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Clinical Trial Results:
A Phase 3, Randomized, Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination with Ofatumumab for Previously Treated Chronic Lymphocytic Leukemia

Summary
EudraCT number	2012-001236-65
Trial protocol	BE IE GB SE ES DK FR
Global end of trial date	15 Aug 2018

Results information
Results version number	v1(current)
This version publication date	21 Aug 2019
First version publication date	21 Aug 2019
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

GS-US-312-0119

ISRCTN number

-

US NCT number

NCT01659021

WHO universal trial number (UTN)

-

Sponsor organisation name

Gilead Sciences

Sponsor organisation address

333 Lakeside Drive, Foster City, CA, United States, 94404

Public contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com

Scientific contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

15 Aug 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Aug 2018

Global end of trial reached?

Yes

Global end of trial date

15 Aug 2018

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of this study was to evaluate the effect of the addition of idelalisib to ofatumumab on progression-free survival (PFS) in participants with previously treated chronic lymphocytic leukemia (CLL).

Protection of trial subjects

The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

04 Dec 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 36

Country: Number of subjects enrolled

Spain: 13

Country: Number of subjects enrolled

Sweden: 6

Country: Number of subjects enrolled

United Kingdom: 17

Country: Number of subjects enrolled

Belgium: 6

Country: Number of subjects enrolled

Denmark: 4

Country: Number of subjects enrolled

France: 24

Country: Number of subjects enrolled

Ireland: 11

Country: Number of subjects enrolled

United States: 93

Country: Number of subjects enrolled

Australia: 29

Country: Number of subjects enrolled

Canada: 22

Worldwide total number of subjects

261

EEA total number of subjects

117

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

94

From 65 to 84 years

166

85 years and over

1

Subject disposition

Top of page

Recruitment details

Participants were enrolled at study sites in North America, Europe, and Australia. The first participant was screened on 04 December 2012. The last study visit occurred on 15 August 2018.

Screening details

310 participants were screened.

Period 1 title

Main Study

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Idelalisib+Ofatumumab

Arm description

Randomized Initial Therapy (24 weeks): Idelalisib 150 mg tablets twice daily + ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 1000 mg weekly for 7 weeks, and then 1000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Idelalisib 150 mg tablets twice daily until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.

Arm type

Experimental

Investigational medicinal product name

Idelalisib

Investigational medicinal product code

Other name

Zydelig®, GS-1101, CAL-101

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

150 mg administered twice daily

Investigational medicinal product name

Ofatumumab

Investigational medicinal product code

Other name

Arzerra®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses)

Ofatumumab

Arm description

Randomized Initial Therapy (24 weeks): Ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Observation until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.

Arm type

Active comparator

Investigational medicinal product name

Ofatumumab

Investigational medicinal product code

Other name

Arzerra®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses)

Number of subjects in period 1	Idelalisib+Ofatumumab	Ofatumumab
Started	174	87
Randomized and Treated	173	86
Completed: Disease Progression or Death	100	50
Completed	100	50
Not completed	74	37
Physician decision	34	16
Adverse Event	2	3
Unknown Reasons	2	1
Withdrawal by Subject	19	16
Study Terminated by Sponsor	16	1
Lost to follow-up	1	-

Period 2 title

Long-Term Follow Up

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

The arms in the LTFU period are mutually exclusive, but due to system restrictions, "No" was entered for this field to allow entry of appropriate data.

Are arms mutually exclusive

No

Idelalisib+Ofatumumab (LTFU)

Arm description

Long-Term Follow-up (LTFU): Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Ofatumumab (LTFU)

Arm description

LTFU: Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Idelalisib+Ofatumumab (LTFU)	Ofatumumab (LTFU)
Started	138	69
Completed	133	65
Not completed	5	4
Withdrawal by Subject	2	1
Lost to follow-up	3	3

Baseline characteristics

Top of page

Reporting group title

Idelalisib+Ofatumumab

Reporting group description

Randomized Initial Therapy (24 weeks): Idelalisib 150 mg tablets twice daily + ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 1000 mg weekly for 7 weeks, and then 1000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Idelalisib 150 mg tablets twice daily until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.

