinal product name

Navitoclax

Investigational medicinal product code

ABT-263

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects were instructed to self-administer navitoclax orally once daily (QD) within 30 minutes after the completion of breakfast.

Navitoclax 14/21 Day Cycle: 110 mg

Arm description

Navitoclax 110 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Arm type

Experimental

Investigational medicinal product name

Navitoclax

Investigational medicinal product code

ABT-263

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects were instructed to self-administer navitoclax orally once daily (QD) within 30 minutes after the completion of breakfast.

Navitoclax 14/21 Day Cycle: 200 mg

Arm description

Navitoclax 200 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Arm type

Experimental

Investigational medicinal product name

Navitoclax

Investigational medicinal product code

ABT-263

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects were instructed to self-administer navitoclax orally once daily (QD) within 30 minutes after the completion of breakfast.

Navitoclax 14/21 Day Cycle: 250 mg

Arm description

Navitoclax 250 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Arm type

Experimental

Investigational medicinal product name

Navitoclax

Investigational medicinal product code

ABT-263

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects were instructed to self-administer navitoclax orally once daily (QD) within 30 minutes after the completion of breakfast.

Navitoclax 21/21 Day Cycle: 125 mg

Arm description

Navitoclax 125 mg administered for 21 consecutive days to complete a 21-day cycle.

Arm type

Experimental

Investigational medicinal product name

Navitoclax

Investigational medicinal product code

ABT-263

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects were instructed to self-administer navitoclax orally once daily (QD) within 30 minutes after the completion of breakfast.

Navitoclax 21/21 Day Cycle: 200 mg

Arm description

Navitoclax 200 mg administered for 21 consecutive days to complete a 21-day cycle.

Arm type

Experimental

Investigational medicinal product name

Navitoclax

Investigational medicinal product code

ABT-263

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects were instructed to self-administer navitoclax orally once daily (QD) within 30 minutes after the completion of breakfast.

Navitoclax 21/21 Day Cycle: 250 mg

Arm description

Navitoclax 250 mg administered for 21 consecutive days to complete a 21-day cycle.

Arm type

Experimental

Investigational medicinal product name

Navitoclax

Investigational medicinal product code

ABT-263

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects were instructed to self-administer navitoclax orally once daily (QD) within 30 minutes after the completion of breakfast.

Navitoclax 21/21 Day Cycle: 300 mg

Arm description

Navitoclax 300 mg administered for 21 consecutive days to complete a 21-day cycle.

Arm type

Experimental

Investigational medicinal product name

Navitoclax

Investigational medicinal product code

ABT-263

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects were instructed to self-administer navitoclax orally once daily (QD) within 30 minutes after the completion of breakfast.

Phase 2: Navitoclax 100 mg

Arm description

Navitoclax 100 mg in subjects with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s).

Arm type

Experimental

Investigational medicinal product name

Navitoclax

Investigational medicinal product code

ABT-263

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects were instructed to self-administer navitoclax orally once daily (QD) within 30 minutes after the completion of breakfast.

Phase 2: Navitoclax 250 mg

Arm description

Navitoclax 250 mg in subjects with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s).

Arm type

Experimental

Investigational medicinal product name

Navitoclax

Investigational medicinal product code

ABT-263

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects were instructed to self-administer navitoclax orally once daily (QD) within 30 minutes after the completion of breakfast.

Number of subjects in period 1	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg	Phase 2: Navitoclax 100 mg	Phase 2: Navitoclax 250 mg
Started	3	6	3	3	3	4	3	4	4	27
Completed	0	0	0	0	0	0	0	0	0	0
Not completed	3	6	3	3	3	4	3	4	4	27
Consent withdrawn by subject	-	1	1	-	-	-	-	-	1	6
Progressive disease other	1	1	-	1	1	1	-	2	-	-
Other, not specified	-	1	1	-	-	1	-	-	-	4
Adverse event	1	2	-	1	1	1	2	1	1	6
Progressive disease clinical	-	-	-	-	-	-	-	-	1	7
Progressive disease clinical National Cancer Inst.	1	1	-	-	-	1	-	-	-	-
No reason given	-	-	1	1	1	-	1	1	1	4

Baseline characteristics

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Reporting group title

Navitoclax 14/21 Day Cycle: 10 mg

Reporting group description

Navitoclax 10 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 14/21 Day Cycle: 110 mg

Reporting group description

Navitoclax 110 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 14/21 Day Cycle: 200 mg

Reporting group description

Navitoclax 200 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 14/21 Day Cycle: 250 mg

Reporting group description

Navitoclax 250 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 125 mg

Reporting group description

Navitoclax 125 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 200 mg

Reporting group description

Navitoclax 200 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 250 mg

Reporting group description

Navitoclax 250 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 300 mg

Reporting group description

Navitoclax 300 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Phase 2: Navitoclax 100 mg

Reporting group description

Navitoclax 100 mg in subjects with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s).

Reporting group title

Phase 2: Navitoclax 250 mg

Reporting group description

Navitoclax 250 mg in subjects with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s).

Reporting group values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg	Phase 2: Navitoclax 100 mg	Phase 2: Navitoclax 250 mg	Total
Number of subjects	3	6	3	3	3	4	3	4	4	27	60
Age categorical
Units: Subjects
< 65 years	1	0	1	1	1	3	0	1	1	10	19
>= 65 years	2	6	2	2	2	1	3	3	3	17	41
Gender categorical
Units: Subjects
Female	2	1	0	1	2	1	0	3	0	8	18
Male	1	5	3	2	1	3	3	1	4	19	42
Race
Units: Subjects
White	3	6	2	3	2	3	2	3	4	24	52
Black	0	0	0	0	0	0	0	0	0	1	1
American Indian/Alaska Native	0	0	0	0	0	0	0	0	0	0	0
Native Hawaiian or Pacific Islander	0	0	0	0	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0	0	0	1	1
Mixed	0	0	0	0	0	1	0	0	0	0	1
Other	0	0	1	0	1	0	1	1	0	1	5
Missing	0	0	0	0	0	0	0	0	0	0	0
Ethnicity
Units: Subjects
Hispanic	0	0	0	0	0	0	0	0	0	0	0
No Ethnicity	3	6	3	3	3	4	3	4	4	27	60

End points

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Reporting group title

Navitoclax 14/21 Day Cycle: 10 mg

Reporting group description

Navitoclax 10 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 14/21 Day Cycle: 110 mg

Reporting group description

Navitoclax 110 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 14/21 Day Cycle: 200 mg

Reporting group description

Navitoclax 200 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 14/21 Day Cycle: 250 mg

Reporting group description

Navitoclax 250 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 125 mg

Reporting group description

Navitoclax 125 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 200 mg

Reporting group description

Navitoclax 200 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 250 mg

Reporting group description

Navitoclax 250 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 300 mg

Reporting group description

Navitoclax 300 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Phase 2: Navitoclax 100 mg

Reporting group description

Navitoclax 100 mg in subjects with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s).

