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Clinical Trial Results:
A Phase III, Open Label, Randomized Trial of Ofatumumab Added to Fludarabine-Cyclophosphamide vs. Fludarabine-Cyclophosphamide Combination in Subjects with Relapsed Chronic Lymphocytic Leukemia Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

Summary
EudraCT number	2008-005811-16
Trial protocol	NL DE GR IT ES GB BG RO
Global end of trial date	25 Oct 2017

Results information
Results version number	v1(current)
This version publication date	04 Nov 2018
First version publication date	04 Nov 2018
Other versions

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

110913

ISRCTN number

US NCT number

NCT00824265

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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

25 Oct 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

25 Oct 2017

Was the trial ended prematurely?

Main objective of the trial

To evaluate and compare PFS of subjects treated with O+FC for the treatment of relapsed CLL to those treated with FC

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Mar 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Brazil: 10

Country: Number of subjects enrolled

Bulgaria: 14

Country: Number of subjects enrolled

Canada: 12

Country: Number of subjects enrolled

Germany: 19

Country: Number of subjects enrolled

United Kingdom: 17

Country: Number of subjects enrolled

Greece: 10

Country: Number of subjects enrolled

India: 29

Country: Number of subjects enrolled

Italy: 14

Country: Number of subjects enrolled

Mexico: 5

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

Poland: 90

Country: Number of subjects enrolled

Romania: 4

Country: Number of subjects enrolled

Russian Federation: 39

Country: Number of subjects enrolled

Spain: 17

Country: Number of subjects enrolled

Taiwan: 5

Country: Number of subjects enrolled

Thailand: 6

Country: Number of subjects enrolled

Ukraine: 66

Country: Number of subjects enrolled

United States: 5

Worldwide total number of subjects

365

EEA total number of subjects

188

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)

231

From 65 to 84 years

133

85 years and over

Subject disposition

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Recruitment details

Participants (par) were screened within 14 days prior to the start of study drug administration to determine eligibility.

Screening details

Eligible par were stratified by Stage (Binet A vs. B vs. C) and number of prior therapies (1-2 vs. ≥3). Par in each stratum were then centrally randomized in a 1:1 ratio to recive intravenous (IV) fludarabine and cyclophosphamide in combination with ofatumumab or IV fludarabine and cyclophosphamide alone.

Period 1 title

Treatment phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects

Arm description

Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.

Arm type

Experimental

Investigational medicinal product name

Ofatumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cycle 1-Day 1 300mg, Cycle 1-Day 8 1000mg, then Cycles 2-6 Day 1 1000mg every 28 days

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

Fludarabine + Cyclophosphamide_ ITT subjects

Arm description

Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.

Arm type

Active comparator

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

Number of subjects in period 1	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Started	183	182
Completed	119	102
Not completed	64	80
Physician decision	6	12
Consent withdrawn by subject	6	15
Adverse Event,non-fatal	50	52
Lost to follow-up	1	1
Protocol deviation	1	-

Period 2 title

Follow-up phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects

Arm description

Arm type

Experimental

Investigational medicinal product name

Ofatumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cycle 1-Day 1 300mg, Cycle 1-Day 8 1000mg, then Cycles 2-6 Day 1 1000mg every 28 days

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

Fludarabine + Cyclophosphamide_ ITT subjects

Arm description

Arm type

Active comparator

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

Number of subjects in period 2	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Started	172	160
Completed	154	129
Not completed	18	31
w/drew consent, no f/u, or MD choice	18	31

Period 3 title

Survival follow-up phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects

Arm description

Arm type

Experimental

Investigational medicinal product name

Ofatumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cycle 1-Day 1 300mg, Cycle 1-Day 8 1000mg, then Cycles 2-6 Day 1 1000mg every 28 days

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

Fludarabine + Cyclophosphamide_ ITT subjects

Arm description

Arm type

Active comparator

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

Number of subjects in period 3	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Started	96	89
Completed	87	73
Not completed	9	16
w/drew consent, no f/u, or MD choice	9	16

Baseline characteristics

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Reporting group title

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects

Reporting group description

Reporting group title

Fludarabine + Cyclophosphamide_ ITT subjects

Reporting group description

Reporting group values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects	Total
Number of subjects	183	182	365
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	121	110	231
From 65-84 years	62	71	133
85 years and over	0	1	1
Age continuous
Units: years
arithmetic mean (standard deviation)	61.4 ( 8.82 )	61.6 ( 10.21 )	-
Sex: Female, Male
Units: Subjects
Female	79	66	145
Male	104	116	220
Race/Ethnicity, Customized
Units: Subjects
African American/African Heritage	3	5	8
American Indian or Alaska Native	3	1	4
Asian - Central/South Asian Heritage	13	16	29
Asian - East Asian Heritage	3	3	6
Asian - South East Asian Heritage	3	3	6
White - Arabic/North African Heritage	0	1	1
White - White/Caucasian/European Heritage	158	153	311
AgeContinuous
Units: Years
arithmetic mean (standard deviation)	61.4 ( 8.82 )	61.6 ( 10.21 )	-

End points

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Reporting group title

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects

Reporting group description

Reporting group title

Fludarabine + Cyclophosphamide_ ITT subjects

Reporting group description

Reporting group title

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects

Reporting group description

Reporting group title

Fludarabine + Cyclophosphamide_ ITT subjects

Reporting group description

Reporting group title

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects

Reporting group description

Reporting group title

Fludarabine + Cyclophosphamide_ ITT subjects

Reporting group description

Subject analysis set title

Ofatumumab+Fludarabine+Cyclophosphamide_anti-CLL therapies

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Fludarabine+Cyclophosphamide_anti-CLL therapies

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: Progression-free survival (PFS), as assessed by the Independent Review Committee (IRC)

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End point title

Progression-free survival (PFS), as assessed by the Independent Review Committee (IRC)

End point description

PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression (progressive disease,PD) and the date of death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia (CLL).

End point type

Primary

End point timeframe

From randomization up to 5 years after last dose of study drug

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Months
median (confidence interval 95%)	28.94 (22.80 to 35.88)	18.83 (14.42 to 25.82)

PFS as assessed by the IRC

Comparison groups

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects

Number of subjects included in analysis

365

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0032

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

0.88

Secondary: Overall survival (OS)

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End point title

Overall survival (OS)

End point description

Overall survival is defined as the time from randomization to death due to any cause. Each participant was followed at the time when the last IRC-assessed PFS events occurred. Participants who had not died were censored at the date of last contact.

End point type

Secondary

End point timeframe

From randomization up to 5 years after last dose of study drug

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Months
median (confidence interval 95%)	62.65 (44.58 to 999)	46.23 (37.72 to 56.57)

PFS as assessed by IRC

Comparison groups

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects

Number of subjects included in analysis

365

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1427

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.59

upper limit

1.09

Secondary: Time to response, as assessed by the IRC

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End point title

Time to response, as assessed by the IRC

End point description

Time to response is defined as the time from randomization to the first response. Complete Response/remission(CR) all the criteria at least 2 months after last treatment: no lymphadenopathy(Ly) > 1.5 cm/ hepatomegaly/spleenomegaly/constitutional symptoms; neutrophils >1500 per microliter(µL), platelets(PL) >100,000/µL, hemoglobin(Hb) >11 grams/deciliter(g/dL), lymphocytes(LC) <4000/µL, bone marrow(BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. Incomplete bone marrow recovery(CRi): CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. Partial Remission/response(PR): >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline(BL), Hb >11 g/dL or 50% improvement over BL. Nodular PR(nPR): persistent nodules BM.

End point type

Secondary

End point timeframe

From randomization up to 5 years after last dose of study drug

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	152	123
Units: Months
median (confidence interval 95%)	0.99 (0.95 to 1.08)	0.99 (0.95 to 1.18)

Time to response as assessed by IRC

Comparison groups

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects

Number of subjects included in analysis

275

Analysis specification

Pre-specified

Analysis type

P-value

= 0.449

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.37

Secondary: Duration of Response (DOR), as assessed by the IRC

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End point title

Duration of Response (DOR), as assessed by the IRC

End point description

DOR is defined as the time from the initial response (CR, CRi, nPR, or PR) to the first documented sign of PD or death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.

End point type

Secondary

End point timeframe

From time of initial response to disease progression or death, whichever came first (up to 5 years after the last dose of study drug)

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	152	123
Units: Months
median (confidence interval 95%)	29.63 (25.03 to 41.46)	24.90 (18.99 to 28.12)

Duration of Response as assessed by the IRC

Comparison groups

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects

Number of subjects included in analysis

275

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0878

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.05

Secondary: Time to progression, as assessed by the IRC

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End point title

Time to progression, as assessed by the IRC

End point description

Time to progression is defined as the time from the date of randomization to PD. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.

End point type

Secondary

End point timeframe

From randomization up to 5 years after the last dose of study drug

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Months
median (confidence interval 95%)	42.12 (28.94 to 47.67)	26.78 (22.51 to 31.87)

Time to progression as assessed by the IRC

Comparison groups

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects

Number of subjects included in analysis

365

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0036

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

0.45

upper limit

0.87

Secondary: Time to next therapy

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End point title

Time to next therapy

End point description

Time to next therapy is defined as the time from randomization until the start of the next-line of treatment. Data are presented for participants who took anti-cancer therapies and participants in the ITT population.

End point type

Secondary

End point timeframe

From the start of study drug until the start of the next anti-CLL therapy (up to 5 years after the last dose of study drug)

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects	Ofatumumab+Fludarabine+Cyclophosphamide_anti-CLL therapies	Fludarabine+Cyclophosphamide_anti-CLL therapies
Number of subjects analysed	183	182	74	67
Units: Months
median (confidence interval 95%)	52.96 (43.56 to 62.98)	40.08 (32.85 to 48.39)	29.68 (24.97 to 32.66)	21.03 (16.79 to 28.35)

Time to next therapy

Comparison groups

Ofatumumab+Fludarabine+Cyclophosphamide_anti-CLL therapies v Fludarabine+Cyclophosphamide_anti-CLL therapies

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

^[1]

P-value

= 0.0109

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

0.94

Notes
[1] - Participants who took anti-cancer therapies

Time to next therapy

Comparison groups

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects

Number of subjects included in analysis

365

Analysis specification

Pre-specified

Analysis type

^[2]

P-value

= 0.1143

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

1.08

Notes
[2] - Participants in the ITT population

Secondary: Number of participants with improvement in Eastern Cooperative Oncology Group (ECOG) performance status

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End point title

Number of participants with improvement in Eastern Cooperative Oncology Group (ECOG) performance status

End point description

The ECOG performance status scales and criteria are used by doctors and researchers to assess how a participant's disease is progressing, how the disease affects the daily living, and determines appropriate treatment and prognosis. ECOG performance status are measured at Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1 and Cycle 6 Day1. During follow period, 1 M after study drug therapy, then every 3 month up to 5 year (up to 60 months). Improvement is defined as a decrease from baseline by at least one step on the ECOG performance status scale (yes/no).