Reporting group title

Ofatumumab

Reporting group description

Randomized Initial Therapy (24 weeks): Ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Observation until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.

Reporting group values	Idelalisib+Ofatumumab	Ofatumumab	Total
Number of subjects	174	87	261
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	67 ± 9.0	67 ± 9.7	-
Gender categorical
Units: Subjects
Female	50	25	75
Male	124	62	186
Ethnicity
Units: Subjects
Hispanic or Latino	7	3	10
Not Hispanic or Latino	141	74	215
Unknown or Not Reported	26	10	36
Race
Units: Subjects
White	149	71	220
Black or African American	0	4	4
Native Hawaiian or Other Pacific Islander	1	0	1
Asian	2	0	2
Other	2	3	5
Not Permitted	20	9	29
17p deletion and/ or TP53 mutation
Units: Subjects
Either	70	33	103
Neither	104	54	158
Immunoglobulin heavy chain variable region (IGHV) mutation status
Units: Subjects
Mutated	37	19	56
Unmutated	137	68	205
Disease Status
Refractory: CLL progression < 6 months from completion of prior therapy; Relapsed: CLL progression ≥ 6 months from completion of prior therapy.
Units: Subjects
Refractory	82	47	129
Relapsed	92	40	132
Time Since Diagnosis
Only participants who were randomized and treated are included. Idelalisib+Ofatumumab = 173 participants; Ofatumumab = 86 participants
Units: months
arithmetic mean (standard deviation)	101.0 ± 60.21	94.3 ± 52.51	-

End points

Top of page

Reporting group title

Idelalisib+Ofatumumab

Reporting group description

Randomized Initial Therapy (24 weeks): Idelalisib 150 mg tablets twice daily + ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 1000 mg weekly for 7 weeks, and then 1000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Idelalisib 150 mg tablets twice daily until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.

Reporting group title

Ofatumumab

Reporting group description

Randomized Initial Therapy (24 weeks): Ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Observation until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.

Reporting group title

Idelalisib+Ofatumumab (LTFU)

Reporting group description

Long-Term Follow-up (LTFU): Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.

Reporting group title

Ofatumumab (LTFU)

Reporting group description

LTFU: Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.

Primary: Progression-Free Survival (PFS)

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End point title

Progression-Free Survival (PFS)

End point description

PFS was defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression was CLL progression based on standard criteria (other than lymphocytosis alone) as defined by the 2008 update of the International Workshop on CLL guidelines, ie, appearance of any new lesion; increase by ≥ 50% in the sum of the products of the perpendicular diameters of measured lymph nodes (SPD); new or ≥ 50% enlargement of liver or spleen; transformation to a more aggressive histology (eg, Richter's or prolymphocytic transformation); reduction in the number of blood cells (cytopenia) attributable to CLL. PFS was analyzed using Kaplan-Meier (KM) estimates. Intent-to-Treat (ITT) Analysis Set included participants who were randomized regardless of whether they received any study drug(s), or received a different regimen from that to which they were randomized. Treatment was according to randomization.

End point type

Primary

End point timeframe

Randomization to End of Study (up to 60 months)

End point values	Idelalisib+Ofatumumab	Ofatumumab
Number of subjects analysed	174	87
Units: months
median (confidence interval 95%)	16.6 (13.7 to 19.6)	8.0 (5.7 to 8.4)

Statistical Analysis for Progression-Free Survival

Comparison groups

Idelalisib+Ofatumumab v Ofatumumab

Number of subjects included in analysis

261

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

0.37

Notes
[1] - P-value: stratified log-rank test, adjusted for randomization stratification factors (17p deletion/TP53 mutation, IGHV mutation, and disease status). Hazard Ratio & 95% CIs: proportional hazard model, adjusted for randomization stratification factors

Secondary: Overall Response Rate

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End point title

Overall Response Rate

End point description

Overall response rate was defined as the percentage of participants who achieved a best overall response of complete response or partial response. • Complete response was defined as no lymphadenopathy, hepatomegaly, splenomegaly; normal complete blood count; confirmed by bone marrow aspirate & biopsy. • Partial response was defined as >1 of the following criteria: a 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver size, spleen size; plus ≥ 1 of the following: ≥ 1500/μL absolute neutrophil count, > 100000/ μL platelets, > 11.0 g/dL hemoglobin or 50% improvement for either of these parameters without transfusions or growth factors. Overall response rate was analyzed using KM estimates. Participants in the ITT Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Randomization to End of Study (up to 60 months)