Reporting group title

Phase 2: Navitoclax 250 mg

Reporting group description

Navitoclax 250 mg in subjects with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s).

Subject analysis set title

Participants Receiving 14/21-Day Dosing Schedule in Phase 1

Subject analysis set type

Intention-to-treat

Subject analysis set description

Navitoclax 10, 110, 200, or 250 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Subject analysis set title

Participants Receiving 21/21-Day Dosing Schedule in Phase 1

Subject analysis set type

Intention-to-treat

Subject analysis set description

Navitoclax 125, 200, 250, or 300 mg administered for 21 consecutive days to complete a 21-day cycle.

Subject analysis set title

Participants Receiving Navitoclax QD Dosing in Phase 2

Subject analysis set type

Intention-to-treat

Subject analysis set description

Navitoclax 100 mg or 250 mg in participants with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s).

Primary: Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs)

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End point title

Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) ^[1] ^[2]

End point description

An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An SAE is one that: results in death, hospitalization, prolongation of hospitalization, or persistent or significant disability/incapacity; is life-threatening, a congenital anomaly, or other important medical event. Events were graded as 1=mild, 2=moderate, 3=severe, 4=life-threatening, or 5=death. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A treatment-emergent adverse event is defined as any adverse event with onset or worsening reported by a subject from the time that the first dose of study drug is administered until 30 days have elapsed following discontinuation of study drug administration. Deaths category included non treatment emergent deaths.

End point type

Primary

End point timeframe

From first dose of study drug to 30 days post-last dose. Participants enrolled in the 14/21-day cycle received a mean of 21.7 treatment cycles; participants enrolled in the 21/21-day cycle received a mean of 19.4 treatment cycles.

Notes
[1] - 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: Descriptive statistics are presented per protocol.
[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: This analysis was for Phase 1 participants only.

End point values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg
Number of subjects analysed	3	6	3	3	3	4	3	4
Units: participants
Any AE	3	6	3	3	3	4	3	4
Any AE at least possibly related to navitoclax	3	4	3	3	3	4	3	4
Any AE with NCI CTCAE Grade ≥ 3	2	4	3	2	2	4	3	4
Any AE with NCI CTCAE Grade 3 or 4	2	4	3	2	2	4	3	4
Any SAE	2	4	2	2	2	4	2	3
Any AE leading to navitoclax discontinuation	1	2	0	1	2	1	2	1
Any AE leading to navitoclax dose reduction	0	1	1	2	0	1	2	0
Any AE leading to navitoclax interruption	0	4	3	2	1	4	3	4
Any AE leading to dose delay	2	3	1	2	0	0	0	2
Any DLT	0	2	0	2	0	2	2	2
Any fatal AE	0	1	0	0	1	0	0	0
Deaths	0	1	0	0	1	0	0	0

No statistical analyses for this end point

Primary: Phase 1: Number of Participants with Dose Limiting Toxicity (DLT) in the Dose Escalation Phase

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End point title

Phase 1: Number of Participants with Dose Limiting Toxicity (DLT) in the Dose Escalation Phase ^[3] ^[4]

End point description

DLTs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 (grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life threatening; grade 5=death). Any of the following events, considered possibly or probably related to the administration of navitoclax, were considered a DLT: Grade 4 thrombocytopenia (< 25,000/mm^3); platelet counts < 25,000/mm^3, Grade 2 or higher bleeding associated with thrombocytopenia; all other Grade 3, 4 or 5 adverse events were considered a DLT. Exceptions included: Grade 3, 4 febrile neutropenia less than 7 days; Grade 3, 4 leukopenia; Grade 3, 4 lymphopenia; Grade 3 nausea, vomiting and/or diarrhea unless unresponsive to treatment; Grade 2 toxicity that requires dose modification or delay of > 1 week.

End point type

Primary

End point timeframe

Cycle 1 (Up to 21 days) plus 7 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: Descriptive statistics are presented per protocol.
[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: This analysis was for Phase 1 participants only.

End point values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg
Number of subjects analysed	3	6	3	3	3	4	3	4
Units: participants	0	1	0	2	0	1	1	1

No statistical analyses for this end point

Primary: Phase 1: Maximum Tolerated Dose (MTD) in the Dose Escalation Phase

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End point title

Phase 1: Maximum Tolerated Dose (MTD) in the Dose Escalation Phase ^[5]

End point description

The MTD was defined as the dose at which 30% of participants experienced a DLT during the first cycle. DLTs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 (grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life threatening; grade 5=death). Any of the following events, considered possibly or probably related to the administration of navitoclax, were considered a DLT: Grade 4 thrombocytopenia (< 25,000/mm^3); platelet counts < 25,000/mm^3, Grade 2 or higher bleeding associated with thrombocytopenia; all other Grade 3, 4 or 5 adverse events were considered a DLT. Exceptions included: Grade 3, 4 febrile neutropenia less than 7 days; Grade 3, 4 leukopenia; Grade 3, 4 lymphopenia; Grade 3 nausea, vomiting and/or diarrhea unless unresponsive to treatment; Grade 2 toxicity that requires dose modification or delay of > 1 week.

End point type

Primary

End point timeframe

Cycle 1 (Up to 21 days) plus 7 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: Planned statistics are included in the data table.

End point values	Participants Receiving 14/21-Day Dosing Schedule in Phase 1	Participants Receiving 21/21-Day Dosing Schedule in Phase 1
Number of subjects analysed	15	14
Units: mg	200	250

No statistical analyses for this end point

Primary: Phase 1: Recommended Phase 2 Dose (RPTD) Determined in the Dose Escalation Phase

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End point title

Phase 1: Recommended Phase 2 Dose (RPTD) Determined in the Dose Escalation Phase ^[6]

End point description

The RPTD was determined based on observed DLTs and/or determination of the MTD in phase 1.

End point type

Primary

End point timeframe

Cycle 1 (Up to 21 days) plus 7 days

Notes
[6] - 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: Planned statistics are included in the data table.

End point values	Participants Receiving 14/21-Day Dosing Schedule in Phase 1	Participants Receiving 21/21-Day Dosing Schedule in Phase 1
Number of subjects analysed	15	14
Units: mg	250	250

No statistical analyses for this end point

Primary: Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax

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End point title

Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax ^[7] ^[8]

End point description

NOTE: One subject in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to 14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.

End point type

Primary

End point timeframe

Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

Notes
[7] - 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: Planned statistics are included in the data table.
[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: This analysis was for Phase 1 participants only.