End point type

Secondary

End point timeframe

Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day1, follow up (FU) at 1Month (M) after study drug therapy, 3M, then every 3 month up to 5 year (up to 60 months)

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Participants
Cycle 2 Day 1, n= 170, 168\|	15	13
Cycle 3 Day 1, n= 165,157\|	16	13
Cycle 4 Day 1, n= 153, 132\|	19	13
Cycle 5 Day 1, n= 135, 118\|	20	15
Cycle 6 Day 1, n= 120, 96\|	26	16
1 M, FU, n= 159, 145\|	31	22
3 M, FU, n= 152, 119\|	31	21
6 M, FU, n= 136, 104\|	30	18
9 M, FU, n= 127, 96\|	31	23
12 M, FU, n= 118, 87\|	30	20
15 M, FU, n= 102, 70\|	23	18
18 M, FU, n= 96 ,65\|	23	18
21 M, FU, n= 92, 59\|	22	16
24 M, FU, n= 80, 53\|	20	15
27 M, FU, n= 74, 44\|	15	13
30 M, FU, n= 69, 35\|	14	8
33 M, FU, n= 65, 29\|	15	7
36 M, FU, n= 58, 23\|	12	7
39 M, FU, n= 51, 18\|	12	7
42 M, FU, n= 44, 16\|	11	6
45 M, FU, n= 39, 14\|	8	4
48 M, FU, n= 37, 12\|	8	2
51 M, FU, n= 32, 12\|	7	3
54 M, FU, n= 30, 9\|	7	2
57 M, FU, n= 26, 9\|	3	3
60 M, FU, n= 26, 8\|	3	3

No statistical analyses for this end point

Secondary: Number of Participants with no B-Symptoms or at least one B-symptoms over the time

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End point title

Number of Participants with no B-Symptoms or at least one B-symptoms over the time

End point description

Participants with no B-symptoms (B-Sy) (no night sweat, no weight loss, no fever and no extreme fatigue) and at least one indicated B-sy(night sweats, weight loss, fever or extreme fatigue) were presented at Screening, Cycle 1 Day 1, Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day 1 and during follow up period at 1 M after study drug therapy, then every 3 M up to 5 year (up to 60 months).

End point type

Secondary

End point timeframe

Screening, Cycle1 Day 1, Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day 1 and During at 1M after study drug therapy, 3M, then every 3 M up to 5 year (up to 60 months)

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Participants
Cycle 5 Day 1, no B-sy, n= 134, 118\|	120	97
36 M, FU, no B-sy, n=58, 23\|	56	23
Screening, no B-sy, n= 183, 180\|	63	59
Screening, one B-sy, n= 183, 180\|	120	121
Cycle 1 Day 1, no B-sy, n= 179, 179\|	64	68
Cycle 1 Day 1, one B-sy, n= 179, 179\|	115	111
Cycle 2 Day 1,no B-sy, n= 168, 170\|	116	108
Cycle 2 Day 1, one B-sy, n= 168, 170\|	52	62
Cycle 3 Day 1, no B-sy, n= 165, 156\|	131	116
Cycle 3 Day 1, one B-sy, n= 165, 156\|	34	40
Cycle 4 Day 1, no B-sy, n= 154, 132\|	129	107
Cycle 4 Day 1, one B-sy, n= 154, 132\|	25	25
Cycle 5 Day 1, one B-sy, n= 134, 118\|	14	21
Cycle 6 Day 1, no B-sy, n= 120, 95\|	111	82
Cycle 6 Day 1, one B-sy, n= 120, 95\|	9	13
1 M, FU, no B-sy, n= 161, 145\|	141	116
1 M, FU, one B-sy, n= 161, 145\|	20	29
3 M, FU, no B-sy, n= 153, 119\|	136	105
3 M, FU, one B-sy, n= 153, 119\|	17	14
6 M, FU, no B-sy, n= 138, 107\|	123	96
6 M, FU, one B-sy, n= 138, 107\|	15	11
9 M, FU, no B-sy, n= 129, 96\|	116	87
9 M, FU, one B-sy, n= 129, 96\|	13	9
12 M, FU, no B-sy, n= 119, 87\|	108	74
12 M, FU, one B-sy, n= 119, 87\|	11	13
15 M, FU, no B-sy, n= 103, 71\|	98	63
15 M, FU, one B-sy, n= 103, 71\|	5	8
18 M, FU, no B-sy, n= 98, 64\|	93	58
18 M, FU, one B-sy, n= 98, 64\|	5	6
21 M, FU, no B-sy, n= 94, 60\|	87	55
21 M, FU, one B-sy , n= 94, 60\|	7	5
24 M, FU, no B-sy, n= 80, 52\|	79	48
24 M, FU, one B-sy, n= 80, 52\|	1	4
27 M, FU, no B-sy, n= 74, 45\|	71	41
27 M, FU, one B-syn, n= 74, 45\|	4	3
30 M, FU, no B-sy, n= 70, 35\|	68	33
30 M, FU, one B-sy, n= 70, 35\|	2	2
33 M, FU, no B-sy, n= 66, 29\|	63	27
33 M, FU, one B-sy, n= 66, 29\|	3	2
36 M, FU, one B-sy, n=58, 23\|	2	0
39 M, FU, no B-sy, n=52, 18\|	49	18
39 M, FU, one B-sy, n=52, 18\|	3	0
42 M, FU, no B-sy, n=45, 16\|	45	16
42 M, FU, one B-sy, n=45, 16\|	0	0
45 M, FU, no B-sy, n=n=41, 15\|	41	14
45 M, FU, one B-sy, n=41, 15\|	0	1
48 M, FU, no B-sy, n=37, 13\|	36	13
48 M, FU, one B-sy, n=37, 13\|	1	0
51 M, FU, no B-sy, n=32, 12\|	32	11
51 M, FU, one B-sy, n=32, 12\|	0	1
54 M, FU, no B-sy, n=30, 10\|	30	10
54 M, FU, one B-sy, n=30, 10\|	0	0
57 M, FU, no B-sy, n=26, 9\|	26	9
57 M, FU, one B-sy, n=26, 9\|	0	0
60 M, FU, no B-sy, n=25, 9\|	24	9
60 M, FU, one B-sy, n=25, 9\|	1	0

No statistical analyses for this end point

Secondary: Percentage of participants with the best Overall Response (OR), as assessed by the IRC

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End point title

Percentage of participants with the best Overall Response (OR), as assessed by the IRC

End point description

OR is defined as the number of participants achieving an objective response (complete response [CR], CR with incomplete bone marrow recovery [CRi], partial response [PR], and nodular PR [nPR]). CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly) > 1.5 cm/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils >1500 per microliter (µL), platelets (PL) >100,000/µL, hemoglobin (Hb) >11 grams/deciliter (g/dL), lymphocytes (LC) <4000/µL, bone marrow (BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. PR: >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline (BL), Hb >11 g/dL or 50% improvement over BL. nPR: persistent nodules BM.

End point type

Secondary

End point timeframe

From randomization up to 5 years after last dose of study drug

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Percentage of participants
CR\|	27	7
CRi\|	2	1
nPR\|	0	0
PR\|	55	59
Stable disease\|	11	28
Progressive Disease\|	0	0
Not Evaluable\|	4	2
Missing\|	1	2

Best OR as assessed by IRC

Comparison groups

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects

Number of subjects included in analysis

365

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0003

Method

Cochran-Mantel-Haenszel

Confidence interval

Secondary: Percentage of participants with the best OR, as assessed by the Investigator

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End point title

Percentage of participants with the best OR, as assessed by the Investigator

End point description

End point type

Secondary

End point timeframe

From randomization up to 5 years after last dose of study drug

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Percentage of participants
CR\|	45	24
CRi\|	12	4
nPR\|	2	8
PR\|	107	113
Stable disease\|	9	21
Progressive Disease\|	0	3
Missing\|	8	9
Responder\|	166	149

Best OR as assessed by Investigator

Comparison groups

Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects

Number of subjects included in analysis

365

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0166

Method

Cochran-Mantel-Haenszel

Confidence interval

Secondary: Number of participants who were negative for Minimal Residual Disease (MRD) assessed by IRC

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End point title

Number of participants who were negative for Minimal Residual Disease (MRD) assessed by IRC

End point description

MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR. MRD analysis was performed for the participants who were suspected of achieving a primary endpoint CR. MDR was performed by flow cytometry on a bone marrow or peripheral blood sample taken at least 2 months after final treatment. MRD negative was defined as less than one CLL cell per 10000 leukocytes.

End point type

Secondary

End point timeframe

From randomization up to 5 years after last dose of study drug

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Participants
Screening, n= 46, 13\|	0	0
Cycle 1 Day 1, n= 2, 0\|	0	999
3 M, FU, n= 44, 12\|	21	7
6 M, FU, n= 35, 11\|	25	6
9 M, FU, n= 29, 8\|	20	4
12 M, FU, n= 25, 4\|	16	1
15 M, FU, n= 20, 3\|	14	1
18 M, FU, n= 16, 2\|	12	1
21 M, FU, n= 13, 2\|	9	1
24 M, FU, n= 9, 2\|	8	1
27 M, FU, n= 9, 1\|	8	0
30 M, FU, n= 9, 2\|	8	2
33 M, FU, n= 5, 2\|	3	1
36 M, FU, n= 5, 2\|	5	1
39 M, FU, n= 2, 1\|	2	1
42 M, FU, n= 2, 0\|	2	999
45 M, FU, n= 1, 1\|	1	1
48 M, FU, n= 2, 1\|	2	1
51 M, FU, n= 2, 1\|	2	1
54 M, FU, n= 2, 1\|	2	1

No statistical analyses for this end point

Secondary: Number of participants who were negative for MRD assessed by investigator

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End point title

Number of participants who were negative for MRD assessed by investigator

End point description

End point type

Secondary

End point timeframe

From randomization up to 5 years after last dose of study drug

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Participants
Screening, n= 177, 171\|	0	1
3 M, FU, n= 120, 76\|	39	15
6 M, FU, n= 87, 57\|	48	11
9 M, FU, n= 71, 29\|	35	6
12 M, FU, n= 55, 18\|	31	3
15 M, FU, n= 38, 14\|	23	2
18 M, FU, n= 31, 13\|	20	2
21 M, FU, n= 27, 9\|	16	3
24 M, FU, n= 15, 4\|	13	2
27 M, FU, n= 18, 5\|	14	1
30 M, FU, n= 15, 3\|	12	3
33 M, FU, n= 13, 3\|	8	2
36 M, FU, n= 10, 4\|	9	2
39 M, FU, n= 7, 3\|	6	2
42 M, FU, n= 8, 1\|	7	1
45 M, FU, n= 7, 2\|	6	2
48 M, FU, n= 6, 3\|	6	2
51 M, FU, n= 6, 2\|	5	1
54 M, FU, n= 7, 2\|	4	2
57 M, FU, n= 4, 3\|	3	2
60 M, FU, n= 3, 3\|	3	2

No statistical analyses for this end point

Secondary: Number of participants with any Adverse Event (AE) or Serious Adverse Event (SAE)

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End point title

Number of participants with any Adverse Event (AE) or Serious Adverse Event (SAE)

End point description

End point type

Secondary

End point timeframe

From first dose of study medication to 60 Days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	181	178
Units: Participants
AE\|	170	153
SAE\|	108	86

No statistical analyses for this end point

Secondary: Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result at indicated time points

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End point title

Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result at indicated time points

End point description

Serum samples for analysis of HAHA were collected at Baseline (Screening), after 3 cycles were compelted, after 1 M and 6 M post last dose. All samples were first tested in a screening step; positive samples from the screening were further evaluated in a confirmation test. The confirmed positive samples were reported as HAHA-positive.