End point values	Idelalisib+Ofatumumab	Ofatumumab
Number of subjects analysed	174	87
Units: percentage of participants
number (confidence interval 95%)	75.3 (68.2 to 81.5)	17.2 (10.0 to 26.8)

Statistical Analysis for Overall Response Rate

Comparison groups

Ofatumumab v Idelalisib+Ofatumumab

Number of subjects included in analysis

261

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

16.85

Confidence interval

level

95%

sides

2-sided

lower limit

8.17

upper limit

34.76

Notes
[2] - P-value, odds ratio, and 95% CIs were calculated from the Cochran-Mantel-Haenszel (CMH) Chi-square test stratified by stratification factors.

Secondary: Lymph Node Response Rate

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End point title

Lymph Node Response Rate

End point description

Lymph node response rate was defined as the proportion of participants who achieved a ≥ 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lymph nodes. Participants in the ITT Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Randomization to End of Study (up to 60 months)

End point values	Idelalisib+Ofatumumab	Ofatumumab
Number of subjects analysed	164	81
Units: percentage of participants
number (confidence interval 95%)	92.7 (87.6 to 96.2)	4.9 (1.4 to 12.2)

Statistical Analysis for Lymph Node Response Rate

Comparison groups

Idelalisib+Ofatumumab v Ofatumumab

Number of subjects included in analysis

245

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[3]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

483.16

Confidence interval

level

95%

sides

2-sided

lower limit

94.63

upper limit

2467.02

Notes
[3] - P-value, odds ratio, and 95% CI were calculated from the CMH Chi-square test stratified by stratification factors.

Secondary: Overall Survival

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End point title

Overall Survival

End point description

Overall survival was defined as the interval from randomization to death from any cause. Overall survival was analyzed using KM estimates. Participants in the ITT Analysis Set were analyzed. 999 = Not applicable, too few events to estimate the upper limit of the confidence interval.

End point type

Secondary

End point timeframe

Randomization to Last Long-Term Follow-Up Visit (up to maximum of 5 years)

End point values	Idelalisib+Ofatumumab	Ofatumumab
Number of subjects analysed	174	87
Units: months
median (confidence interval 95%)	45.2 (34.1 to 999)	39 (23.0 to 999)

Statistical Analysis for Overall Survival

Comparison groups

Idelalisib+Ofatumumab v Ofatumumab

Number of subjects included in analysis

261

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.247 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.15

Notes
[4] - P-value is from stratified log-rank test, adjusted for randomization stratification factors (17p deletion/TP53 mutation, IGHV mutation, and disease status).

Secondary: Progression-Free Survival in Subgroup of Participants With Chromosome 17p Deletion and/or TP53 Mutation

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End point title

Progression-Free Survival in Subgroup of Participants With Chromosome 17p Deletion and/or TP53 Mutation

End point description

Progression-free survival in subgroup of participants with chromosome 17p deletion and/or TP53 mutation was analyzed using KM estimates. Participants in the ITT Analysis Set with chromosome 17p deletion and/or TP53 mutation were analyzed.

End point type

Secondary

End point timeframe

Randomization to End of Study (up to 60 months)

End point values	Idelalisib+Ofatumumab	Ofatumumab
Number of subjects analysed	70	33
Units: months
median (confidence interval 95%)	16.2 (11.1 to 19.1)	5.8 (4.5 to 8.4)

Statistical Analysis for PFS in Subgroup

Comparison groups

Idelalisib+Ofatumumab v Ofatumumab

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

other ^[5]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

0.51

Notes
[5] - Hazard ratio and 95% CIs were calculated using the Cox proportional hazards model without any adjustments.