End point values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg
Number of subjects analysed	3 ^[9]	6 ^[10]	3 ^[11]	3 ^[12]	3 ^[13]	4 ^[14]	3 ^[15]	4 ^[16]
Units: hours
arithmetic mean (standard deviation)
Cycle 1 Day 1; n=3, 6, 3, 3, 3, 4, 3, 4	6.0 ( 2.0 )	5.9 ( 1.6 )	6.7 ( 1.2 )	7.3 ( 1.2 )	7.3 ( 1.2 )	6.5 ( 1.0 )	6.7 ( 2.3 )	7.5 ( 1.0 )
Cycle 1 Day 14; n=3, 3, 4, 2, 3, 3, 3, 3	4.3 ( 1.5 )	3.5 ( 2.8 )	6.8 ( 1.5 )	5.7 ( 0.4 )	5.8 ( 1.8 )	6.7 ( 1.2 )	6.9 ( 1.8 )	7.3 ( 1.2 )

Notes
[9] - n=participants with an assessment at given time point
[10] - n=participants with an assessment at given time point
[11] - n=participants with an assessment at given time point
[12] - n=participants with an assessment at given time point
[13] - n=participants with an assessment at given time point
[14] - n=participants with an assessment at given time point
[15] - n=participants with an assessment at given time point
[16] - n=participants with an assessment at given time point

No statistical analyses for this end point

Primary: Phase 1: Maximum Observed Plasma Concentration (Cmax)

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End point title

Phase 1: Maximum Observed Plasma Concentration (Cmax) ^[17] ^[18]

End point description

NOTE: One subject in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to 14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.

End point type

Primary

End point timeframe

Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

Notes
[17] - 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: Planned statistics are included in the data table.
[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: This analysis was for Phase 1 participants only.

End point values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg
Number of subjects analysed	3 ^[19]	6 ^[20]	3 ^[21]	3 ^[22]	3 ^[23]	4 ^[24]	3 ^[25]	4 ^[26]
Units: μg/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1; n=3, 6, 3, 3, 3, 4, 3, 4	0.25 ( 0.14 )	1.19 ( 0.37 )	2.60 ( 1.54 )	5.19 ( 2.70 )	2.24 ( 0.98 )	2.73 ( 0.82 )	2.59 ( 1.60 )	3.30 ( 1.20 )
Cycle 1 Day 14; n=3, 3, 4, 2, 3, 3, 3, 3	0.42 ( 0.17 )	1.87 ( 0.71 )	4.44 ( 3.59 )	3.21 ( 0.12 )	2.68 ( 1.11 )	3.46 ( 1.57 )	3.74 ( 1.19 )	3.11 ( 2.26 )

Notes
[19] - n=participants with an assessment at given time point
[20] - n=participants with an assessment at given time point
[21] - n=participants with an assessment at given time point
[22] - n=participants with an assessment at given time point
[23] - n=participants with an assessment at given time point
[24] - n=participants with an assessment at given time point
[25] - n=participants with an assessment at given time point
[26] - n=participants with an assessment at given time point

No statistical analyses for this end point

Primary: Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8)

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End point title

Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) ^[27] ^[28]

End point description

NOTE: One subject in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to 14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.

End point type

Primary

End point timeframe

Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

Notes
[27] - 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: Planned statistics are included in the data table.
[28] - 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: This analysis was for Phase 1 participants only.

End point values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg
Number of subjects analysed	3 ^[29]	6 ^[30]	3 ^[31]	3 ^[32]	3 ^[33]	4 ^[34]	3 ^[35]	4 ^[36]
Units: μg•hr/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1; n=3, 4, 3, 3, 3, 4, 3, 4	1.0 ( 0.65 )	5.7 ( 2.7 )	10.6 ( 4.0 )	19.8 ( 14.0 )	12.0 ( 4.2 )	12.3 ( 3.0 )	12.0 ( 9.2 )	14.3 ( 5.7 )
Cycle 1 Day 14; n=3, 3, 4, 2, 3, 3, 3, 3	2.2 ( 0.95 )	11.1 ( 2.7 )	24.2 ( 18.1 )	17.8 ( 2.3 )	15.7 ( 6.8 )	18.4 ( 8.7 )	24.4 ( 5.7 )	21.6 ( 15.6 )

Notes
[29] - n=participants with an assessment at given time point
[30] - n=participants with an assessment at given time point
[31] - n=participants with an assessment at given time point
[32] - n=participants with an assessment at given time point
[33] - n=participants with an assessment at given time point
[34] - n=participants with an assessment at given time point
[35] - n=participants with an assessment at given time point
[36] - n=participants with an assessment at given time point

No statistical analyses for this end point

Primary: Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24)

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End point title

Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) ^[37] ^[38]

End point description

NOTE: One subject in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to 14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.

End point type

Primary

End point timeframe

Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

Notes
[37] - 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: Planned statistics are included in the data table.
[38] - 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: This analysis was for Phase 1 participants only.

End point values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg
Number of subjects analysed	3 ^[39]	6 ^[40]	3 ^[41]	3 ^[42]	3 ^[43]	4 ^[44]	3 ^[45]	4 ^[46]
Units: μg•hr/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1; n=3, 6, 3, 3, 3, 4, 3, 4	2.7 ( 1.0 )	15.0 ( 3.2 )	34.0 ( 13.8 )	67.8 ( 27.7 )	37.5 ( 16.0 )	44.0 ( 18.7 )	49.5 ( 12.3 )	52.9 ( 20.1 )
Cycle 1 Day 14; n=3, 3, 4, 2, 3, 3, 3, 3	5.5 ( 2.7 )	30.9 ( 7.7 )	68.7 ( 42.9 )	50.6 ( 0.36 )	43.5 ( 16.6 )	56.2 ( 28.6 )	72.7 ( 14.4 )	64.8 ( 49.4 )

Notes
[39] - n=participants with an assessment at given time point
[40] - n=participants with an assessment at given time point
[41] - n=participants with an assessment at given time point
[42] - n=participants with an assessment at given time point
[43] - n=participants with an assessment at given time point
[44] - n=participants with an assessment at given time point
[45] - n=participants with an assessment at given time point
[46] - n=participants with an assessment at given time point

No statistical analyses for this end point

Primary: Phase 1: Cmax/Dose

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End point title

Phase 1: Cmax/Dose ^[47] ^[48]

End point description

NOTE: One subject in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to 14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.

End point type

Primary

End point timeframe

Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

Notes
[47] - 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: Planned statistics are included in the data table.
[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: This analysis was for Phase 1 participants only.

End point values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg
Number of subjects analysed	3 ^[49]	6 ^[50]	3 ^[51]	3 ^[52]	3 ^[53]	4 ^[54]	3 ^[55]	4 ^[56]
Units: ng/mL/mg
arithmetic mean (standard deviation)
Cycle 1 Day 1; n=3, 6, 3, 3, 3, 4, 3, 4	24.5 ( 13.9 )	10.7 ( 3.4 )	13.0 ( 7.7 )	20.8 ( 10.8 )	17.9 ( 7.9 )	13.7 ( 4.1 )	10.4 ( 6.4 )	11.0 ( 4.0 )
Cycle 1 Day 14; n=3, 3, 4, 2, 3, 3, 3, 3	42.3 ( 16.6 )	17.0 ( 6.4 )	22.2 ( 17.9 )	12.8 ( 0.48 )	21.4 ( 8.9 )	17.3 ( 7.9 )	15.0 ( 4.8 )	10.4 ( 7.5 )

Notes
[49] - n=participants with an assessment at given time point
[50] - n=participants with an assessment at given time point
[51] - n=participants with an assessment at given time point
[52] - n=participants with an assessment at given time point
[53] - n=participants with an assessment at given time point
[54] - n=participants with an assessment at given time point
[55] - n=participants with an assessment at given time point
[56] - n=participants with an assessment at given time point

No statistical analyses for this end point

Primary: Phase 1: AUC8/Dose

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End point title

Phase 1: AUC8/Dose ^[57] ^[58]

End point description

NOTE: One subject in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to 14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.