End point type

Secondary

End point timeframe

From start of study drug until 60 days after the last dose of study medication

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	181	178
Units: Participants
Screening Visit, n= 179,177\|	8	1
Cycle 4 Day 1, n= 151,130\|	0	2
1 M, FU, n= 148,132\|	0	2
3 M, FU, n= 0,1\|	0	0
6 M, FU, n= 130, 99\|	2	0
9 M, FU, n= 0, 2\|	0	0
30 M, FU, n= 2, 0\|	0	0

No statistical analyses for this end point

Secondary: Number of participants with Autoimmune Hemolytic Anaemia (AIHA)

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End point title

Number of participants with Autoimmune Hemolytic Anaemia (AIHA)

End point description

AIHA is a condition where the body's immune system fails to recognize red blood cells as "self" and begins destroying these red blood cells. The number of participants experienced AIHA are presented.

End point type

Secondary

End point timeframe

From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	181	178
Units: Participants	3	2

No statistical analyses for this end point

Secondary: Mean level of Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM

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End point title

Mean level of Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM

End point description

Immunoglobulins, or antibodies, are large proteins used by the immune system to identify and neutralize foreign particles such as bacteria and viruses. Their normal blood levels indicate proper immune status. Low levels indicate immuno-suppression. Blood samples were collected from each participant and IgA, IgG, and IgM were measured at Baseline, and 1M and 6M after last dose during follow up period.

End point type

Secondary

End point timeframe

Baseline, 1M and 6M follow up

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	181	178
Units: Gram per liter
arithmetic mean (standard deviation)
Cycle 1 Day 1, IgA, n= 179, 175\|	1.0 ( 0.74 )	0.9 ( 0.68 )
Cycle 1 Day 1, IgG, n= 179, 175\|	8.7 ( 5.22 )	8.2 ( 3.86 )
Cycle 1 Day 1, IgM, n= 179, 175\|	0.6 ( 1.36 )	0.8 ( 1.77 )
1 M, FU, IgA, n= 150, 131\|	1.0 ( 0.79 )	1.0 ( 0.77 )
1 M, FU, IgG, n= 150, 131\|	7.9 ( 4.05 )	7.9 ( 3.38 )
1 M, FU, IgM, n= 150, 131\|	0.5 ( 1.16 )	0.8 ( 1.88 )
6 M, FU, IgA, n= 130, 101\|	1.0 ( 0.77 )	1.0 ( 0.76 )
6 M, FU, IgG, n= 130, 101\|	7.8 ( 3.97 )	8.9 ( 4.31 )
6 M, FU, IgM, n= 130, 101\|	0.4 ( 0.50 )	1.1 ( 1.98 )
9 M, FU, IgA, n= 1, 2\|	0.9 ( 999 )	0.9 ( 0.21 )
9 M, FU, IgG, n= 1, 2\|	15.2 ( 999 )	8.8 ( 6.87 )
9 M, FU, IgM, n= 1, 2\|	0.8 ( 999 )	0.2 ( 0.04 )
18 M, FU, IgA, n= 0, 1\|	999 ( 999 )	2.4 ( 999 )
18 M, FU, IgG, n= 0, 1\|	999 ( 999 )	9.1 ( 999 )
18 M, FU, IgM, n= 0, 1\|	999 ( 999 )	1.0 ( 999 )
30 M, FU, IgA, n= 2, 0\|	1.3 ( 1.17 )	999 ( 999 )
30 M, FU, IgG, n= 2, 0\|	4.7 ( 0.33 )	999 ( 999 )
30 M, FU, IgM, n= 2, 0\|	0.4 ( 0.26 )	999 ( 999 )

No statistical analyses for this end point

Secondary: Change from baseline in Cluster of Differentiation (CD) Cell Counts, CD5+ and CD19+

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End point title

Change from baseline in Cluster of Differentiation (CD) Cell Counts, CD5+ and CD19+

End point description

CD5+ and CD19+ cells were counted by flow cytometry at Screening (Baseline) on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 during the treatment period and after last dose of study drug at 1 M and then every three month follow up up to 45 M. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. day 1 if available, otherwise, screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

End point type

Secondary

End point timeframe

Screening, Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and after last dose at 1 M and then every three months up to 45 M during Follow-up Period

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: cells/uL
arithmetic mean (standard deviation)
Cycle 1 Day 1,n=71, 65\|	43180.6 ( 48784.64 )	53208.7 ( 70944.56 )
Cycle 1 Day 15, n= 69, 62\|	2656.9 ( 6418.02 )	9244.0 ( 19610.62 )
Cycle 2 Day 1, n= 68, 63\|	2057.4 ( 5525.72 )	10318.8 ( 21453.15 )
Cycle 2 Day 15, n= 68, 59\|	513.7 ( 1717.65 )	6874.4 ( 20632.64 )
Cycle 3 Day 1,n= 68, 59\|	790.0 ( 2953.42 )	6423.6 ( 19725.57 )
Cycle 4 Day 1, n= 62, 49\|	402.1 ( 1768.74 )	2643.2 ( 8092.22 )
Cycle 5 Day 1,n= 57, 45\|	142.6 ( 472.24 )	2838.6 ( 8314.08 )
Cycle 6 Day 1, n= 56, 39\|	109.8 ( 398.77 )	3862.7 ( 13312.14 )
1 M, FU, n= 64, 61\|	163.5 ( 685.41 )	5514.3 ( 17369.97 )
3 M, FU, n= 69, 47\|	671.3 ( 2786.99 )	2604.9 ( 9229.90 )
6 M, FU, n= 61, 42\|	1591.6 ( 8857.22 )	2275.6 ( 5118.00 )
9 M, FU, n= 56, 37\|	910.5 ( 2495.85 )	3408.4 ( 7438.45 )
12 M, FU, n= 47, 30\|	2303.2 ( 6675.70 )	2876.5 ( 6252.53 )
15 M, FU, n= 35, 18\|	3325.8 ( 8006.48 )	3072.7 ( 9038.23 )
18 M, FU, n= 22, 12\|	1607.5 ( 2935.82 )	4549.8 ( 8839.23 )
21 M, FU, n= 22, 10\|	3830.8 ( 8989.02 )	5236.9 ( 10537.31 )
24 M, FU, n= 9, 6\|	1244.6 ( 1300.01 )	7843.3 ( 11897.55 )
27 M, FU, n= 7, 4\|	1877.4 ( 2117.84 )	6128.0 ( 9161.38 )
30 M, FU, n= 6, 2\|	5029.7 ( 8266.90 )	6515.5 ( 5916.36 )
33 M, FU, n= 4, 1\|	14166.8 ( 20166.09 )	5208.0 ( 999 )
36 M, FU, n= 3, 1\|	1187.0 ( 1407.79 )	8184.0 ( 999 )
39 M, FU, n=1, 0\|	557.0 ( 999 )	999 ( 999 )
42 M, FU, n= 1, 0\|	1640.0 ( 999 )	999 ( 999 )
45 M, FU, n= 2, 0\|	4689.0 ( 1493.41 )	999 ( 999 )
48 M FU, n= 1, 1\|	27755.0 ( 999 )	29155.0 ( 999 )
54 M FU, n= 1, 0\|	189849.0 ( 999 )	999 ( 999 )

No statistical analyses for this end point

Secondary: Change from Baseline in Cell Counts, CD5- CD19+

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End point title

Change from Baseline in Cell Counts, CD5- CD19+

End point description

CD5- CD19+ cells were counted by flow cytometry at Screening (baseline) at Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 during treatment period and after last dose of study drug at 1 M and then every three month up to 45 M during follow up period. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. Day 1 if available otherwise screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

End point type

Secondary

End point timeframe

Screening, Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and after last dose at 1 M and then every three month up to 45 M during Follow-up Period

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	181	178
Units: cells/uL
arithmetic mean (standard deviation)
Screening, n= 71, 62\|	4817.8 ( 20948.17 )	6959.1 ( 39980.14 )
Cycle 1 Day 1,n= 71, 65\|	5996.7 ( 22331.29 )	2041.3 ( 4418.63 )
Cycle 1 Day 15, n= 69, 62\|	239.0 ( 1052.19 )	351.7 ( 1377.56 )
Cycle 2 Day 1, n= 68, 63\|	115.4 ( 403.09 )	465.7 ( 1610.05 )
Cycle 2 Day 15,n= 68, 59\|	35.6 ( 133.75 )	331.3 ( 1177.18 )
Cycle 3 Day 1,n= 68, 59\|	39.5 ( 144.64 )	179.7 ( 520.63 )
Cycle 4 Day 1, n= 62, 49\|	25.7 ( 92.88 )	95.3 ( 369.19 )
Cycle 5 Day 1, n= 57, 45\|	15.9 ( 77.11 )	195.5 ( 945.34 )
Cycle 6 Day 1, n= 56, 39\|	10.0 ( 29.85 )	649.7 ( 3606.28 )
1 M, FU, n= 64, 61\|	7.5 ( 19.54 )	863.8 ( 5001.84 )
3 M, FU, n= 69, 47\|	40.1 ( 238.18 )	172.0 ( 681.28 )
6 M, FU, n= 61, 42\|	21.2 ( 58.16 )	50.7 ( 49.13 )
9 M, FU, n= 56, 37\|	85.7 ( 359.01 )	92.0 ( 101.16 )
12 M, FU, n= 47, 30\|	89.9 ( 226.06 )	220.1 ( 698.57 )
15 M, FU, n= 35, 18\|	67.3 ( 59.52 )	94.6 ( 70.17 )
18 M, FU, n= 22, 12\|	126.1 ( 188.25 )	92.3 ( 69.14 )
21 M, FU, n= 22, 10\|	375.5 ( 1307.35 )	108.3 ( 95.86 )
24 M, FU, n= 9, 6\|	74.0 ( 57.46 )	104.5 ( 70.46 )
27 M, FU, n= 7, 4\|	73.9 ( 60.40 )	187.5 ( 200.85 )
30 M, FU, n= 6, 2\|	74.2 ( 58.82 )	129.5 ( 5303 )
33 M, FU, n= 4, 1\|	41.8 ( 40.13 )	1003.0 ( 999 )
36 M, FU, n= 3, 1\|	107.3 ( 86.75 )	1506.0 ( 999 )
39 M, FU, n= 1, 0\|	13.0 ( 999 )	999 ( 999 )
42 M, FU, n= 1, 0\|	13.0 ( 999 )	999 ( 999 )
45 M, FU, n= 2, 0\|	166.5 ( 222.74 )	999 ( 999 )
48 M, FU, n= 1,1\|	6528.0 ( 999 )	28.0 ( 999 )
54 M, FU, n= 1, 0\|9	690.0 ( 999 )	999 ( 999 )

No statistical analyses for this end point

Secondary: Prognostic and biological markers correlating with clinical response

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End point title

Prognostic and biological markers correlating with clinical response

End point description

Blood samples were collected for the assessment of the following prognostic markers at BL: immunoglobulin heavy chain variable region(IgVH) homology; Zeta-Chain-Associated Protein Kinase 70(ZAP70), VH3-21 usage; Cytogenetics (by fluorescent in situ hybridization [FISH]); beta 2 microglobulin. Cox-regression model was used to explore the relationship between progression-free survival and the following explanatory variables: treatment group, cytogenetics (analyzed by FISH included 6q-,11q-, +12q, 17p-, 13q-) , ZAP-70 (positive, negative or intermediate), VH3-21 usage (Yes and No), IgVH homology (>98%, 97%-98% and <97%), beta 2 microglobulin (>3500 microgram per liter [µg/L] and <=3500 µg/L). For each covariate, a hazard ratio <1 indicates a lower risk on the first effect tested compared with the other effects tested. Cytogenetics Group (based on >=20%)=cytogenetics (CY G).