Secondary: Complete Response Rate

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End point title

Complete Response Rate

End point description

Complete response rate was defined as the percentage of participants who achieve a complete response and maintain their response for at least 8 weeks (with a 1-week window). Participants in the ITT Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Randomization to End of Study (up to 60 months)

End point values	Idelalisib+Ofatumumab	Ofatumumab
Number of subjects analysed	174	87
Units: percentage of participants
number (not applicable)	1.1	0

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse Events: Start of Treatment to End of Treatment (up to 60 months) plus 30 days; All-Cause Mortality: Baseline to Last Long-Term Follow-Up Visit (up to maximum of 5 years)

Adverse event reporting additional description

All-Cause Mortality was assessed in all randomized participants. All other adverse events were assessed in the Safety Analysis Set (participants who received ≥ 1 dose of study treatment, with treatment assignments designated according to the actual treatment received).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Idelalisib+Ofatumumab

Reporting group description

Randomized Initial Therapy (24 weeks): Idelalisib 150 mg tablets twice daily + ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 1000 mg weekly for 7 weeks, and then 1000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Idelalisib 150 mg tablets twice daily until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation Long-Term Follow-up: Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.

Reporting group title

Ofatumumab

Reporting group description

Randomized Initial Therapy (24 weeks): Ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Observation until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation Long-Term Follow-up: Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.