End point type

Primary

End point timeframe

Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

Notes
[57] - 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: Planned statistics are included in the data table.
[58] - 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: This analysis was for Phase 1 participants only.

End point values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg
Number of subjects analysed	3 ^[59]	6 ^[60]	3 ^[61]	3 ^[62]	3 ^[63]	4 ^[64]	3 ^[65]	4 ^[66]
Units: ng•hr/mL/mg
arithmetic mean (standard deviation)
Cycle 1 Day 1; n=3, 6, 3, 3, 3, 4, 3, 4	99.9 ( 65.0 )	52.0 ( 24.7 )	53.1 ( 20.1 )	79.2 ( 56.1 )	95.8 ( 33.5 )	61.3 ( 14.9 )	47.9 ( 36.8 )	47.6 ( 18.8 )
Cycle 1 Day 14; n=3, 3, 4, 2, 3, 3, 3, 3	215 ( 95.1 )	101 ( 24.7 )	121 ( 90.4 )	71.3 ( 9.1 )	125 ( 54.1 )	92.1 ( 43.3 )	97.7 ( 22.6 )	72.0 ( 51.9 )

Notes
[59] - n=participants with an assessment at given time point
[60] - n=participants with an assessment at given time point
[61] - n=participants with an assessment at given time point
[62] - n=participants with an assessment at given time point
[63] - n=participants with an assessment at given time point
[64] - n=participants with an assessment at given time point
[65] - n=participants with an assessment at given time point
[66] - n=participants with an assessment at given time point

No statistical analyses for this end point

Primary: Phase 1: AUC24/Dose

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End point title

Phase 1: AUC24/Dose ^[67] ^[68]

End point description

NOTE: One subject in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to 14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.

End point type

Primary

End point timeframe

Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

Notes
[67] - 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: Planned statistics are included in the data table.
[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: This analysis was for Phase 1 participants only.

End point values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg
Number of subjects analysed	3	6 ^[69]	3 ^[70]	3 ^[71]	3 ^[72]	4 ^[73]	3 ^[74]	4 ^[75]
Units: ng•hr/mL/mg
arithmetic mean (standard deviation)
Cycle 1 Day 1; n=3, 6, 3, 3, 3, 4, 3, 4	268 ( 100 )	136 ( 28.8 )	170 ( 69.2 )	271 ( 111 )	300 ( 128 )	220 ( 93.6 )	198 ( 49.3 )	176 ( 67.0 )
Cycle 1 Day 14; n=3, 3, 4, 2, 3, 3, 3, 3	546 ( 267 )	281 ( 69.9 )	344 ( 215 )	202 ( 1.5 )	348 ( 133 )	281 ( 143 )	291 ( 57.5 )	216 ( 165 )

Notes
[69] - n=participants with an assessment at given time point
[70] - n=participants with an assessment at given time point
[71] - n=participants with an assessment at given time point
[72] - n=participants with an assessment at given time point
[73] - n=participants with an assessment at given time point
[74] - n=participants with an assessment at given time point
[75] - n=participants with an assessment at given time point

No statistical analyses for this end point

Primary: Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax

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End point title

Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax ^[76] ^[77]

End point description

End point type

Primary

End point timeframe

Cycle 1 Day 1: pre-dose, 2, 4, 6, 8 hours post-dose

Notes
[76] - 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: Planned statistics are included in the data table.
[77] - 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: This analysis was for Phase 1 participants only.

End point values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg
Number of subjects analysed	2	3	2	1 ^[78]	0 ^[79]	3	0 ^[80]	1 ^[81]
Units: 1/H
arithmetic mean (standard deviation)	0.072 ( 0.029 )	0.077 ( 0.006 )	0.067 ( 0.030 )	0.059 ( 99999 )	( )	0.066 ( 0.025 )	( )	0.039 ( 99999 )

Notes
[78] - 99999=not applicable (1 participant analyzed)
[79] - no participants analyzed in this arm
[80] - no participants analyzed in this arm
[81] - 99999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Primary: Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax

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End point title

Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax ^[82] ^[83]

End point description

For t1/2, the harmonic mean and psuedo-standard deviation are used.

End point type

Primary

End point timeframe

Cycle 1 Day 1: pre-dose, 2, 4, 6, 8 hours post-dose

Notes
[82] - 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: Planned statistics are included in the data table.
[83] - 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: This analysis was for Phase 1 participants only.

End point values	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg
Number of subjects analysed	2	3	2	1 ^[84]	0 ^[85]	3	0 ^[86]	1 ^[87]
Units: hours
arithmetic mean (standard deviation)	9.62 ( 4.18 )	8.99 ( 0.66 )	10.41 ( 5.21 )	11.72 ( 99999 )	( )	10.51 ( 4.01 )	( )	17.88 ( 99999 )

Notes
[84] - 99999=not applicable (1 participant analyzed)
[85] - no participants analyzed in this arm
[86] - no participants analyzed in this arm
[87] - 99999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Primary: Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs

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End point title

Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs ^[88] ^[89]

End point description

End point type

Primary

End point timeframe

From first dose of study drug to 30 days post-last dose. Participants enrolled in Phase 2 received a mean of 15.6 treatment cycles.

Notes
[88] - 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: Descriptive statistics are presented per protocol.
[89] - 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: Descriptive statistics are presented per protocol.

End point values	Phase 2: Navitoclax 100 mg	Phase 2: Navitoclax 250 mg
Number of subjects analysed	4	27
Units: participants
Any AE	4	27
Any AE at least possibly related to navitoclax	4	26
Any AE with NCI CTCAE Grade ≥ 3	3	23
Any AE with NCI CTCAE Grade 3 or 4	3	23
Any SAE	1	12
Any AE leading to navitoclax discontinuation	1	9
Any AE leading to navitoclax dose reduction	1	10
Any AE leading to navitoclax interruption	2	16
Any AE leading to navitoclax dose delay	2	5
Any fatal AE	0	1
Deaths	1	8

No statistical analyses for this end point

Primary: Phase 2: Dose-Normalized Plasma Concentrations after Navitoclax Once Daily Dosing

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End point title

Phase 2: Dose-Normalized Plasma Concentrations after Navitoclax Once Daily Dosing ^[90]

End point description

End point type

Primary

End point timeframe

Cycle 1 Day 1: 4-8 h postdose; Cycle 1 Day 15: predose; Cycle 3 Day 1: predose, 4-8 h postdose; Cycle 5 Day 1: predose, 4-8 h postdose; Cycle 7 Day 1: predose, 4-8 h postdose; Cycle 9 Day 1: predose, 4-8 h postdose

Notes
[90] - 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: Planned statistics are included in the data table.