End point type

Secondary

End point timeframe

From randomization up to 5 years after last dose of study drug

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Participants
B2 Microglobulin G 1: > 3500 μg/L	79	78
B2 Microglobulin G 1: ≤3500 μg/L, n=51,47\|	22	26
CY G 1: 11q-, n=40, 31\|	29	19
CY G 1: 17p-, n=7, 13\|	6	9
CY G 1: 6q- or +12q or 13q-, n=84, 80\|	38	48
CY G 1: no aberration, n=45, 47\|	27	27
VH3-21 Usage Flag: Yes, n=9, 7\|	6	4
VH3-21 Usage Flag: No, n=159, 162\|	93	96
IgVH Homology, <97%, n=40, 43\|	13	15
IgVH Homology, 97%-98%, n=12, 10\|	5	7
IgVH Homology, >98%, n=115, 116\|	80	78
ZAP70 G 1, Negative, n=28, 32\|	14	13
ZAP70 G 1, Intermediate, n=54, 46\|	27	23
ZAP70, G1 Positive, n=94, 91\|	60	65

No statistical analyses for this end point

Secondary: Changes in Patient Reported Outcome (PRO) measures and scores for European organization for research and treatment of cancer quality of life questionnaire, chronic lymphocytic leukaemia 16 item module (EORTC QLQ-CLL 16)

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End point title

Changes in Patient Reported Outcome (PRO) measures and scores for European organization for research and treatment of cancer quality of life questionnaire, chronic lymphocytic leukaemia 16 item module (EORTC QLQ-CLL 16)

End point description

The EORTC QLQ-CLL16 is comprised of 16 questions that address 5 domains of health-related quality of life (HRQoL) important in CLL. There are 4 multi-item scales – fatigue (2 items), treatment side effects ([TSE], 4 items), disease symptoms (disease effects scale [DES], 4 items), and infection scale [IS] (4 items) – and single item scales (social activities [Social Problems (SP) Scale] and future health worries[Future Health (FH) Scale].). These are measured on a four point scale where 1 = not at all and 4 = very much. These scores are transformed to give a rating from 0 – 100, where 0 =no symptoms or problems and 100 = a severe symptoms or problems. EORTC QLQ-CLL16 was assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value was obtained at randomization.

End point type

Secondary

End point timeframe

Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: scores on a scale
arithmetic mean (standard deviation)
FH, 18 M, FU, n=90, 58\|	-15.9 ( 31.69 )	-18.4 ( 33.72 )
DES, Cycle 4 Day 1, n=142,125\|	-8.5 ( 18.08 )	-9.0 ( 17.16 )
DES, 1 M, FU, n=138, 123\|	-9.7 ( 19.18 )	-9.8 ( 19.89 )
DES, 3 M, FU, n=145, 109\|	-8.2 ( 19.48 )	-10.9 ( 19.07 )
DES, 6 M, FU, n= 126, 99\|	-9.8 ( 17.99 )	-11.6 ( 18.05 )
DES, 9 M, FU, n=115, 85\|	-8.2 ( 20.70 )	-12.0 ( 17.04 )
DES. 12 M, FU, n=109, 76\|	-10.1 ( 18.64 )	-10.2 ( 16.09 )
DES, 15 M, FU, n=98, 62\|	-8.6 ( 18.08 )	-10.2 ( 16.91 )
DES, 18 M, FU, n=90, 59\|	-8.5 ( 18.53 )	-11.6 ( 18.79 )
DES, 21 M, FU, n=87, 53\|	-8.2 ( 18.48 )	-11.3 ( 17.60 )
DES, 24 M, FU, n=70, 50\|	-7.1 ( 19.93 )	-13.6 ( 16.18 )
Fatigue Scale (FS), Cycle 4 Day 1, n=142, 125\|	-7.0 ( 22.57 )	-7.1 ( 24.16 )
FS, 1 M, FU, n=139, 123\|	-5.4 ( 29.16 )	-6.2 ( 28.74 )
FS, 3 M, FU, n=144, 109\|	-4.4 ( 26.30 )	-8.3 ( 30.14 )
FS, 6 M, FU, n=126, 99\|	-7.1 ( 25.94 )	-12.0 ( 25.98 )
FS, 9 M, FU, n= 115, 85\|	-6.2 ( 27.08 )	-10.6 ( 26.95 )
FS. 12 M, FU, n=109, 76\|	-7.3 ( 27.26 )	-8.1 ( 25.75 )
FS, 15 M, FU, n=97, 62\|	-7.6 ( 22.57 )	-9.9 ( 24.04 )
FS, 18 M, FU, n=90,59\|	-7.0 ( 23.03 )	-3.7 ( 33.34 )
FS, 21 M, FU, n=87, 53\|	-10.3 ( 24.28 )	-8.2 ( 27.27 )
FS, 24 M, FU, n=69, 50\|	-8.7 ( 24.19 )	-8.7 ( 25.48 )
FH, Cycle 4 Day 1, n=141, 123\|	-11.8 ( 32.89 )	-10.6 ( 27.76 )
FH, 1 M, FU, n=139, 120\|	-15.3 ( 35.04 )	-11.9 ( 29.56 )
FH, 3 M, FU, n=145, 107\|	-14.3 ( 33.96 )	-14.0 ( 32.06 )
FH, 6 M, FU, n=126, 96\|	-13.4 ( 33.98 )	-17.7 ( 30.57 )
FH, 9 M, FU, n=113, 81\|	-15.6 ( 33.65 )	-13.2 ( 34.43 )
FH. 12 M, FU, n=109, 74\|	-14.1 ( 32.80 )	-14.9 ( 33.63 )
FH, 15 M, FU, n=98, 61\|	-14.6 ( 29.14 )	-14.2 ( 34.13 )
FH, 21 M, FU, n=87, 52\|	-16.9 ( 28.70 )	-15.4 ( 29.12 )
FH, 24 M, FU, n=70, 49\|	-21.0 ( 29.58 )	-17.7 ( 30.51 )
IS, Cycle 4 Day 1, n=142,125\|	0.5 ( 17.65 )	-1.4 ( 18.23 )
IS, 1 M, FU, n=138, 122\|	2.9 ( 22.79 )	2.7 ( 24.06 )
IS, 3 M, FU, n=144, 109\|	0.8 ( 19.42 )	0.8 ( 20.99 )
IS, 6 M, FU, n=126, 99\|	-1.2 ( 18.46 )	-0.9 ( 20.40 )
IS, 9 M, FU, n=115, 85\|	-1.4 ( 18.81 )	1.4 ( 22.45 )
IS. 12 M, FU, n=109, 76\|	0.4 ( 19.22 )	2.1 ( 20.92 )
IS, 15 M, FU, n=97, 60\|	0.5 ( 17.56 )	0.3 ( 18.79 )
IS, 18 M, FU, n=89, 59\|	-2.0 ( 16.04 )	0.9 ( 19.04 )
IS, 21 M, FU, n=87, 53\|	-2.5 ( 18.13 )	2.5 ( 22.09 )
IS, 24 M, FU, n=69, 49\|	-0.5 ( 18.85 )	0.5 ( 21.34 )
SP Scale Cycle 4 Day 1, n=141, 125\|	1.9 ( 25.44 )	0.3 ( 26.94 )
SP Scale, 1 M, FU, n=137, 121\|	3.2 ( 34.51 )	0.0 ( 35.22 )
SP Scale, 3 M, FU, n=143, 109\|	-1.9 ( 33.04 )	-4.3 ( 35.75 )
SP Scale, 6 M, FU, n=124, 98\|	-5.6 ( 31.73 )	-10.9 ( 30.56 )
SP Scale, 9 M, FU, n=114, 85\|	-5.0 ( 30.15 )	-11.0 ( 31.45 )
SP Scale. 12 M, FU, n=107, 75\|	-7.2 ( 31.06 )	-7.6 ( 34.47 )
SP Scale, 15 M, FU, n=95, 61\|	-6.7 ( 30.21 )	-13.7 ( 30.05 )
SP Scale, 18 M, FU, n=89, 59\|	-7.1 ( 31.57 )	-8.5 ( 40.40 )
SP Scale, 21 M, FU, n=86, 53\|	-8.1 ( 31.07 )	-7.5 ( 37.92 )
SP Scale, 24 M, FU, n=68, 50\|	-11.8 ( 24.27 )	-8.7 ( 36.15 )
TSE, Cycle 4 Day 1, n=142, 125\|	-4.7 ( 16.15 )	-4.0 ( 16.78 )
TSE, 1 M, FU, n=139, 123\|	-5.0 ( 18.09 )	-3.2 ( 19.08 )
TSE, 3 M, FU, n=145,109\|	-3.7 ( 19.41 )	-4.3 ( 17.03 )
TSE, 6 M, FU, n=126, 99\|	-6.0 ( 15.25 )	-4.8 ( 16.96 )
TSE, 9 M, FU, n=115, 85\|	-4.3 ( 17.22 )	-5.1 ( 16.38 )
TSE. 12 M, FU, n=109, 76\|	-5.2 ( 16.44 )	-3.2 ( 13.94 )
TSE, 15 M, FU, n=98, 62\|	-4.0 ( 14.92 )	-4.2 ( 13.73 )
TSE, 18 M, FU, n=90, 60\|	-4.4 ( 17.10 )	-3.6 ( 19.18 )
TSE, 21 M, FU, n=87, 54\|	-4.7 ( 16.63 )	-4.0 ( 15.91 )
TSE, 24 M, FU, n=70, 50\|	-5.4 ( 17.52 )	-6.5 ( 14.12 )

No statistical analyses for this end point

Secondary: Change from Baseline in Patient Reported Outcome (PRO) as assessed by EuroQoL Five-Dimension (EQ-5D) score at indicated visit

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End point title

Change from Baseline in Patient Reported Outcome (PRO) as assessed by EuroQoL Five-Dimension (EQ-5D) score at indicated visit

End point description

EQ-5D is comprised of a 5-item health status measure and a visual analogue scale (VAS) and is used to generate two scores: the utility score and the thermometer score. The utility score measures mobility, self-care, usual activities, pain, discomfort, and anxiety/depression. Responses to each of the 5 health states are measured on a 3-point scale (level 1 = no problem; level 2 = some or moderate problem(s) and level 3 = unable, or extreme problems). Responses are typically converted into health utilities or valuations on a scale ranging from 0 (death) to 1 (perfect health). The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A Negative health status describes health state worse than death.Baseline is the most recent, non-missing value prior to or on the first study drug dose date.