Serious adverse events	Idelalisib+Ofatumumab	Ofatumumab
Total subjects affected by serious adverse events
subjects affected / exposed	136 / 173 (78.61%)	36 / 86 (41.86%)
number of deaths (all causes)	87	40
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anogenital warts
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Central nervous system leukaemia
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Colon cancer metastatic
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Invasive lobular breast carcinoma
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant ascites
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mycosis fungoides
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal neoplasm
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	7 / 173 (4.05%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	2 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery aneurysm
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	23 / 173 (13.29%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	17 / 37	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Asthenia
subjects affected / exposed	2 / 173 (1.16%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired self-care
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza like illness
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Strangulated hernia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumonitis
subjects affected / exposed	7 / 173 (4.05%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	7 / 7	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Respiratory failure
subjects affected / exposed	6 / 173 (3.47%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	4 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Dyspnoea
subjects affected / exposed	4 / 173 (2.31%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspiration
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis chronic
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Lower respiratory tract inflammation
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Bipolar I disorder
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mania
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device occlusion
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Neutrophil count decreased
subjects affected / exposed	6 / 173 (3.47%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	6 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 173 (0.58%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
C-reactive protein increased
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphocyte count decreased
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Troponin increased
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	3 / 173 (1.73%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	3 / 173 (1.73%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 3	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Acute myocardial infarction
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Cardiogenic shock
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Myocardial infarction
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Acute coronary syndrome
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic valve disease
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bradycardia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Hemiparesis
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aphasia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Embolic stroke
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotonia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Locked-in syndrome
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peroneal nerve palsy
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sciatica
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	19 / 173 (10.98%)	3 / 86 (3.49%)
occurrences causally related to treatment / all	19 / 25	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	13 / 173 (7.51%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	10 / 18	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	8 / 173 (4.62%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	2 / 8	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	5 / 173 (2.89%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 9	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Granulocytopenia
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Autoimmune haemolytic anaemia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
External ear inflammation
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vertigo
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	23 / 173 (13.29%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	25 / 32	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	13 / 173 (7.51%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	14 / 15	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	7 / 173 (4.05%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	4 / 7	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	3 / 173 (1.73%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	3 / 173 (1.73%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal wall haematoma
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	5 / 173 (2.89%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	3 / 173 (1.73%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle haemorrhage
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myalgia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Polyarthritis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue necrosis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tenosynovitis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	27 / 173 (15.61%)	9 / 86 (10.47%)
occurrences causally related to treatment / all	13 / 35	2 / 9
deaths causally related to treatment / all	3 / 7	1 / 2
Sepsis
subjects affected / exposed	11 / 173 (6.36%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	6 / 13	0 / 1