End point values	Participants Receiving Navitoclax QD Dosing in Phase 2
Number of subjects analysed	31 ^[91]
Units: (ng/mL)/mg
arithmetic mean (standard deviation)
Cycle 1 Day 1: 4-8 h postdose; n=25	9.49 ( 4.80 )
Cycle 1 Day 15: predose; n=22	9.64 ( 5.85 )
Cycle 3 Day 1: predose; n=20	9.84 ( 3.55 )
Cycle 3 Day 1: 4-8 h postdose; n=17	15.2 ( 8.04 )
Cycle 5 Day 1: predose; n=21	9.84 ( 4.38 )
Cycle 5 Day 1: 4-8 h postdose; n=19	15.7 ( 8.28 )
Cycle 7 Day 1: predose; n=9	10.4 ( 5.26 )
Cycle 7 Day 1: 4-8 h postdose; n=9	15.9 ( 9.14 )
Cycle 9 Day 1: predose; n=5	11.4 ( 9.68 )
Cycle 9 Day 1: 4-8 h postdose; n=4	13.5 ( 6.41 )

Notes
[91] - n=participants with a valid assessment at given time point

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug to 30 days post-last dose. Phase 1 14/21-day cycle participants: mean of 21.7 treatment cycles. Phase 1 21/21-day cycle participants: mean of 19.4 treatment cycles. Phase 2 participants: mean of 15.6 treatment cycles.

Adverse event reporting additional description

All Cause mortality: Median time on study: 135, 89.5, 608, 441, 299, 307, 561, 152.5, 486.5, 803 days for Ph 1 14/21 Day Cycle 10 mg, 110 mg, 200 mg, 250 mg, Ph 1 21/21 Day Cycle 125 mg, 200 mg, 250 mg, 300mg and Ph 2 100 mg , 250 mg arms, respectively.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Navitoclax 14/21 Day Cycle: 110 mg

Reporting group description

Navitoclax 110 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 14/21 Day Cycle: 10 mg

Reporting group description

Navitoclax 10 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 14/21 Day Cycle: 250 mg

Reporting group description

Navitoclax 250 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 14/21 Day Cycle: 200 mg

Reporting group description

Navitoclax 200 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 125 mg

Reporting group description

Navitoclax 125 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 200 mg

Reporting group description

Navitoclax 200 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 250 mg

Reporting group description

Navitoclax 250 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Navitoclax 21/21 Day Cycle: 300 mg

Reporting group description

Navitoclax 300 mg administered for 21 consecutive days to complete a 21-day cycle.

Reporting group title

Phase 2: Navitoclax 100 mg

Reporting group description

Navitoclax 100 mg in subjects with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s).

Reporting group title

Phase 2: Navitoclax 250 mg

Reporting group description

Navitoclax 250 mg in subjects with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s).