End point type

Secondary

End point timeframe

Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Score on a scale
arithmetic mean (standard deviation)
UT, Cycle 4 Day 1, n=136, 121\|	0.0 ( 0.27 )	0.0 ( 0.21 )
UT, 1 M, FU, n=133, 117\|	0.1 ( 0.22 )	0.0 ( 0.28 )
UT, 3 M, FU, n=141, 102\|	0.0 ( 0.27 )	0.1 ( 0.23 )
UT, 6 M, FU, n=122, 96\|	0.1 ( 0.24 )	0.1 ( 0.24 )
UT, 9 M, FU, n=110, 81\|	0.1 ( 0.26 )	0.1 ( 0.24 )
UT. 12 M, FU, n=107, 71\|	0.1 ( 0.21 )	0.1 ( 0.22 )
UT, 15 M, FU, n=96, 58\|	0.0 ( 0.23 )	0.1 ( 0.24 )
UT, 18 M, FU, n=88, 57\|	0.1 ( 0.21 )	0.0 ( 0.34 )
UT, 21 M, FU, n= 87, 52\|	0.1 ( 0.21 )	0.1 ( 0.26 )
UT, 24 M, FU, n=68, 47\|	0.1 ( 0.19 )	0.1 ( 0.28 )
VAS Cycle 4 Day 1, n=137, 122\|	6.1 ( 17.68 )	5.6 ( 17.64 )
VAS, 1 M, FU, n=138, 122\|	5.6 ( 20.73 )	5.9 ( 22.83 )
VAS, 3 M, FU, n=141, 107\|	5.7 ( 19.92 )	9.6 ( 20.88 )
VAS, 6 M, FU, n=124, 99\|	8.2 ( 18.84 )	11.1 ( 19.08 )
VAS, 9 M, FU, n=114, 85\|	8.1 ( 18.33 )	11.9 ( 20.59 )
VAS. 12 M, FU, n=108, 75\|	7.0 ( 21.93 )	10.3 ( 21.21 )
VAS, 15 M, FU, n=95, 62\|	8.0 ( 17.52 )	13.1 ( 21.06 )
VAS, 18 M, FU, n=89, 60\|	9.4 ( 17.86 )	11.1 ( 25.40 )
VAS, 21 M, FU, n=87, 53\|	8.1 ( 16.42 )	11.3 ( 24.16 )
VAS, 24 M, FU, n=69, 50\|	8.8 ( 19.50 )	15.2 ( 21.88 )

No statistical analyses for this end point

Secondary: Change from baseline in the European organization for the research and treatment of cancer quality of life questionnaire core 30 (EORTC QLQ-C30) score

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End point title

Change from baseline in the European organization for the research and treatment of cancer quality of life questionnaire core 30 (EORTC QLQ-C30) score

End point description

EORTC QLQ-C30, a self-reported, cancer-specific instrument assessing 15 domains: physical, role, emotional, cognitive and social functioning, pain,fatigue, nausea and vomiting, insomnia, loss of appetite, constipation, diarrhea, and dyspnea, financial difficulties and a global health status/quality of life (QOF). Functional and symptoms scales were measured on four point Likert scale where 1 = not at all and 4 = very much. Pat. assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Clinically meaningful changes or minimally important differences (MIDs)have been previously established for the EORTC QLQ C30, and categorized as ‘small’ if the mean change in scores is 5-10 points, ‘moderate’ if 10-20 points, and ‘large’ if >20points.