deaths causally related to treatment / all	1 / 3	0 / 0
Lower respiratory tract infection
subjects affected / exposed	7 / 173 (4.05%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	4 / 10	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	8 / 173 (4.62%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	6 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	7 / 173 (4.05%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	4 / 173 (2.31%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	1 / 4	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	5 / 173 (2.89%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	2 / 5	0 / 1
deaths causally related to treatment / all	1 / 4	0 / 1
Respiratory tract infection
subjects affected / exposed	3 / 173 (1.73%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	1 / 3	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Bronchitis
subjects affected / exposed	4 / 173 (2.31%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	4 / 173 (2.31%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumocystis jirovecii infection
subjects affected / exposed	1 / 173 (0.58%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Progressive multifocal leukoencephalopathy
subjects affected / exposed	0 / 173 (0.00%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	1 / 2
Pseudomonal bacteraemia
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aspergillus infection
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Candida infection
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Candida pneumonia
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Candida sepsis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Chronic sinusitis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cytomegalovirus colitis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Folliculitis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Genital herpes
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes simplex
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster disseminated
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Listeria sepsis
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomonal sepsis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomonas infection
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection bacterial
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rhinovirus infection
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicella
subjects affected / exposed	0 / 173 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral sepsis
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	6 / 173 (3.47%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	2 / 11	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	3 / 173 (1.73%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	3 / 173 (1.73%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	1 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	4 / 173 (2.31%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	2 / 173 (1.16%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cachexia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudohyperkalaemia
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	1 / 173 (0.58%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Idelalisib+Ofatumumab	Ofatumumab
Total subjects affected by non serious adverse events
subjects affected / exposed	167 / 173 (96.53%)	79 / 86 (91.86%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma
subjects affected / exposed	11 / 173 (6.36%)	3 / 86 (3.49%)
occurrences all number	20	3
Vascular disorders
Hypertension
subjects affected / exposed	21 / 173 (12.14%)	6 / 86 (6.98%)
occurrences all number	23	7
Hypotension
subjects affected / exposed	14 / 173 (8.09%)	5 / 86 (5.81%)
occurrences all number	18	7
General disorders and administration site conditions
Fatigue
subjects affected / exposed	60 / 173 (34.68%)	24 / 86 (27.91%)
occurrences all number	82	25
Pyrexia
subjects affected / exposed	55 / 173 (31.79%)	19 / 86 (22.09%)
occurrences all number	106	28
Oedema peripheral
subjects affected / exposed	35 / 173 (20.23%)	9 / 86 (10.47%)
occurrences all number	41	11
Chills
subjects affected / exposed	27 / 173 (15.61%)	13 / 86 (15.12%)
occurrences all number	31	17
Asthenia
subjects affected / exposed	27 / 173 (15.61%)	9 / 86 (10.47%)
occurrences all number	30	9
Influenza like illness
subjects affected / exposed	14 / 173 (8.09%)	1 / 86 (1.16%)
occurrences all number	18	1
Pain
subjects affected / exposed	13 / 173 (7.51%)	2 / 86 (2.33%)
occurrences all number	16	2
Peripheral swelling
subjects affected / exposed	12 / 173 (6.94%)	1 / 86 (1.16%)
occurrences all number	13	1
Chest pain
subjects affected / exposed	9 / 173 (5.20%)	2 / 86 (2.33%)
occurrences all number	10	2
Malaise
subjects affected / exposed	10 / 173 (5.78%)	1 / 86 (1.16%)
occurrences all number	11	1
Immune system disorders
Hypogammaglobulinaemia
subjects affected / exposed	11 / 173 (6.36%)	3 / 86 (3.49%)
occurrences all number	12	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	60 / 173 (34.68%)	18 / 86 (20.93%)
occurrences all number	89	21
Dyspnoea
subjects affected / exposed	34 / 173 (19.65%)	11 / 86 (12.79%)
occurrences all number	45	15
Oropharyngeal pain
subjects affected / exposed	17 / 173 (9.83%)	3 / 86 (3.49%)
occurrences all number	20	3
Nasal congestion
subjects affected / exposed	11 / 173 (6.36%)	6 / 86 (6.98%)
occurrences all number	13	6
Productive cough
subjects affected / exposed	17 / 173 (9.83%)	0 / 86 (0.00%)
occurrences all number	23	0
Epistaxis
subjects affected / exposed	9 / 173 (5.20%)	6 / 86 (6.98%)
occurrences all number	11	6
Rhinorrhoea
subjects affected / exposed	12 / 173 (6.94%)	1 / 86 (1.16%)
occurrences all number	12	1
Dysphonia
subjects affected / exposed	9 / 173 (5.20%)	1 / 86 (1.16%)
occurrences all number	11	1
Psychiatric disorders
Insomnia
subjects affected / exposed	30 / 173 (17.34%)	12 / 86 (13.95%)
occurrences all number	36	12
Anxiety