Serious adverse events	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg	Phase 2: Navitoclax 100 mg	Phase 2: Navitoclax 250 mg
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 6 (66.67%)	2 / 3 (66.67%)	2 / 3 (66.67%)	2 / 3 (66.67%)	2 / 3 (66.67%)	4 / 4 (100.00%)	2 / 3 (66.67%)	3 / 4 (75.00%)	1 / 4 (25.00%)	12 / 27 (44.44%)
number of deaths (all causes)	1	0	0	0	1	0	0	0	1	8
number of deaths resulting from adverse events	1	0	0	0	1	0	0	0	0	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BASAL CELL CARCINOMA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
CHRONIC LYMPHOCYTIC LEUKAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 1
COLORECTAL CANCER METASTATIC
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
MALIGNANT MELANOMA OF EYELID
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
RECTAL ADENOCARCINOMA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA OF SKIN
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
SUPERFICIAL SPREADING MELANOMA STAGE UNSPECIFIED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
ANGINA PECTORIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
MYOCARDIAL INFARCTION
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
DIZZINESS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
NEURALGIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
SCIATICA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0
TRANSIENT ISCHEMIC ATTACK
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PANCYTOPENIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
PYREXIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
RECTAL HAEMORRHAGE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
SMALL INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
CHOLELITHIASIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHIECTASIS
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
URINARY RETENTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
LUMBAR SPINAL STENOSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
ABSCESS LIMB
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
AMOEBIASIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
APPENDICITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
ASPERGILLUS INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
BACTERAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHOPULMONARY ASPERGILLOSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA BACTERAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA URINARY TRACT INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS SALMONELLA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
PHARYNGITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA KLEBSIELLA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PSEUDOMONAL SEPSIS
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
GOUT
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
HYPERCALCAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TUMOUR LYSIS SYNDROME
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Navitoclax 14/21 Day Cycle: 110 mg	Navitoclax 14/21 Day Cycle: 10 mg	Navitoclax 14/21 Day Cycle: 250 mg	Navitoclax 14/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 125 mg	Navitoclax 21/21 Day Cycle: 200 mg	Navitoclax 21/21 Day Cycle: 250 mg	Navitoclax 21/21 Day Cycle: 300 mg	Phase 2: Navitoclax 100 mg	Phase 2: Navitoclax 250 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)	4 / 4 (100.00%)	27 / 27 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BASAL CELL CARCINOMA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 4 (25.00%)	1 / 27 (3.70%)
occurrences all number	0	0	5	0	0	1	0	2	1	1
COLORECTAL ADENOMA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
SKIN PAPILLOMA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
SQUAMOUS CELL CARCINOMA OF SKIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0
Vascular disorders
FLUSHING
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
HAEMATOMA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	1	0	0	0	0	0	0	0	0	1
HYPERTENSION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	1	1	0	1	0	0	1
HYPOTENSION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	1	1	0	0	0	0	2
VASCULITIS
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
General disorders and administration site conditions
ADVERSE DRUG REACTION
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
ASTHENIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
CHEST DISCOMFORT
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	0
CHEST PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0
FATIGUE
subjects affected / exposed	3 / 6 (50.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	2 / 3 (66.67%)	0 / 3 (0.00%)	2 / 4 (50.00%)	2 / 3 (66.67%)	1 / 4 (25.00%)	1 / 4 (25.00%)	10 / 27 (37.04%)
occurrences all number	7	0	2	4	0	3	2	1	2	14
FEELING HOT
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
GAIT DISTURBANCE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	1	0	0	1	0	0
INFLUENZA LIKE ILLNESS
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	1	0	0	0	0	1	1	0	0	1
OEDEMA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
OEDEMA PERIPHERAL
subjects affected / exposed	1 / 6 (16.67%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	7 / 27 (25.93%)
occurrences all number	1	1	2	1	1	1	0	2	0	7
PAIN
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	1	0	1	0	0	0	1	0	0	2
PERIPHERAL SWELLING
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	1	0	0	0	0	0	0	2
PYREXIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 4 (0.00%)	4 / 27 (14.81%)
occurrences all number	1	0	0	0	0	0	0	2	0	5
SECRETION DISCHARGE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
VESSEL PUNCTURE SITE PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Immune system disorders
ALLERGY TO ARTHROPOD BITE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
SEASONAL ALLERGY
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	2	0	0	1	0	1
Reproductive system and breast disorders
BENIGN PROSTATIC HYPERPLASIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
ERECTILE DYSFUNCTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
PENILE CURVATURE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
PROSTATITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	1	0	0	0	0	2
Respiratory, thoracic and mediastinal disorders
ASTHMA
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	3	0	0	0	0	0	0	0	0
COUGH
subjects affected / exposed	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)	2 / 4 (50.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 4 (25.00%)	6 / 27 (22.22%)
occurrences all number	2	0	1	4	1	2	2	0	1	7
DYSPNOEA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	4	0	0	1	1	0	0	1
EPISTAXIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)
occurrences all number	0	0	5	0	1	0	7	0	0	5
HAEMOPTYSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
HAEMOTHORAX
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
NASAL CONGESTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
OROPHARYNGEAL PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 4 (50.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	5	1	2	0	0	2	2
PRODUCTIVE COUGH
subjects affected / exposed	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	2	0	0	0	0	1	0	1	0	1
PULMONARY OEDEMA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
RESPIRATORY TRACT CONGESTION
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
SINUS CONGESTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	2	0	0	0	0
SPUTUM DISCOLOURED
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
THROAT IRRITATION
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0
WHEEZING
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Psychiatric disorders
AGITATION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	1	0	0	0	0	1	0	1
ANXIETY
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)
occurrences all number	1	0	3	0	0	0	0	0	0	3
INSOMNIA
subjects affected / exposed	2 / 6 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)
occurrences all number	2	1	1	0	1	0	0	0	0	3
MENTAL STATUS CHANGES
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)	1 / 4 (25.00%)	3 / 27 (11.11%)
occurrences all number	0	0	0	0	0	0	9	0	2	6
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 4 (25.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	0	0	0	1	0	1	3
BLOOD CREATININE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	0	0	0	0	0	0	2
BLOOD GLUCOSE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
BLOOD LACTATE DEHYDROGENASE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	0	0	0	0	0	1	2
BLOOD MAGNESIUM DECREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
ELECTROCARDIOGRAM QT PROLONGED
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
HAEMOGLOBIN DECREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	0	0	0	0	0	0	5
HEART RATE IRREGULAR
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
LIPASE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
WEIGHT DECREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)
occurrences all number	0	0	0	2	0	0	1	2	0	3
WEIGHT INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
Injury, poisoning and procedural complications
CONTUSION
subjects affected / exposed	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)
occurrences all number	2	0	2	0	0	2	0	0	0	3
FALL
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	0	0	0	0	0	0	2
HUMERUS FRACTURE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
LIGAMENT SPRAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
MENISCUS INJURY
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
PROCEDURAL PAIN
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	1	1	0	0	0	0	0
SKIN ABRASION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
SKIN LACERATION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
SUNBURN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
WOUND
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Congenital, familial and genetic disorders
PHIMOSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Cardiac disorders
ANGINA PECTORIS
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
BRADYCARDIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
CARDIAC FAILURE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
VENTRICULAR EXTRASYSTOLES
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0
Nervous system disorders
APHASIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
DIZZINESS
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	4 / 27 (14.81%)
occurrences all number	0	1	1	0	3	0	0	3	0	4
DYSGEUSIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	1	0	0	0	0	0	0	0	0	1
HEADACHE
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	3 / 27 (11.11%)
occurrences all number	0	1	0	1	1	1	0	0	2	4
LETHARGY
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	2	0	1	0	0	0	1
NEUROPATHY PERIPHERAL
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	1	0	1	0	0	0	1
SENSORY DISTURBANCE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
TASTE DISORDER
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)
occurrences all number	0	0	0	2	0	0	0	0	0	3
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	4 / 27 (14.81%)
occurrences all number	1	0	0	0	0	0	0	1	0	7
LYMPHADENOPATHY
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	2	1	0	0	0	1
NEUTROPENIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 4 (0.00%)	7 / 27 (25.93%)
occurrences all number	0	0	1	2	0	4	0	5	0	20
THROMBOCYTOPENIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	2 / 3 (66.67%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 4 (25.00%)	13 / 27 (48.15%)
occurrences all number	1	0	9	10	0	5	0	3	2	39
Ear and labyrinth disorders
EAR CONGESTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
EAR DISCOMFORT
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
EAR PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0
Eye disorders
CATARACT
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
CONJUNCTIVAL HAEMORRHAGE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0
DACRYOSTENOSIS ACQUIRED
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
ECTROPION
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0
EYE HAEMORRHAGE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
RETINAL HAEMORRHAGE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
SWELLING OF EYELID
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Gastrointestinal disorders
ABDOMINAL DISCOMFORT
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 4 (50.00%)	3 / 27 (11.11%)
occurrences all number	0	0	0	0	1	0	0	0	2	6
ABDOMINAL PAIN
subjects affected / exposed	1 / 6 (16.67%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	2 / 27 (7.41%)
occurrences all number	1	2	0	0	0	1	0	0	3	3
ABDOMINAL PAIN UPPER
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)
occurrences all number	0	0	2	1	1	0	0	0	0	3
CONSTIPATION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 4 (25.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	0	0	2	1	0	1	2
DENTAL CARIES
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0	0
DIARRHOEA
subjects affected / exposed	4 / 6 (66.67%)	1 / 3 (33.33%)	3 / 3 (100.00%)	3 / 3 (100.00%)	2 / 3 (66.67%)	3 / 4 (75.00%)	3 / 3 (100.00%)	3 / 4 (75.00%)	4 / 4 (100.00%)	20 / 27 (74.07%)
occurrences all number	9	2	4	15	8	6	10	8	5	30
DRY MOUTH
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
DYSPEPSIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	5 / 27 (18.52%)
occurrences all number	0	0	2	0	1	1	0	1	0	6
DYSPHAGIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
FLATULENCE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	0	1	0	0	1	0	2
FREQUENT BOWEL MOVEMENTS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	2	0	0	0	0	0	0	2
GINGIVAL BLEEDING
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	0	0	0	2	0	1
MOUTH ULCERATION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0	0	0
NAUSEA
subjects affected / exposed	3 / 6 (50.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	2 / 3 (66.67%)	3 / 3 (100.00%)	2 / 4 (50.00%)	2 / 3 (66.67%)	2 / 4 (50.00%)	2 / 4 (50.00%)	13 / 27 (48.15%)
occurrences all number	3	2	2	8	6	6	2	2	2	17
NONINFECTIVE GINGIVITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0	0
ORAL PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0
RECTAL FISSURE
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
RECTAL HAEMORRHAGE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0	1	0	0	0	1	0
RECTAL POLYP
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
STOMATITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0	0	0	1	1	0	0
TONGUE ULCERATION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
TOOTHACHE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	1	0	0	0	0	0	0	2
VOMITING
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 3 (66.67%)	2 / 4 (50.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	1 / 4 (25.00%)	5 / 27 (18.52%)
occurrences all number	0	1	1	2	9	3	2	1	1	5
Hepatobiliary disorders
HYPERBILIRUBINAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	0	0	1	0	0	4
Skin and subcutaneous tissue disorders
ACTINIC KERATOSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	6	1	0	0	0	0	0	0
ALOPECIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0
BLOOD BLISTER
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
COLD SWEAT
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
DERMATOSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
DRY SKIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	1	1	0	0	0	0	0
ERYTHEMA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
NIGHT SWEATS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	2	0	0	1	0	1
RASH
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)
occurrences all number	1	0	0	0	1	0	0	2	0	3
RASH VESICULAR
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
SKIN DISCOLOURATION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
SKIN LESION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	1	0	1	0	0
URTICARIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	2	0	0	1	0	0	0	0	0	0
Renal and urinary disorders
DYSURIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	0	0	2	0	0	1
HAEMATURIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
NOCTURIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	0
POLLAKIURIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
RENAL CYST
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
RENAL PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Endocrine disorders
AUTOIMMUNE HYPOTHYROIDISM
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	5 / 27 (18.52%)
occurrences all number	0	1	1	1	0	0	1	0	0	5
BACK PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)
occurrences all number	0	0	0	2	0	1	1	1	0	4
BONE PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
DUPUYTREN'S CONTRACTURE
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
GROIN PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
JOINT SWELLING
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0	0
LIMB DISCOMFORT
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
MUSCLE SPASMS
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences all number	1	0	0	0	0	0	0	0	0	2
MUSCULOSKELETAL DISCOMFORT
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
MUSCULOSKELETAL PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
MYALGIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
NECK PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	1	0	0	0	1	0	0	2
OSTEITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
OSTEOPENIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
OSTEOPOROSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
PAIN IN EXTREMITY
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	5 / 27 (18.52%)
occurrences all number	0	0	1	1	0	0	1	0	0	5
Infections and infestations
ACUTE SINUSITIS
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
BRONCHITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	5
CELLULITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	1	0	1	0	0
CONJUNCTIVITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
ESCHERICHIA INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
ESCHERICHIA URINARY TRACT INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
EYE INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0
GASTROENTERITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
HAEMOPHILUS INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	0	0	1	0	0	1
HERPES SIMPLEX
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 4 (50.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	1	2	3	0	0	0	0
HERPES ZOSTER
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
INFLUENZA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	1	0	0	0	0	1	0	0	0	1
LICE INFESTATION
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
LOCALISED INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	1	0
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	2	0	0	0	0	0	5
NASOPHARYNGITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 4 (25.00%)	5 / 27 (18.52%)
occurrences all number	0	0	5	2	4	1	3	0	1	7
ORAL CANDIDIASIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	2	0	0	0
ORAL HERPES
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	1	0	1	0	2	0	1
OTITIS MEDIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
PARONYCHIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
PNEUMONIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
PNEUMONIA KLEBSIELLA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0
RESPIRATORY TRACT INFECTION VIRAL
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
RHINITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
RHINOVIRUS INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
SINUSITIS
subjects affected / exposed	1 / 6 (16.67%)	1 / 3 (33.33%)	3 / 3 (100.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	1	1	3	0	0	2	0	1	0	1
SKIN INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	2	0	0	0	0	0	1
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	1	1	0	0	0	0	0	0	1
TOOTH ABSCESS
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 6 (16.67%)	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 4 (50.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	8 / 27 (29.63%)
occurrences all number	1	1	5	1	6	2	3	0	0	11
URINARY TRACT INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 4 (0.00%)	5 / 27 (18.52%)
occurrences all number	0	0	1	1	3	0	1	5	0	10
VASCULAR DEVICE INFECTION
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
VIRAL INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	1	3	1	0	0	0	1
VULVOVAGINAL CANDIDIASIS
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 4 (50.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 4 (25.00%)	8 / 27 (29.63%)
occurrences all number	1	0	0	2	1	2	0	2	1	10
DEHYDRATION
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	1	0	1	1	0
HYPERGLYCAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	0	0	0	0	1	0	0	3
HYPERPHOSPHATAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
HYPERURICAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)
occurrences all number	0	0	1	0	0	0	1	0	0	5
HYPOKALAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	1	2	0	0
HYPOMAGNESAEMIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	1	0	1	0	0
HYPOVOLAEMIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
TUMOUR LYSIS SYNDROME
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	1 / 27 (3.70%)
occurrences all number	1	0	0	0	0	0	0	0	1	1
VITAMIN D DEFICIENCY
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