End point type

Secondary

End point timeframe

Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Scores on a scale
arithmetic mean (standard deviation)
Diarrhoea, 6 M, FU, n=124, 98\|	0.0 ( 20.38 )	-3.1 ( 16.64 )
Financial Difficulties, 6 M, FU, n=126, 98\|	-5.8 ( 24.61 )	-8.8 ( 26.89 )
Global Health Status, 6 M, FU, n=125, 97\|	7.5 ( 21.57 )	13.7 ( 23.01 )
Appetite Loss, Cycle 4 Day 1, n=140, 124\|	0.5 ( 25.60 )	-1.9 ( 26.65 )
Appetite Loss, 1 M, FU, n=136, 119\|	-0.2 ( 26.14 )	-3.9 ( 28.52 )
Appetite Loss, 3 M, FU, n=142, 108\|	-0.7 ( 26.77 )	-7.4 ( 28.22 )
Appetite Loss, 6 M, FU, n=123, 97\|	-6.0 ( 23.00 )	-12.4 ( 26.05 )
Appetite Loss, 9 M, FU, n=112, 83\|	-3.9 ( 20.38 )	-9.6 ( 25.25 )
Appetite Loss. 12 M, FU, n=107, 72\|	-4.0 ( 22.76 )	-6.0 ( 27.59 )
Appetite Loss, 15 M, FU, n=96, 60\|	-3.8 ( 23.13 )	-9.4 ( 28.19 )
Appetite Loss, 18 M, FU, n=89, 60\|	-7.9 ( 20.11 )	-9.4 ( 30.12 )
Appetite Loss, 21 M, FU, n=87, 52\|	-3.4 ( 20.36 )	-7.7 ( 27.70 )
Appetite Loss, 24 M, FU, n=69, 48\|	-3.9 ( 22.53 )	-12.5 ( 29.68 )
Cognitive Functioning, Cycle 4 Day 1, n=142, 126\|	3.4 ( 18.25 )	2.5 ( 18.39 )
Cognitive Functioning, 1 M, FU, n=139, 122\|	-0.4 ( 18.40 )	3.0 ( 19.87 )
Cognitive Functioning, 3 M, FU, n= 145, 109\|	0.0 ( 18.74 )	2.3 ( 21.69 )
Cognitive Functioning, 6 M, FU, n=126, 99\|	1.7 ( 18.95 )	2.7 ( 20.99 )
Cognitive Functioning, 9 M, FU, n=115, 85\|	-0.6 ( 20.58 )	2.4 ( 19.61 )
Cognitive Functioning. 12 M, FU, n=110, 76\|	-2.1 ( 19.17 )	-1.8 ( 21.36 )
Cognitive Functioning, 15 M, FU, n=97, 62\|	-1.0 ( 17.97 )	0.3 ( 20.58 )
Cognitive Functioning, 18 M, FU, n=89, 61\|	-0.9 ( 20.00 )	-0.3 ( 22.67 )
Cognitive Functioning, 21 M, FU, n=88, 53\|	-1.9 ( 21.65 )	-1.9 ( 21.84 )
Cognitive Functioning, 24 M, FU, n=70, 50\|	1.0 ( 20.83 )	-1.3 ( 21.25 )
Constipation, Cycle 4 Day 1, n=142, 126\|	2.1 ( 21.46 )	0.8 ( 18.60 )
Constipation, 1 M, FU, n=139, 122\|	-0.7 ( 19.02 )	0.3 ( 18.92 )
Constipation, 3 M, FU, n= 145, 109\|	-2.1 ( 19.33 )	-0.9 ( 20.01 )
Constipation, 6 M, FU, n=125, 98\|	-3.5 ( 19.32 )	0.3 ( 18.22 )
Constipation, 9 M, FU, n=115, 85\|	-1.2 ( 19.71 )	0.4 ( 18.18 )
Constipation. 12 M, FU, n=109, 76\|	-0.0 ( 23.13 )	0.4 ( 19.24 )
Constipation, 15 M, FU, n=96, 62\|	-1.7 ( 21.29 )	-3.8 ( 20.11 )
Constipation, 18 M, FU, n=90, 61\|	-0.4 ( 21.49 )	-1.1 ( 24.32 )
Constipation, 21 M, FU, n=87, 53\|	-1.9 ( 22.93 )	-3.8 ( 23.26 )
Constipation, 24 M, FU, n=70, 50\|	0.0 ( 21.23 )	-3.3 ( 21.56 )
Diarrhoea, Cycle 4 Day 1,n= 141, 125\|	0.2 ( 19.72 )	-2.4 ( 17.54 )
Diarrhoea, 1 M, FU, n=135, 121\|	-3.5 ( 20.87 )	0.8 ( 21.28 )
Diarrhoea, 3 M, FU, n=143, 109\|	1.6 ( 22.49 )	1.5 ( 20.98 )
Diarrhoea, 9 M, FU, n=114, 85\|	0.3 ( 20.56 )	-2.7 ( 17.97 )
Diarrhoea. 12 M, FU, n=108, 76\|	-3.4 ( 15.75 )	-2.2 ( 19.12 )
Diarrhoea, 15 M, FU, n=96, 61\|	-1.7 ( 19.57 )	-4.4 ( 20.62 )
Diarrhoea, 18 M, FU, n=89, 61\|	-1.9 ( 17.67 )	-1.1 ( 17.18 )
Diarrhoea, 21 M, FU, n=87, 53\|	-2.3 ( 18.88 )	0.6 ( 21.17 )
Diarrhoea, 24 M, FU, n=68, 50\|	-2.9 ( 17.02 )	-0.7 ( 20.75 )
Dyspnoea Cycle 4 Day 1,n= 138, 124\|	-4.6 ( 22.85 )	-4.6 ( 23.41 )
Dyspnoea, 1 M, FU, n=139, 121\|	-1.0 ( 26.60 )	-2.8 ( 25.67 )
Dyspnoea, 3 M, FU, n=141, 108\|	-3.1 ( 26.40 )	-1.5 ( 25.53 )
Dyspnoea, 6 M, FU, n=124, 97\|	-2.7 ( 21.92 )	-7.2 ( 24.17 )
Dyspnoea, 9 M, FU, n=113, 83\|	-2.7 ( 26.03 )	-6.4 ( 23.55 )
Dyspnoea. 12 M, FU, n=108, 73\|	-3.4 ( 24.52 )	-4.1 ( 22.87 )
Dyspnoea, 15 M, FU, n=95, 60\|	-2.5 ( 20.77 )	-2.2 ( 26.66 )
Dyspnoea, 18 M, FU, n=90, 59\|	-3.0 ( 24.81 )	-2.8 ( 29.22 )
Dyspnoea, 21 M, FU, n=87, 52\|	-3.4 ( 24.92 )	-1.9 ( 21.30 )
Dyspnoea, 24 M, FU, n=69, 49\|	-2.4 ( 26.39 )	-4.8 ( 24.53 )
Emotional Functioning Cycle 4 Day 1, n=142, 125\|	4.4 ( 17.91 )	5.4 ( 19.59 )
Emotional Functioning, 1 M, FU, n=139, 122\|	5.4 ( 20.26 )	7.2 ( 24.08 )
Emotional Functioning, 3 M, FU, n=145, 109\|	5.7 ( 20.93 )	7.8 ( 20.90 )
Emotional Functioning, 6 M, FU, n=126, 99\|	4.8 ( 22.57 )	8.9 ( 22.34 )
Emotional Functioning, 9 M, FU, n=115, 85\|	3.4 ( 22.95 )	6.7 ( 18.52 )
Emotional Functioning. 12 M, FU, n=110, 76\|	3.9 ( 22.11 )	8.0 ( 21.92 )
Emotional Functioning, 15 M, FU, n=98, 62\|	5.1 ( 21.54 )	6.5 ( 21.15 )
Emotional Functioning, 18 M, FU, n=90, 61\|	5.1 ( 22.94 )	6.5 ( 26.35 )
Emotional Functioning, 21 M, FU, n=88, 52\|	5.3 ( 22.43 )	7.7 ( 23.56 )
Emotional Functioning, 24 M, FU, n=70, 50\|	7.1 ( 23.02 )	7.1 ( 26.16 )
Fatigue Cycle 4 Day 1, n=142, 126\|	-4.3 ( 21.37 )	-6.3 ( 22.66 )
Fatigue, 1 M, FU, n=138, 122\|	-7.4 ( 25.16 )	-4.5 ( 28.64 )
Fatigue, 3 M, FU, n=145, 109\|	-5.4 ( 24.01 )	-9.3 ( 27.83 )
Fatigue, 6 M, FU, n=126, 99\|	-8.2 ( 23.64 )	-12.2 ( 22.43 )
Fatigue, 9 M, FU, n=115, 86\|	-8.8 ( 23.80 )	-9.8 ( 24.56 )
Fatigue. 12 M, FU, n=110, 76\|	-6.8 ( 25.28 )	-10.3 ( 23.44 )
Fatigue, 15 M, FU, n=97, 76\|	-7.6 ( 19.83 )	-8.9 ( 27.61 )
Fatigue, 18 M, FU, n=90, 62\|	-7.0 ( 22.25 )	-6.1 ( 30.15 )
Fatigue, 21 M, FU, n=88, 53\|	-9.6 ( 20.44 )	-9.1 ( 25.34 )
Fatigue, 24 M, FU, n=70, 50\|	-9.1 ( 23.01 )	-11.7 ( 25.30 )
Financial Difficulties Cycle 4 Day 1, n=141, 126\|	-4.5 ( 23.98 )	-6.1 ( 29.93 )
Financial Difficulties, 1 M, FU, n=136, 122\|	-5.9 ( 26.57 )	-5.2 ( 26.07 )
Financial Difficulties, 3 M, FU, n=145, 108\|	-4.1 ( 28.30 )	-9.0 ( 29.40 )
Financial Difficulties, 9 M, FU, n=114, 84\|	-6.1 ( 27.54 )	-8.7 ( 27.44 )
Financial Difficulties. 12 M, FU, n=110, 76\|	-6.4 ( 24.93 )	-9.6 ( 28.71 )
Financial Difficulties, 15 M, FU, n=96, 62\|	-8.3 ( 23.69 )	-9.7 ( 27.91 )
Financial Difficulties, 18 M, FU, n=90, 60\|	-4.1 ( 24.39 )	-12.2 ( 30.04 )
Financial Difficulties, 21 M, FU, n=88, 51\|	-10.6 ( 22.34 )	-11.1 ( 28.02 )
Financial Difficulties, 24 M, FU, n=70, 50\|	-6.2 ( 24.93 )	-12.0 ( 27.57 )
Nausea and Vomiting Cycle 4 Day 1, n=142, 126\|	2.0 ( 16.06 )	3.7 ( 18.37 )
Nausea and Vomiting, 1 M, FU, n=139, 122\|	1.0 ( 14.85 )	0.1 ( 19.22 )
Nausea and Vomiting, 3 M, FU, n=145, 109\|	0.1 ( 15.90 )	-2.9 ( 14.49 )
Nausea and Vomiting, 6 M, FU, n=126, 99\|	-2.8 ( 13.12 )	-2.5 ( 14.36 )
Nausea and Vomiting, 9 M, FU, n=115, 86\|	-1.3 ( 13.81 )	-1.2 ( 15.08 )
Nausea and Vomiting. 12 M, FU, n=110, 76\|	-2.9 ( 13.52 )	-1.8 ( 12.35 )
Nausea and Vomiting, 15 M, FU, n=97, 62\|	-3.3 ( 11.45 )	-2.7 ( 11.76 )
Nausea and Vomiting, 18 M, FU, n=90, 61\|	-3.3 ( 12.03 )	-2.5 ( 10.02 )
Nausea and Vomiting, 21 M, FU, n=88, 53\|	-4.0 ( 13.37 )	1.3 ( 11.72 )
Nausea and Vomiting, 24 M, FU, n=70, 50\|	-2.4 ( 13.69 )	-0.3 ( 11.90 )
Pain Cycle 4 Day 1, n=142, 126\|	-3.6 ( 20.64 )	-4.2 ( 20.43 )
Pain, 1 M, FU, n=139, 122\|	-2.8 ( 23.02 )	-5.5 ( 22.31 )
Pain, 3 M, FU, n=145, 109\|	-3.8 ( 25.13 )	-2.1 ( 24.44 )
Pain, 6 M, FU, n=126, 99\|	-5.3 ( 23.54 )	-6.6 ( 20.59 )
Pain, 9 M, FU, n=115, 86\|	-4.2 ( 23.86 )	-4.8 ( 22.12 )
Pain. 12 M, FU, n=110, 76\|	-3.5 ( 24.43 )	-3.7 ( 21.01 )
Pain, 15 M, FU, n=98, 62\|	-2.9 ( 23.08 )	-3.5 ( 22.00 )
Pain, 18 M, FU, n=90, 61\|	-3.3 ( 19.39 )	0.5 ( 28.05 )
Pain, 21 M, FU, n=88, 53\|	-5.9 ( 19.74 )	-0.9 ( 25.82 )
Pain, 24 M, FU, n=70, 50\|	-1.7 ( 23.25 )	-3.0 ( 24.67 )
Physical Functioning Cycle 4 Day 1, n=141, 124\|	1.2 ( 14.50 )	0.6 ( 16.81 )
Physical Functioning, 1 M, FU, n=139, 122\|	0.4 ( 19.52 )	-0.7 ( 21.15 )
Physical Functioning, 3 M, FU, n=142, 108\|	0.9 ( 18.66 )	0.9 ( 19.68 )
Physical Functioning, 6 M, FU, n=124, 98\|	3.2 ( 16.41 )	5.7 ( 17.01 )
Physical Functioning, 9 M, FU, n=113, 83\|	3.9 ( 17.30 )	6.2 ( 17.25 )
Physical Functioning. 12 M, FU, n=109, 73\|	2.4 ( 17.98 )	3.5 ( 17.52 )
Physical Functioning, 15 M, FU, n=96, 60\|	3.8 ( 14.65 )	2.7 ( 18.46 )
Physical Functioning, 18 M, FU, n=90, 60\|	4.1 ( 16.65 )	0.1 ( 22.09 )
Physical Functioning, 21 M, FU, n=88, 52\|	4.7 ( 17.14 )	2.1 ( 18.88 )
Physical Functioning, 24 M, FU, n=69, 49\|	5.3 ( 17.44 )	3.7 ( 20.57 )
Global Health Status Cycle 4 Day 1, n=140, 122\|	6.4 ( 23.46 )	6.8 ( 17.54 )
Global Health Status, 1 M, FU, n=136, 119\|	6.5 ( 24.23 )	6.9 ( 26.32 )
Global Health Status, 3 M, FU, n=142, 105\|	5.0 ( 21.45 )	12.3 ( 21.15 )
Global Health Status, 9 M, FU, n=112, 83\|	7.6 ( 23.24 )	11.7 ( 22.35 )
Global Health Status. 12 M, FU, n=110, 74\|	7.6 ( 23.64 )	12.2 ( 21.77 )
Global Health Status, 15 M, FU, n=93, 61\|	7.6 ( 20.40 )	12.7 ( 22.29 )
Global Health Status, 18 M, FU, n= 89, 60\|	9.2 ( 23.03 )	10.4 ( 27.00 )
Global Health Status, 21 M, FU, n=87, 53\|	10.8 ( 20.26 )	12.7 ( 21.53 )
Global Health Status, 24 M, FU, n=68, 48\|	12.1 ( 24.28 )	12.3 ( 24.31 )
Role Functioning Cycle 4 Day 1,n=140, 124\|	1.4 ( 23.27 )	0.1 ( 24.83 )
Role Functioning, 1 M, FU, n= 138, 120\|	-0.1 ( 25.83 )	-0.7 ( 27.53 )
Role Functioning, 3 M, FU, n=141, 107\|	0.5 ( 25.19 )	0.9 ( 28.94 )
Role Functioning, 6 M, FU, n=124, 97\|	4.3 ( 25.49 )	5.5 ( 26.54 )
Role Functioning, 9 M, FU, n=113, 83\|	4.1 ( 26.21 )	6.2 ( 25.60 )
Role Functioning. 12 M, FU, n=109, 72\|	2.1 ( 26.46 )	3.9 ( 24.78 )
Role Functioning, 15 M, FU, n=96, 60\|	3.8 ( 24.84 )	1.9 ( 25.13 )
Role Functioning, 18 M, FU, n=90, 60\|	7.0 ( 24.09 )	-0.0 ( 28.95 )
Role Functioning, 21 M, FU, n=88, 51\|	5.3 ( 22.82 )	2.6 ( 26.74 )
Role Functioning, 24 M, FU, n=69, 49\|	5.8 ( 25.54 )	3.7 ( 30.10 )
Social Functioning Cycle 4 Day 1, n=142, 126\|	3.1 ( 20.30 )	-0.9 ( 23.50 )
Social Functioning, 1 M, FU, n=138, 122\|	0.4 ( 25.98 )	0.8 ( 27.93 )
Social Functioning, 3 M, FU, n=145, 109\|	0.8 ( 23.76 )	4.3 ( 26.29 )
Social Functioning, 6 M, FU, n= 126, 99\|	3.4 ( 22.04 )	6.1 ( 26.24 )
Social Functioning, 9 M, FU, n=115, 84\|	2.3 ( 21.84 )	4.2 ( 25.46 )
Social Functioning. 12 M, FU, n= 110, 76\|	3.0 ( 23.04 )	3.3 ( 21.95 )
Social Functioning, 15 M, FU, n=96, 62\|	6.2 ( 18.30 )	1.6 ( 27.61 )
Social Functioning, 18 M, FU, n=90, 61\|	6.5 ( 19.78 )	2.7 ( 29.69 )
Social Functioning, 21 M, FU, n=88, 52\|	6.6 ( 18.83 )	4.5 ( 24.72 )
Social Functioning, 24 M, FU, n=70, 50\|	7.9 ( 19.60 )	7.7 ( 24.56 )
Insomnia Cycle 4 Day 1, n=138, 123\|	-3.1 ( 26.07 )	-8.7 ( 26.94 )
Insomnia, 1 M, FU, n=135, 120\|	-5.9 ( 29.04 )	-11.1 ( 27.78 )
Insomnia, 3 M, FU, n=139, 108\|	-6.2 ( 29.64 )	-13.3 ( 28.07 )
Insomnia, 6 M, FU, n=121, 98\|	-5.2 ( 26.18 )	-17.0 ( 25.88 )
Insomnia, 9 M, FU, n=112, 81\|	-3.0 ( 30.53 )	-13.2 ( 31.04 )
Insomnia. 12 M, FU, n=106, 73\|	-6.9 ( 25.91 )	-10.5 ( 29.33 )
Insomnia, 15 M, FU, n=96, 59\|	-5.9 ( 29.02 )	-17.5 ( 26.52 )
Insomnia, 18 M, FU, n=89, 59\|	-7.5 ( 28.32 )	-15.3 ( 28.58 )
Insomnia, 21 M, FU, n=86, 52\|	-8.5 ( 25.15 )	-10.3 ( 34.64 )
Insomnia, 24 M, FU, n=68, 49\|	-1.5 ( 33.30 )	-13.6 ( 35.95 )

No statistical analyses for this end point

Secondary: Mean of Health Change Questionnaire (HCQ)

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End point title

Mean of Health Change Questionnaire (HCQ)

End point description

The HCQ consists of a single question in which the participant is asked if he/she has experienced any change in his/her health overall since beginning the study. For HCQ, values from 1 to 9 were assigned to the 9 responses in the HCQ questionnaire, ranging from 1 for ‘my health is a great deal better’ to 9 for ‘my health is a great deal worse’ since the beginning of the study. Lower scores represent better conditions.