subjects affected / exposed	15 / 173 (8.67%)	2 / 86 (2.33%)
occurrences all number	15	2
Confusional state
subjects affected / exposed	10 / 173 (5.78%)	0 / 86 (0.00%)
occurrences all number	16	0
Investigations
Weight decreased
subjects affected / exposed	28 / 173 (16.18%)	5 / 86 (5.81%)
occurrences all number	31	5
Alanine aminotransferase increased
subjects affected / exposed	19 / 173 (10.98%)	2 / 86 (2.33%)
occurrences all number	32	2
Neutrophil count decreased
subjects affected / exposed	16 / 173 (9.25%)	2 / 86 (2.33%)
occurrences all number	29	2
Aspartate aminotransferase increased
subjects affected / exposed	14 / 173 (8.09%)	2 / 86 (2.33%)
occurrences all number	22	2
Platelet count decreased
subjects affected / exposed	9 / 173 (5.20%)	1 / 86 (1.16%)
occurrences all number	10	1
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	30 / 173 (17.34%)	23 / 86 (26.74%)
occurrences all number	40	35
Contusion
subjects affected / exposed	18 / 173 (10.40%)	3 / 86 (3.49%)
occurrences all number	21	3
Cardiac disorders
Tachycardia
subjects affected / exposed	10 / 173 (5.78%)	2 / 86 (2.33%)
occurrences all number	12	2
Nervous system disorders
Headache
subjects affected / exposed	37 / 173 (21.39%)	9 / 86 (10.47%)
occurrences all number	67	10
Dizziness
subjects affected / exposed	17 / 173 (9.83%)	5 / 86 (5.81%)
occurrences all number	20	6
Neuropathy peripheral
subjects affected / exposed	11 / 173 (6.36%)	6 / 86 (6.98%)
occurrences all number	11	6
Paraesthesia
subjects affected / exposed	11 / 173 (6.36%)	4 / 86 (4.65%)
occurrences all number	11	4
Dysgeusia
subjects affected / exposed	11 / 173 (6.36%)	3 / 86 (3.49%)
occurrences all number	13	3
Hypoaesthesia
subjects affected / exposed	10 / 173 (5.78%)	1 / 86 (1.16%)
occurrences all number	13	1
Peripheral sensory neuropathy
subjects affected / exposed	6 / 173 (3.47%)	5 / 86 (5.81%)
occurrences all number	7	5
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	57 / 173 (32.95%)	14 / 86 (16.28%)
occurrences all number	136	21
Anaemia
subjects affected / exposed	38 / 173 (21.97%)	7 / 86 (8.14%)
occurrences all number	50	7
Thrombocytopenia
subjects affected / exposed	25 / 173 (14.45%)	5 / 86 (5.81%)
occurrences all number	26	5
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	96 / 173 (55.49%)	21 / 86 (24.42%)
occurrences all number	196	33
Nausea
subjects affected / exposed	62 / 173 (35.84%)	23 / 86 (26.74%)
occurrences all number	93	25
Constipation
subjects affected / exposed	39 / 173 (22.54%)	13 / 86 (15.12%)
occurrences all number	54	13
Vomiting
subjects affected / exposed	29 / 173 (16.76%)	12 / 86 (13.95%)
occurrences all number	43	13
Abdominal pain
subjects affected / exposed	28 / 173 (16.18%)	5 / 86 (5.81%)
occurrences all number	37	6
Abdominal pain upper
subjects affected / exposed	15 / 173 (8.67%)	4 / 86 (4.65%)
occurrences all number	19	4
Gastrooesophageal reflux disease
subjects affected / exposed	15 / 173 (8.67%)	3 / 86 (3.49%)
occurrences all number	16	3
Colitis
subjects affected / exposed	17 / 173 (9.83%)	0 / 86 (0.00%)
occurrences all number	19	0
Dyspepsia
subjects affected / exposed	13 / 173 (7.51%)	3 / 86 (3.49%)
occurrences all number	15	3
Stomatitis
subjects affected / exposed	9 / 173 (5.20%)	0 / 86 (0.00%)
occurrences all number	9	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	36 / 173 (20.81%)	7 / 86 (8.14%)
occurrences all number	50	10
Night sweats
subjects affected / exposed	17 / 173 (9.83%)	10 / 86 (11.63%)
occurrences all number	19	10
Pruritus
subjects affected / exposed	21 / 173 (12.14%)	6 / 86 (6.98%)
occurrences all number	23	6
Dry skin
subjects affected / exposed	11 / 173 (6.36%)	1 / 86 (1.16%)
occurrences all number	12	1
Rash maculo-papular
subjects affected / exposed	12 / 173 (6.94%)	0 / 86 (0.00%)
occurrences all number	14	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	28 / 173 (16.18%)	11 / 86 (12.79%)
occurrences all number	33	12
Arthralgia
subjects affected / exposed	19 / 173 (10.98%)	5 / 86 (5.81%)
occurrences all number	26	5
Pain in extremity
subjects affected / exposed	19 / 173 (10.98%)	5 / 86 (5.81%)
occurrences all number	21	5
Muscle spasms
subjects affected / exposed	18 / 173 (10.40%)	2 / 86 (2.33%)
occurrences all number	22	2
Myalgia
subjects affected / exposed	15 / 173 (8.67%)	1 / 86 (1.16%)
occurrences all number	16	1
Musculoskeletal pain
subjects affected / exposed	13 / 173 (7.51%)	1 / 86 (1.16%)
occurrences all number	13	1
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	47 / 173 (27.17%)	9 / 86 (10.47%)
occurrences all number	61	9
Sinusitis
subjects affected / exposed	23 / 173 (13.29%)	3 / 86 (3.49%)
occurrences all number	33	3
Bronchitis
subjects affected / exposed	25 / 173 (14.45%)	0 / 86 (0.00%)
occurrences all number	31	0
Urinary tract infection
subjects affected / exposed	18 / 173 (10.40%)	6 / 86 (6.98%)
occurrences all number	26	6
Pneumonia
subjects affected / exposed	21 / 173 (12.14%)	2 / 86 (2.33%)
occurrences all number	23	2
Oral candidiasis
subjects affected / exposed	15 / 173 (8.67%)	0 / 86 (0.00%)
occurrences all number	18	0
Lower respiratory tract infection
subjects affected / exposed	11 / 173 (6.36%)	2 / 86 (2.33%)
occurrences all number	19	2
Oral herpes
subjects affected / exposed	10 / 173 (5.78%)	2 / 86 (2.33%)
occurrences all number	14	2
Respiratory tract infection
subjects affected / exposed	9 / 173 (5.20%)	1 / 86 (1.16%)
occurrences all number	13	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	37 / 173 (21.39%)	7 / 86 (8.14%)
occurrences all number	42	8
Hypokalaemia
subjects affected / exposed	32 / 173 (18.50%)	4 / 86 (4.65%)
occurrences all number	55	5
Hyperglycaemia
subjects affected / exposed	15 / 173 (8.67%)	1 / 86 (1.16%)
occurrences all number	18	1
Dehydration
subjects affected / exposed	14 / 173 (8.09%)	0 / 86 (0.00%)
occurrences all number	22	0
Hypomagnesaemia
subjects affected / exposed	11 / 173 (6.36%)	3 / 86 (3.49%)
occurrences all number	15	3
Hyponatraemia
subjects affected / exposed	12 / 173 (6.94%)	1 / 86 (1.16%)
occurrences all number	15	2

More information

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Were there any global substantial amendments to the protocol? Yes

09 Nov 2012

● Added the exclusion criterion “Prior participation in a GS-1101 clinical trial” ● Updated information regarding secondary and tertiary/exploratory endpoints ● Clarified that the IRC findings would be primary for analyses of PFS and other tumor control endpoints ● Updated plan to control Type I error rate for secondary endpoints ● Increased washout period to 6 weeks ● Provided clarification on phototoxicity risk ● Added details regarding diagnosis/management of progressive multifocal leukoencephalopathy (PML) consistent with Arzerra product label ● Added guidelines for monitoring participants for ofatumumab infusion toxicity ● Added urine pregnancy testing at intervals ≤ 6 weeks after Week 48 ● Clarified timing of scans in participants who had a temporary cessation of therapy ● Clarified duration of therapy for each study treatment in Group A of the study ● Clarified that participants in Group B who prematurely discontinued 1 drug could continue the other ● Increased number of participating centers and study locations ● Updated safety and clinical information to align with IB Ed. 7 ● Added new references regarding modifications in the assessment of absolute lymphocyte counts (ALC) in determining disease response and progression in participants with CLL ● Modified protocol to achieve 129 events with planned sample size ● Added new section to differentiate discontinuation from study versus discontinuation of drug ● Clarified that modifications were to be made for AEs or laboratory abnormalities that the investigator considered related to study drug ● Provided description of the standard accountability procedures because Gilead was supplying ofatumumab ● Modified protocol to allow enrollment of individuals with a positive HBV antibody if HBV DNA was undetectable by quantitative polymerase chain reaction (PCR) ● Updated inclusion criteria relating to contraception ● Added the Per Protocol Analysis Set ● Modified the spleen ULN from 10 cm to 12 cm

17 Oct 2013

● Increased planned sample size to 255 participants to ensure PFS events would be met in a timely manner; up to 270 participants could be enrolled to permit eligible participants who were in screening at the time of enrollment closure to join the study ● Updated “Hepatic Events” section to add monitoring guidelines for participants who were HBc antibody positive at screening ● Updated order of key secondary endpoints ● Updated the nonclinical toxicology and clinical pharmacology sections to align with current understanding and to simplify and remove redundancy with the investigator’s brochure (IB), Edition 8 ● Updated data for the recently completed Phase 1 monotherapy study (101-02) in participants with hematologic malignancies ● Removed AEs as a reason for discontinuation from study ● Updated the clinical response section to align with the criteria for the independent review committee (IRC) ● Updated the pregnancy risk language based on current nonclinical toxicology ● Updated AE reporting to align with Gilead guidelines

13 Jan 2014

● Updated response sections for consistency with central reader rules and to align across Gilead oncology studies ● Added “Sample Storage” section to request tissue samples collected as part of standard of care ● Updated the “Long-Term Follow-Up” section to change the interval to annual and to describe the data to be collected

04 Mar 2014

● Added a formal interim efficacy analysis to be conducted when approximately 50% of the planned 129 events occurred and a second interim to be performed when approximately 75% of expected events occurred ● Gave participants in Group B (ofatumumab monotherapy) the option to receive idelalisib (IDL) in the event that the data monitoring committee (DMC) observed substantial evidence of benefit in Group A (IDL + ofatumumab) based on the interim data

26 Sep 2014

● Added secondary objective "To evaluate the effect of the addition of IDL to ofatumumab on the onset, magnitude, and duration of tumor control for participants with 17p deletion and/or TP53 mutation" ● Added information regarding the possible crossover of Group B participants to IDL in the event that the data monitoring committee (DMC) and Gilead decided to stop the study after the first interim or second interim analysis

17 Dec 2014

Removed crossover study allowance

28 Mar 2016

Updated the safety information and guidelines for toxicity management to be consistent across IDL study protocols; the specific changes included mandating prophylaxis for Pneumocystis jirovecii pneumonia, cytomegalovirus surveillance, and increased monitoring

04 Aug 2016

● Clarified the definition of recommended versus required actions related to dose modifications for AEs ● Modified the safety measures to require monitoring of subjects for Pneumocystis jirovecii pneumonia prophylaxis for 2 to 6 months after the last dose of IDL

24 Oct 2016

In order to provide clear guidance for IDL administration in the event of pneumonitis, the language around actions to be taken was revised.

30 Aug 2017

Organizing pneumonia emerged as a potential safety signal during routine signal detection monitoring. This protocol was amended to add organizing pneumonia as a potential risk.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
15 Aug 2018	This study was terminated by the sponsor. The last subject last observation occurred on 15 August 2018.	-

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

None reported

http://www.ncbi.nlm.nih.gov/pubmed/28257752

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