01 Dec 2010

● Added the ABT-263 Meltrex® tablet formulation (once available) in Section 5.5 (Treatments). ● Removed the option to supply ABT-263 stabilized solution in bottles (i.e., it must be provided in prefilled syringes) in Section 5.5 (Treatments). ● Changed the requirement for ABT-263 to be administered within 30 minutes after the completion of breakfast throughout the protocol to ensure that ABT-263 is taken closer to the time of a meal, as the Meltrex® tablet formulation is known to have a food effect. ● In Section 5.3.2.1 (Collection of Samples for Analysis), added the requirement to record the date and time of doses and whether or not doses were taken within 30 minutes of completing breakfast for the pre-dose (0 hour) PK sampling day and for the two days prior to each PK sampling day. These changes were made due to the known food effect of the Meltrex® formulation. ● Added (Cycle/Day) abbreviations to column header in Table 3 Schedule of Assessments. ● Retitled Table 6 to better indicate that it pertains to the Phase 2a, 21/21 Day Continuous Dosing Schedule. ● Added a reference to Table 5 for pharmacokinetic sampling timepoints during Cycle 1 of the Phase 1 - 14/21 Day Dosing Schedule in Section 5.3.1.1 (Study Procedures). ● Changed the shipping contact, e-mail and address for the Bcl-2/Bim Ratio samples in Section 5.3.1.4 (Specimen for Pharmacodynamic Analyses). ● Added that if a follow-up visit is not performed, the reason should be noted in the subject's source documentation in Section 5.4.1 (Discontinuation of Individual Subjects). ● Clarified that a designee for the site pharmacist may prepare and dispense prefilled stabilized solution syringes in Section 5.5.2 (Identity of Investigational Product). ● Added Adapt-a-Caps for bottles of oral solution to the list of ancillary materials supplied by Abbott in Section 5.5.2 (Identity of Investigational Product). ● Retitled Table 6 to better indicate that it pertains to the Phase 2a, 21/21 Day Schedule.

01 Dec 2010

(continued) ● Clarified that empty bottles of study drug will be destroyed at the site in Section 5.5.7 (Drug Accountability). ● Removed "Hospitalization" as a stand alone criterion in Section 6.1.2 (Serious Adverse Events) as it is already covered under the "Hospitalization or Prolongation of Hospitalization" criterion. ● Added cellular phone number for the Abbott Medical Monitor in Section 1.0 (Title Page) and Section 7.0 (Protocol Deviations) and corrected it in Section 6.5 (Adverse Event Reporting). ● Updated Sponsor contact information in Section 7.0 (Protocol Deviations). ● Updated Appendix B to reflect current protocol signatories. ● Corrected typographical errors.