End point type

Secondary

End point timeframe

Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183	182
Units: Unit on a scale
arithmetic mean (standard deviation)
Cycle 4 Day 1, n=139, 124\|	2.6 ( 1.62 )	2.8 ( 1.59 )
1 M, FU, n=138, 121\|	3.0 ( 2.05 )	3.2 ( 2.30 )
3 M, FU, n=141, 108\|	3.0 ( 2.11 )	2.8 ( 1.86 )
6 M, FU, n=124, 98\|	2.6 ( 1.76 )	2.6 ( 1.82 )
9 M, FU, n=112, 85\|	2.5 ( 1.78 )	2.4 ( 1.57 )
12 M, FU, n=108, 74\|	2.5 ( 1.80 )	2.5 ( 1.78 )
15 M, FU, n=96, 61\|	2.2 ( 1.57 )	2.3 ( 1.68 )
18 M, FU, n=88, 58\|	2.4 ( 1.67 )	2.7 ( 2.01 )
21 M, FU, n= 87, 52\|	2.3 ( 1.50 )	2.3 ( 1.52 )
24 M, FU, n=69, 49\|	2.3 ( 1.76 )	2.6 ( 1.89 )

No statistical analyses for this end point

Secondary: Mean area under the time-concentration curve (AUC) curve over the dosing interval (AUC[0-tau]) of ofatumumab

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End point title

Mean area under the time-concentration curve (AUC) curve over the dosing interval (AUC[0-tau]) of ofatumumab ^[3]

End point description

Area under the time-concentration curve (AUC) over the dosing interval (AUC[0-tau]) was evaluated. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).

End point type

Secondary

End point timeframe

Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5,6

Notes
[3] - 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

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183
Units: hournanogram/mililiter (hng/mL)
geometric mean (confidence interval 95%)
cycle 1, week 1, n=158\|	3554.910 (3224.844 to 3918.759)
cycle 1, week 2, n=129\|	34109.67 (30042.08 to 38728.00)
cycle 2, n=147\|	67069.79 (59485.45 to 75621.13)
cycle 3, n=129\|	84620.05 (76209.86 to 93958.35)
cycle 4, 107\|	89091.35 (78326.34 to 101335.9)
cycle 5, n=97\|	96829.23 (84488.81 to 110972.1)
cycle 6, n=91\|	104798.0 (90904.74 to 120814.6)

No statistical analyses for this end point

Secondary: Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) of Ofatumumab

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End point title

Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) of Ofatumumab ^[4]

End point description

Blood samples were collected to assess the plasma concentration of ofatumumab.Cmax and Ctrough were determined. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).

End point type

Secondary

End point timeframe

Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5

Notes
[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: descriptive statistics

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183
Units: Micrograms per milliliter
geometric mean (confidence interval 95%)
Cmax cycle 1, week 1, n=154\|	61.355 (55.444 to 67.897)
Cmax cycle 1, week 2, n=159\|	241.192 (210.492 to 276.369)
Cmax cycle 4, n=140\|	312.745 (287.708 to 339.961)
Ctrough cycle 1, week 1, n=167\|	3.551 (2.417 to 5.217)
Ctrough cycle 1, week 2, n=165\|	9.496 (6.565 to 13.736)
Ctrough cycle 2, n=162\|	24.281 (17.953 to 32.840)
Ctrough cycle 3,n=150\|	25.632 (18.884 to 34.791)
Ctrough cycle 4,n=130\|	58.640 (44.465 to 77.333)
Ctrough cycle 5, n=113\|	70.398 (55.257 to 89.686)

No statistical analyses for this end point

Secondary: Time of occurrence of Cmax (Tmax) of ofatumumab

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End point title

Time of occurrence of Cmax (Tmax) of ofatumumab ^[5]

End point description

Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4.

End point type

Secondary

End point timeframe

Cycle 1 Week 1, Cycle 1 Week 2, Cycle 4

Notes
[5] - 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

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	183
Units: Hour
geometric mean (confidence interval 95%)
cycle 1, week 1,n=154\|	6.106 (5.789 to 6.442)
cycle 1, week 2, n=159\|	5.004 (4.896 to 5.114)
cycle 4, n=140\|	4.878 (4.661 to 5.105)

No statistical analyses for this end point

Secondary: Number of participants with drug related infections reported as AEs and SAEs of maximum severity of Grade 3 or Higher

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End point title

Number of participants with drug related infections reported as AEs and SAEs of maximum severity of Grade 3 or Higher

End point description

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Maximum severity grades were evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).

End point type

Secondary

End point timeframe

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	181	178
Units: Participants
AE\|	19	11
SAE\|	25	21

No statistical analyses for this end point

Secondary: Number of participants who received no transfusion or at Least one transfusion during the study

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End point title

Number of participants who received no transfusion or at Least one transfusion during the study

End point description

Participants who received no transfusion and at least one transfusion during the study are presented. Participants who took any blood products or blood supportive care product are included.

End point type

Secondary

End point timeframe

From randomization up to 5 years after last dose of study drug

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	181	178
Units: Participants
At least one transfusion\|	125	99
No transfusions\|	56	79

No statistical analyses for this end point

Secondary: Number of participants with at least one Grade 3/Grade 4 myelosuppression adverse events

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End point title

Number of participants with at least one Grade 3/Grade 4 myelosuppression adverse events

End point description

Participants with at least one Grade 3 or Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented. Myelosuppression is defined as the decrease in the ability of the bone marrow to produce blood cells. AEs were graded according to NCI common terminology criteria for adverse events (CTCAE) grade, version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).

End point type

Secondary

End point timeframe

End point values	Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects	Fludarabine + Cyclophosphamide_ ITT subjects
Number of subjects analysed	181	178
Units: Participants	126	118

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit up to approximately 8.5 years.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Ofatumumab + Fludarabine + Cyclophosphamide

Reporting group description

Ofatumumab + Fludarabine + Cyclophosphamide

Reporting group title

Fludarabine + Cyclophosphamide

Reporting group description

Fludarabine + Cyclophosphamide

Serious adverse events	Ofatumumab + Fludarabine + Cyclophosphamide	Fludarabine + Cyclophosphamide
Total subjects affected by serious adverse events
subjects affected / exposed	108 / 181 (59.67%)	86 / 178 (48.31%)
number of deaths (all causes)	40	42
number of deaths resulting from adverse events	11	9
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplastic syndrome
subjects affected / exposed	3 / 181 (1.66%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	3 / 3	2 / 2
deaths causally related to treatment / all	1 / 1	2 / 2
Acute myeloid leukaemia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder papilloma
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic lymphocytic leukaemia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Chronic myeloid leukaemia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diffuse large B-cell lymphoma
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colon cancer metastatic
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypopharyngeal cancer
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Melanoma recurrent
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Metastatic squamous cell carcinoma
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Non-small cell lung cancer
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Plasma cell myeloma
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	2 / 181 (1.10%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Essential hypertension
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Haemorrhagic vasculitis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hypertension
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shock
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Thrombophlebitis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	9 / 181 (4.97%)	5 / 178 (2.81%)
occurrences causally related to treatment / all	4 / 9	3 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	3 / 181 (1.66%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	1 / 3	0 / 1
Oedema peripheral
subjects affected / exposed	1 / 181 (0.55%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 181 (0.00%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chills
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Graft versus host disease
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	3 / 181 (1.66%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	1 / 3	1 / 2
deaths causally related to treatment / all	1 / 2	1 / 1
Dyspnoea
subjects affected / exposed	3 / 181 (1.66%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Acute pulmonary oedema
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Acute respiratory failure
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchial haemorrhage
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pulmonary embolism
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pulmonary fibrosis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract haemorrhage
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Haemoglobin decreased
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pneumothorax
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Epidermolysis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	2 / 181 (1.10%)	3 / 178 (1.69%)
occurrences causally related to treatment / all	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	2 / 181 (1.10%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure acute
subjects affected / exposed	0 / 181 (0.00%)	4 / 178 (2.25%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 3
Angina pectoris
subjects affected / exposed	0 / 181 (0.00%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Myocardial ischaemia
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Bradycardia
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Extrasystoles
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pericardial effusion
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tachycardia paroxysmal
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Transient ischaemic attack
subjects affected / exposed	2 / 181 (1.10%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular encephalopathy
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Carotid arteriosclerosis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Dementia
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Demyelinating polyneuropathy
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post herpetic neuralgia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 181 (1.10%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	18 / 181 (9.94%)	15 / 178 (8.43%)
occurrences causally related to treatment / all	15 / 24	12 / 24
deaths causally related to treatment / all	2 / 2	0 / 0
Neutropenia
subjects affected / exposed	17 / 181 (9.39%)	14 / 178 (7.87%)
occurrences causally related to treatment / all	17 / 21	15 / 18
deaths causally related to treatment / all	0 / 0	0 / 2
Anaemia
subjects affected / exposed	11 / 181 (6.08%)	12 / 178 (6.74%)
occurrences causally related to treatment / all	2 / 12	12 / 18
deaths causally related to treatment / all	0 / 0	0 / 1
Thrombocytopenia
subjects affected / exposed	7 / 181 (3.87%)	10 / 178 (5.62%)
occurrences causally related to treatment / all	3 / 7	7 / 10
deaths causally related to treatment / all	0 / 0	0 / 1
Pancytopenia
subjects affected / exposed	5 / 181 (2.76%)	5 / 178 (2.81%)
occurrences causally related to treatment / all	4 / 5	3 / 6
deaths causally related to treatment / all	1 / 1	0 / 1
Autoimmune haemolytic anaemia
subjects affected / exposed	2 / 181 (1.10%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	1 / 2	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	2 / 181 (1.10%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	2 / 3	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Agranulocytosis
subjects affected / exposed	0 / 181 (0.00%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	0 / 181 (0.00%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	0 / 181 (0.00%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Aplasia pure red cell
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Granulocytopenia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemolysis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (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	3 / 181 (1.66%)	3 / 178 (1.69%)
occurrences causally related to treatment / all	2 / 4	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	3 / 181 (1.66%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 3	1 / 1
deaths causally related to treatment / all	0 / 2	0 / 0
Colitis
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	2 / 181 (1.10%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 181 (1.10%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	2 / 181 (1.10%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 181 (0.00%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Ileus
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mouth ulceration
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Proctalgia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Salivary hypersecretion
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	2 / 181 (1.10%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hepatitis
subjects affected / exposed	2 / 181 (1.10%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cholecystitis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (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
Skin ulcer
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pruritus
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (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
Renal failure
subjects affected / exposed	1 / 181 (0.55%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Calculus urinary
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal colic
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	5 / 181 (2.76%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	1 / 6	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	2 / 181 (1.10%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle spasms
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myositis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (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 / 181 (0.55%)	0 / 178 (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	28 / 181 (15.47%)	29 / 178 (16.29%)
occurrences causally related to treatment / all	14 / 34	9 / 32
deaths causally related to treatment / all	1 / 4	3 / 11
Urinary tract infection
subjects affected / exposed	6 / 181 (3.31%)	6 / 178 (3.37%)
occurrences causally related to treatment / all	1 / 11	3 / 7
deaths causally related to treatment / all	0 / 2	0 / 0
Sepsis
subjects affected / exposed	4 / 181 (2.21%)	8 / 178 (4.49%)
occurrences causally related to treatment / all	1 / 4	1 / 8
deaths causally related to treatment / all	1 / 4	0 / 4
Neutropenic sepsis
subjects affected / exposed	4 / 181 (2.21%)	5 / 178 (2.81%)
occurrences causally related to treatment / all	3 / 5	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	4 / 181 (2.21%)	5 / 178 (2.81%)
occurrences causally related to treatment / all	1 / 4	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	6 / 181 (3.31%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	2 / 6	0 / 3
deaths causally related to treatment / all	1 / 1	0 / 0
Bronchitis
subjects affected / exposed	3 / 181 (1.66%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	2 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 181 (0.55%)	3 / 178 (1.69%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 2
Cellulitis
subjects affected / exposed	2 / 181 (1.10%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 181 (0.55%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 181 (0.55%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Cytomegalovirus infection
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 181 (0.00%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	2 / 181 (1.10%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 181 (0.55%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic infection
subjects affected / exposed	0 / 181 (0.00%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	0 / 181 (0.00%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 181 (0.00%)	2 / 178 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Acinetobacter bacteraemia
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acinetobacter infection
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Anal abscess
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical mycobacterial infection
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Atypical pneumonia
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Campylobacter gastroenteritis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Campylobacter infection
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal sepsis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal candidiasis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infective exacerbation of bronchiectasis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oropharyngeal candidiasis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pneumocystis jirovecii infection
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Pneumonia haemophilus
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomembranous colitis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Soft tissue infection
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Salmonella sepsis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic mycosis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis B reactivation
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin infection
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	2 / 181 (1.10%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gout
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperuricaemia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 181 (0.00%)	1 / 178 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Starvation
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (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 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 181 (0.55%)	0 / 178 (0.00%)
occurrences causally related to treatment / all	0 / 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	Ofatumumab + Fludarabine + Cyclophosphamide	Fludarabine + Cyclophosphamide
Total subjects affected by non serious adverse events
subjects affected / exposed	149 / 181 (82.32%)	123 / 178 (69.10%)
Investigations
Platelet count decreased
subjects affected / exposed	12 / 181 (6.63%)	5 / 178 (2.81%)
occurrences all number	14	9
Vascular disorders
Hypotension
subjects affected / exposed	11 / 181 (6.08%)	4 / 178 (2.25%)
occurrences all number	12	4
Nervous system disorders
Headache
subjects affected / exposed	15 / 181 (8.29%)	6 / 178 (3.37%)
occurrences all number	18	7
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	38 / 181 (20.99%)	55 / 178 (30.90%)
occurrences all number	50	69
Neutropenia
subjects affected / exposed	93 / 181 (51.38%)	62 / 178 (34.83%)
occurrences all number	192	126
Leukopenia
subjects affected / exposed	27 / 181 (14.92%)	10 / 178 (5.62%)
occurrences all number	38	29
Anaemia
subjects affected / exposed	24 / 181 (13.26%)	38 / 178 (21.35%)
occurrences all number	40	51
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	26 / 181 (14.36%)	15 / 178 (8.43%)
occurrences all number	40	18
Asthenia
subjects affected / exposed	13 / 181 (7.18%)	16 / 178 (8.99%)
occurrences all number	15	16
Fatigue
subjects affected / exposed	15 / 181 (8.29%)	11 / 178 (6.18%)
occurrences all number	19	12
Chills
subjects affected / exposed	14 / 181 (7.73%)	3 / 178 (1.69%)
occurrences all number	19	3
Gastrointestinal disorders
Nausea
subjects affected / exposed	45 / 181 (24.86%)	36 / 178 (20.22%)
occurrences all number	75	73
Vomiting
subjects affected / exposed	19 / 181 (10.50%)	22 / 178 (12.36%)
occurrences all number	23	28
Diarrhoea
subjects affected / exposed	14 / 181 (7.73%)	19 / 178 (10.67%)
occurrences all number	17	22
Constipation
subjects affected / exposed	8 / 181 (4.42%)	11 / 178 (6.18%)
occurrences all number	8	11
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	15 / 181 (8.29%)	10 / 178 (5.62%)
occurrences all number	20	12
Dyspnoea
subjects affected / exposed	15 / 181 (8.29%)	3 / 178 (1.69%)
occurrences all number	22	3
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	23 / 181 (12.71%)	8 / 178 (4.49%)
occurrences all number	30	11
Pruritus
subjects affected / exposed	19 / 181 (10.50%)	2 / 178 (1.12%)
occurrences all number	23	2
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	13 / 181 (7.18%)	8 / 178 (4.49%)
occurrences all number	15	8
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	13 / 181 (7.18%)	8 / 178 (4.49%)
occurrences all number	14	8

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Were there any global substantial amendments to the protocol? Yes

09 Apr 2014

Study Name and Logo added. Name of Physician Study Leader updated. Investigator Agreement Page updated. SAEs no longer reported after commencement of subsequent anti-CLL therapy. Prohibited concomitant medication, Glucocorticoid dosing amended. Requirement to collect anticancer and anti-infectious concomitant medications after 1 month follow-up amended to collect only if associated with an SAE and only until subsequent anti-CLL therapy is initiated. Details regarding reporting of study results to investigators, to a publically available register, and for publication updated. Investigator responsibilities with regard to Quality Compliance and Quality Assurance updated. Minor clarifications and typographical errors addressed.

30 Sep 2014

Clinical Investigational Leader and associated contact information updated. Introduction updated with current published data. Statistical assumptions for event rate projection updated.

20 Feb 2015

Name of Physician Project Lead and Sponsor Signatory updated. The requirement to report SAEs after commencement of subsequent anti-CLL therapy has been reinstated in India only, to comply with changed country-specific requirements.

08 Mar 2016

Delete or replace references to GSK or its staff with that of Novartis/Novartis and its authorized agents. Make administrative changes to align with Novartis processes and procedures.

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.

Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-free survival (PFS), as assessed by the Independent Review Committee (IRC)

Primary: Progression-free survival (PFS), as assessed by the Independent Review Committee (IRC)

Secondary: Overall survival (OS)

Secondary: Overall survival (OS)

Secondary: Time to response, as assessed by the IRC

Secondary: Time to response, as assessed by the IRC

Secondary: Duration of Response (DOR), as assessed by the IRC

Secondary: Duration of Response (DOR), as assessed by the IRC

Secondary: Time to progression, as assessed by the IRC

Secondary: Time to progression, as assessed by the IRC

Secondary: Time to next therapy

Secondary: Time to next therapy

Secondary: Number of participants with improvement in Eastern Cooperative Oncology Group (ECOG) performance status

Secondary: Number of participants with improvement in Eastern Cooperative Oncology Group (ECOG) performance status

Secondary: Number of Participants with no B-Symptoms or at least one B-symptoms over the time

Secondary: Number of Participants with no B-Symptoms or at least one B-symptoms over the time

Secondary: Percentage of participants with the best Overall Response (OR), as assessed by the IRC

Secondary: Percentage of participants with the best Overall Response (OR), as assessed by the IRC

Secondary: Percentage of participants with the best OR, as assessed by the Investigator

Secondary: Percentage of participants with the best OR, as assessed by the Investigator

Secondary: Number of participants who were negative for Minimal Residual Disease (MRD) assessed by IRC

Secondary: Number of participants who were negative for Minimal Residual Disease (MRD) assessed by IRC

Secondary: Number of participants who were negative for MRD assessed by investigator

Secondary: Number of participants who were negative for MRD assessed by investigator

Secondary: Number of participants with any Adverse Event (AE) or Serious Adverse Event (SAE)

Secondary: Number of participants with any Adverse Event (AE) or Serious Adverse Event (SAE)

Secondary: Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result at indicated time points

Secondary: Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result at indicated time points

Secondary: Number of participants with Autoimmune Hemolytic Anaemia (AIHA)

Secondary: Number of participants with Autoimmune Hemolytic Anaemia (AIHA)

Secondary: Mean level of Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM

Secondary: Mean level of Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM

Secondary: Change from baseline in Cluster of Differentiation (CD) Cell Counts, CD5+ and CD19+

Secondary: Change from baseline in Cluster of Differentiation (CD) Cell Counts, CD5+ and CD19+

Secondary: Change from Baseline in Cell Counts, CD5- CD19+

Secondary: Change from Baseline in Cell Counts, CD5- CD19+

Secondary: Prognostic and biological markers correlating with clinical response

Secondary: Prognostic and biological markers correlating with clinical response

Secondary: Changes in Patient Reported Outcome (PRO) measures and scores for European organization for research and treatment of cancer quality of life questionnaire, chronic lymphocytic leukaemia 16 item module (EORTC QLQ-CLL 16)

Secondary: Changes in Patient Reported Outcome (PRO) measures and scores for European organization for research and treatment of cancer quality of life questionnaire, chronic lymphocytic leukaemia 16 item module (EORTC QLQ-CLL 16)

Secondary: Change from Baseline in Patient Reported Outcome (PRO) as assessed by EuroQoL Five-Dimension (EQ-5D) score at indicated visit

Secondary: Change from Baseline in Patient Reported Outcome (PRO) as assessed by EuroQoL Five-Dimension (EQ-5D) score at indicated visit

Secondary: Change from baseline in the European organization for the research and treatment of cancer quality of life questionnaire core 30 (EORTC QLQ-C30) score

Secondary: Change from baseline in the European organization for the research and treatment of cancer quality of life questionnaire core 30 (EORTC QLQ-C30) score

Secondary: Mean of Health Change Questionnaire (HCQ)

Secondary: Mean of Health Change Questionnaire (HCQ)

Secondary: Mean area under the time-concentration curve (AUC) curve over the dosing interval (AUC[0-tau]) of ofatumumab

Secondary: Mean area under the time-concentration curve (AUC) curve over the dosing interval (AUC[0-tau]) of ofatumumab

Secondary: Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) of Ofatumumab

Secondary: Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) of Ofatumumab

Secondary: Time of occurrence of Cmax (Tmax) of ofatumumab

Secondary: Time of occurrence of Cmax (Tmax) of ofatumumab

Secondary: Number of participants with drug related infections reported as AEs and SAEs of maximum severity of Grade 3 or Higher

Secondary: Number of participants with drug related infections reported as AEs and SAEs of maximum severity of Grade 3 or Higher

Secondary: Number of participants who received no transfusion or at Least one transfusion during the study

Secondary: Number of participants who received no transfusion or at Least one transfusion during the study

Secondary: Number of participants with at least one Grade 3/Grade 4 myelosuppression adverse events

Secondary: Number of participants with at least one Grade 3/Grade 4 myelosuppression adverse events

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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