11 May 2011

● Developed an Extension Study to allow subjects who remain active to continue receiving ABT-263 with less frequent study evaluations. Subjects in the Extension Study may continue to receive study drug for up to three years after the last subject transitions to the Extension Study. ● Updated Section 3.0 (Introduction) in order to align with current toxicology findings for ABT-263. ● Updated Section 5.3.1.3 (Blood Samples for Pharmacogenetic Analyses), Section 5.3.1.4 (Specimens for Pharmacodynamic Analyses) and Section 5.3.2.2 (Handling/Processing of Samples) to remove processing and shipping instructions. Added reference to the M06-873 Laboratory Manual to allow for revisions to be made to the Laboratory Manual without the need to amend the protocol. ● Updated Section 5.3.2.3 (Disposition of Samples for ABT-263 Assay) to include sample labeling instructions. ● Revised Section 5.5.2 (Identity of Investigational Product) to remove the option of ABT-263 Powder for Oral Solution, which will no longer be available in the future. ● Clarified in Section 5.5.7 (Drug Accountability) that empty study drug bottles will be destroyed per the site's destruction policy, if applicable. ● Clarified in Section 6.2 (Adverse Event Severity) that if an adverse event increases in severity, a new adverse event should be reported. ● Revised Appendix E to reflect the current sample list of excluded and cautionary medications for ABT-263. ● Added changes previously noted in Administrative Change 3 (09 Dec 2010). ● Updated Sponsor contact information in Section 7.0 (Protocol Deviations). ● Updated Appendix B to reflect current protocol signatories. ● Format changes to Appendix F to reflect Abbott standards. ● Corrected typographical errors.

08 Aug 2016

● Extend the duration of the Extension Phase from 5 years to 7 years after the last subject transitions. ● Update the contact information for AbbVie contacts. ● Update Section 3.0, Introduction ● Clarify Section 5.3.1.1, Study Procedures. ● Update Section 6.5, Adverse Event Reporting, to include 24 hour emergency contact phone number. ● Update Section 5.3.1.4, Specimens for Pharmacodynamic Analyses, the biomarkers ZAP70/CD38 (US sites only), the CGH/FISH (AUS sites only) and Bcl-2/Bim Ratio (US and AUS sites) blood collections have been removed from the Final Visit for subjects in the Extension Study. ● Updated Section 15.0, Reference List. ● Update Appendix B, List of Protocol Signatories. ● Update Appendix D, Responsibilities of the Clinical Investigator. ● Incorporate additional administrative changes.

26 Jul 2018

● Extend the duration of the Extension Phase from 7 years to 9 years after the last subject transitions. ● Update the contact information for AbbVie contacts in Section 1.0, Title Page, Section 6.5, Adverse Event Reporting, and Section 7.0 Protocol Deviation. ● Update Section 5.3.1.4 and update of Table 9 and Appendix G, Table 1 and Table 2. Remove the Biomarker Sample Collection (Phase 2a), at the Final Visit for subjects enrolled in the Extension under this amendment. ● Update Section 5.3.1. Remove the Survival follow up assessment at the 3 monthly intervals after study discontinuation, unless a very small number of patients are available for overall survival (OS) follow-up. ● Updated Section 15.0, Reference List. ● Update Appendix B, List of Protocol Signatories. ● Make minor language or word revisions throughout the document. ● Incorporate additional administrative changes.

29 Jan 2020

● Extend the duration of the Extension Phase from 9 years to 11 years after the last subject transitions. ● Update the contact information for AbbVie contacts in Section 1.0, Title Page, Section 6.5, Adverse Event Reporting, and Section 7.0 Protocol Deviation. ● Updated Section 15.0, Reference List. ● Update Appendix B, List of Protocol Signatories. ● Updated Appendix G, Table 1 (Extension Study: Schedule of Assessments) to delete the post-treatment and biomarker sample collection information ● Deleted Table 2, (Extension Study: Schedule of Biomarker Sample Collection) ● Remove PK sample collections from subjects enrolled into the Extension Study. ● Remove reference to central lab.

03 Sep 2020

● Section 3.0 – Included information on the re-evaluation of the benefit and risk to subjects participating in the study. ● Section 5.4.1 – Added that the investigator should contact the sponsor medical contact before discontinuing a subject from the study for a reason other than "planned per protocol." ● Section 5.5.1 – Added delays in study drug dosing due to the above COVID-19 testing guidance. ● Section 5.5.4 – Included instructions that in the event the subject cannot pick up study drug onsite, DTP (Direct To Patient) shipment can be made, as permitted by local regulations. ● Section 7.0 – clarified that protocol deviations may include modifications due to COVID-19. ● Section 9.1 – Added that AbbVie will modify the study protocol as necessary due to the pandemic. Investigators must also notify AbbVie if any urgent safety measures are taken. ● Section 10.1 – Added that remote monitoring may be employed as needed. ● Appendix A – Addition of COVID-19 and DTP to list of abbreviations. ● In addition, sponsor contact information updates have been made.

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.

None reported

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Clinical Trial Results: A Phase 1/2a Study Evaluating the Safety, Pharmacokinetics, and Efficacy of ABT-263 in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia.

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End points

End points

Primary: Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs)

Primary: Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs)

Primary: Phase 1: Number of Participants with Dose Limiting Toxicity (DLT) in the Dose Escalation Phase

Primary: Phase 1: Number of Participants with Dose Limiting Toxicity (DLT) in the Dose Escalation Phase

Primary: Phase 1: Maximum Tolerated Dose (MTD) in the Dose Escalation Phase

Primary: Phase 1: Maximum Tolerated Dose (MTD) in the Dose Escalation Phase

Primary: Phase 1: Recommended Phase 2 Dose (RPTD) Determined in the Dose Escalation Phase

Primary: Phase 1: Recommended Phase 2 Dose (RPTD) Determined in the Dose Escalation Phase

Primary: Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax

Primary: Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax

Primary: Phase 1: Maximum Observed Plasma Concentration (Cmax)

Primary: Phase 1: Maximum Observed Plasma Concentration (Cmax)

Primary: Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8)

Primary: Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8)

Primary: Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24)

Primary: Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24)

Primary: Phase 1: Cmax/Dose

Primary: Phase 1: Cmax/Dose

Primary: Phase 1: AUC8/Dose

Primary: Phase 1: AUC8/Dose

Primary: Phase 1: AUC24/Dose

Primary: Phase 1: AUC24/Dose

Primary: Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax

Primary: Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax

Primary: Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax

Primary: Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax

Primary: Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs

Primary: Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs

Primary: Phase 2: Dose-Normalized Plasma Concentrations after Navitoclax Once Daily Dosing

Primary: Phase 2: Dose-Normalized Plasma Concentrations after Navitoclax Once Daily Dosing

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 1/2a Study Evaluating the Safety, Pharmacokinetics, and Efficacy of ABT-263 in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia.