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Clinical Trial Results:
A phase III, open label, randomized, multicenter trial of Ofatumumab added to Chlorambucil vs. Chlorambucil Monotherapy in previously untreated patients with 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	2008-004932-19
Trial protocol	NL IE DE ES SE BE CZ FR IT GR GB
Global end of trial date	17 May 2018

Results information
Results version number	v2(current)
This version publication date	31 May 2019
First version publication date	13 Nov 2014
Other versions	v1 (removed from public view)
Version creation reason

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

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Trial information

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Sponsor protocol code

COMB157B2301

ISRCTN number

US NCT number

NCT00748189

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, Novartis.email@novartis.com

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

17 May 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 May 2018

Was the trial ended prematurely?

Yes

Main objective of the trial

To evaluate PFS of ofatumumab added to chlorambucil for previously untreated (front-line) CLL compared to chlorambucil monotherapy.

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

22 Dec 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Brazil: 6

Country: Number of subjects enrolled

Canada: 4

Country: Number of subjects enrolled

Czech Republic: 14

Country: Number of subjects enrolled

Germany: 43

Country: Number of subjects enrolled

United Kingdom: 58

Country: Number of subjects enrolled

Greece: 21

Country: Number of subjects enrolled

India: 42

Country: Number of subjects enrolled

Belgium: 60

Country: Number of subjects enrolled

Ireland: 15

Country: Number of subjects enrolled

Italy: 35

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

Poland: 41

Country: Number of subjects enrolled

Russian Federation: 28

Country: Number of subjects enrolled

Spain: 21

Country: Number of subjects enrolled

Sweden: 16

Country: Number of subjects enrolled

United States: 38

Worldwide total number of subjects

447

EEA total number of subjects

329

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)

139

From 65 to 84 years

301

85 years and over

Subject disposition

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Recruitment details

Screening details

Eligible participants (par.) were stratified by age (<65 years vs. >=65years), stage (Binet A vs. B vs. C) and Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2). Participants in each stratum were then centrally randomized in a 1:1 ratio to receive ofatumumab plus chlorambucil (O+CHL) or chlorambucil alone (CHL).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Chlorambucil

Arm description

Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.

Arm type

Active comparator

Investigational medicinal product name

Chlorambucil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Chlorambucil was administered as 2-mg tablets. The treatment dose was 10 mg/m² given on Days 1-7 every 28 days. For patients suffering from nausea or vomiting, dose splitting to 2 or 3 daily administrations was permitted. Dose delays or reductions were allowed in the event of toxicity

Ofatumumab + Chlorambucil

Arm description

Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.

Arm type

Experimental

Investigational medicinal product name

Ofatumumab

Investigational medicinal product code

OMB157

Other name

Pharmaceutical forms

Cutaneous liquid, Infusion

Routes of administration

Intravenous use

Dosage and administration details

Ofatumumab (GSK1841157) was provided as clear, colorless, liquid 100-mg/mL concentrate in 5-mL glass vials. The ofatumumab infusions were prepared in 1000 mL sterile, to yield a 0.3 mg/mL ofatumumab concentration for the first 300-mg infusion and to yield a 1 mg/mL concentration for subsequent 1000-mg infusions. Ofatumumab was infused IV on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by infusions of 1000 mg on the first day of each subsequent 28-day cycle.

Investigational medicinal product name

Chlorambucil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

hlorambucil was administered as 2-mg tablets. The treatment dose was 10 mg/m² given on Days 1-7 every 28 days. For patients suffering from nausea or vomiting, dose splitting to 2 or 3 daily administrations was permitted. Dose delays or reductions were allowed in the event of toxicity

Number of subjects in period 1	Chlorambucil	Ofatumumab + Chlorambucil
Started	226	221
Completed	10	9
Not completed	216	212
Adverse event, serious fatal	99	84
Consent withdrawn by subject	23	29
Physician decision	16	5
Study terminated by Sponsor	70	79
Lost to follow-up	8	15

Baseline characteristics

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Reporting group title

Chlorambucil

Reporting group description

Reporting group title

Ofatumumab + Chlorambucil

Reporting group description

Reporting group values	Chlorambucil	Ofatumumab + Chlorambucil	Total
Number of subjects	226	221	447
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)	70	69	139
From 65-84 years	151	150	301
85 years and over	5	2	7
Sex: Female, Male
Units: Subjects
Female	86	79	165
Male	140	142	282
Race/Ethnicity, Customized
Units: Subjects
African American/African Heritage	2	4	6
American Indian or Alaskan Native	1	0	1
Asian - Central/South Asian Heritage	22	19	41
Asian - Mixed Race	0	2	2
White	201	196	397
AgeCategoricalOther
Units: Years
median (full range (min-max))	70 (36 to 91)	69 (35 to 92)	-

End points

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Reporting group title

Chlorambucil

Reporting group description

Reporting group title

Ofatumumab + Chlorambucil

Reporting group description

Subject analysis set title

Chlorambucil

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Ofatumumab + Chlorambucil

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Study OMB110911: Ofatumumab + Chlorambucil

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Study LEUA1001: Chlorambucil

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with CLL, Non-Hodgkin’s lymphoma or other refractory malignancies received three different formulations of a 0.2 mg/kilogram(kg) chlorambucil tablet orally with a two-day interval between drug administration.

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 (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 enlarged 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. Par. who were alive and had not progressed at the time of analysis or if a progression event or death occurred after extensive lost-to-follow-up time or if new anti-cancer therapy was started were censored at the date of the last visit with adequate assessment.

End point type

Primary

End point timeframe

From randomization to the date of first documented disease progression or death due to any cause, whichever occured first, reported between day of first patient randomized up to about 49 months

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	226	221
Units: Months
median (confidence interval 95%)	13.1 (10.6 to 13.8)	22.4 (19.0 to 25.2)

PFS as assessed by IRC

Comparison groups

Chlorambucil v Ofatumumab + Chlorambucil

Number of subjects included in analysis

447

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.57

Confidence interval

level

95%

sides

2-sided

lower limit

0.45

upper limit

0.72

Secondary: Number of participants with the best overall response (OR), as assessed by the IRC

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End point title

Number 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 until the 259th PFS event occurred, up to about 49 months

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	226	221
Units: Participants
CR	3	27
CRi	0	5
nPR	0	1
PR	152	149

No statistical analyses for this end point

Secondary: Number of participants who were negative for minimal residual disease (MRD)

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End point title

Number of participants who were negative for minimal residual disease (MRD)

End point description

MRD 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 until the 259th PFS event occurred (Median follow-up approximately 28.9 months)

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	226	221
Units: Participants
MRD negative, irrespective of response	8	26
MRD negative, with an IRC-assessed CR	0	10

No statistical analyses for this end point

Secondary: Overall Survival

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End point title

Overall Survival

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 total 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 about 111 months

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	226	221
Units: Months
median (confidence interval 95%)	84.67 (74.25 to 999)	999 (84.50 to 999)

Overall survival

Statistical analysis description

hazard ratios are obtained using the Pike estimator. A hazard ratio <1 indicates a lower risk with O+CHL treatment compared with chlorambucil

Comparison groups

Chlorambucil v Ofatumumab + Chlorambucil

Number of subjects included in analysis

447

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.363

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

1.17

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 (CR, CRi, nPR, or PR). 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. Participants with unknown or missing responses were considered as non-responders. Only responders (CR, CRi, PR, nPR) were included in the analysis.

End point type

Secondary

End point timeframe

From randomization uo to about 27 months

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	154	182
Units: Months
median (confidence interval 95%)	1.9 (1.2 to 1.9)	1.2 (1.0 to 1.9)

No statistical analyses for this end point

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 enlarged 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. Par. who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time (>= 12 weeks) were censored at the date of the last visit with adequate assessment. Par. with unknown or missing responses were considered as non-responders.

End point type

Secondary

End point timeframe

From randomization up to about 43 months

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	154	182
Units: Months
median (confidence interval 95%)	13.2 (10.8 to 16.4)	22.1 (19.1 to 24.6)

No statistical analyses for this end point

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 disease progression (PD). PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlarged 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. Participants who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time were censored at the date of the last visit with adequate assessment.

End point type

Secondary

End point timeframe

From randomization up to about 49 months

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	226	221
Units: Months
median (confidence interval 95%)	13.6 (11.2 to 14.6)	23.1 (21.2 to 25.8)

No statistical analyses for this end point

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.

End point type

Secondary

End point timeframe

From randomization up to about 49 months

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	99	64
Units: Months
median (confidence interval 95%)	24.67 (22.57 to 29.08)	39.82 (34.69 to 48.79)

No statistical analyses for this end point

Secondary: Number of participants with improvement in ECOG performance status of 0 or 1

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End point title

Number of participants with improvement in ECOG performance status of 0 or 1

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. Grade 0, fully active, able to carry on all pre-disease performance without restriction. Grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Grade 2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50% of waking hours. Grade 3, capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. Grade 4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. Grade 5, dead. Participants with an ECOG performance status of 0 or 1 are shown..

End point type

Secondary

End point timeframe

Baseline, Cycle 3 Day 1, 1 month Follow-up

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	227	217
Units: Participants
ECOG (0, 1) at Baseline	209	200
ECOG (0, 1) at Cycle 3 Day 1	184	189
ECOG (0, 1) 1 Month Follow-up	183	191

No statistical analyses for this end point

Secondary: Number of participants with improvement in constitutional symptoms (CS)

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End point title

Number of participants with improvement in constitutional symptoms (CS)

End point description

Assessment for the presence of the following symptoms were performed at Screening, Day 1 of each treatment cycle and at every Follow-up visit: night sweats (without signs of infection); unexplained, unintentional weight loss >= 10% within the previous 6 months; recurrent, unexplained fever of greater than 38 degrees celsius or 100.5 degrees fahrenheit for 2 weeks; and extreme fatigue. The best response refers to overall best response in terms of CR, CRi, PR or nPR. Data are presented for constitutional response= yes and no.

End point type

Secondary

End point timeframe

Baseline, Cycle 3 Day 1, and 1 month Follow-up

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	226	221
Units: Participants
CS present, Baseline, n=226, 221	120	118
CS present, Cycle 3 Day 1, n=198, 199	44	33
CS present, 1 Month Follow-up, n=198, 200	23	22

No statistical analyses for this end point

Secondary: Number of participants with a human anti-human antibody (HAHA) positive result

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End point title

Number of participants with a human anti-human antibody (HAHA) positive result

End point description

Serum samples for analysis of HAHA were collected at Baseline (Screening), Cycle 4 Day 1 (after 3 months of treatment), and at 1 month and 6 months post last dose of ofatumumab. 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 and further evaluated in the titration test to obtain a titer of HAHA.

End point type

Secondary

End point timeframe

Baseline, Cycle 4 Day 1, 1 Month Follow-up, and 6 Month Follow-up

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	0 ^[1]	202
Units: Participants		0

Notes
[1] - not analyzed for anti-ofatumumab antibody.

No statistical analyses for this end point

Secondary: Cmax and Ctrough of ofatumumab

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End point title

Cmax and Ctrough of ofatumumab

End point description

Blood samples were collected to assess the plasma concentration of ofatumumab. Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) were determined. Blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of treatment.

End point type

Secondary

End point timeframe

Cycle 1 Day 1,Cycle 1 Day 8, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, and Cycle 9 Day 1

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	0 ^[2]	193
Units: Micrograms/Milliliter (µg/mL)
geometric mean (geometric coefficient of variation)
Cmax, Cycle 1 Day 1, n=0, 176	( )	51.8 ( 1.03 )
Cmax, Cycle 1 Day 8, n=0, 193	( )	241 ( 0.46 )
Cmax, Cycle 4 Day 1, n=0, 169	( )	285 ( 0.44 )
Ctrough, Cycle 1 Day 8, n=0, 99	( )	2.5 ( 5.85 )
Ctrough, Cycle 2 Day 1, n=0, 138	( )	5.2 ( 15.37 )
Ctrough, Cycle 3 Day 1, n=0, 142	( )	6.2 ( 17.06 )
Ctrough, Cycle 4 Day 1, n=0, 147	( )	15.5 ( 7.99 )
Ctrough, Cycle 5 Day 1, n=0, 149	( )	33.5 ( 3.61 )
Ctrough, Cycle 6 Day 1, n=0, 155	( )	45.9 ( 2.77 )
Ctrough, Cycle 9 Day 1, n=0, 56	( )	55.6 ( 3.50 )

Notes
[2] - Cmax and Ctrough were not collected for this arm.

No statistical analyses for this end point

Secondary: Total plasma clearance (CL) of ofatumumab

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End point title

Total plasma clearance (CL) of ofatumumab

End point description

Plasma clearance is defined as the plasma volume which is totally cleared of drug per unit of time. Blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to the ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on duration of treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.

End point type

Secondary

End point timeframe

Cycle 4 Day 1

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	0 ^[3]	183
Units: Milliliter/hour (mL/h)
geometric mean (geometric coefficient of variation)	( )	15.4 ( 0.73 )

Notes
[3] - total plasma clearance was not collected for this arm/drug.

No statistical analyses for this end point

Secondary: AUC(0-tau) of ofatumumab

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End point title

AUC(0-tau) of ofatumumab

End point description

Area under the concentration time curve over the dosing interval [AUC(0-tau)] is a measure of drug exposure over time. AUC(0-tau) is defined as the area under the ofatumumab plasma concentration-time curve from dosing to time tau, where tau is the length of the dosing interval of ofatumumab. For estimation of AUC(0-tau), blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hous after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to the ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on duration of treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.

End point type

Secondary

End point timeframe

Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	0 ^[4]	208
Units: µg x hours/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1, n=0, 193	( )	2621 ( 0.76 )
Cycle 1 Day 8, n=0, 208	( )	25369 ( 0.87 )
Cycle 4 Day 1, n=0, 183	( )	65100 ( 0.73 )

Notes
[4] - AUC was not collected for this arm/drug

No statistical analyses for this end point

Secondary: Volume of distribution at steady state (Vss) of ofatumumab

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End point title

Volume of distribution at steady state (Vss) of ofatumumab

End point description

Volume of distribution at steady state (Vss) is defined as the distribution of a drug between plasma and the rest of the body at steady state. Blood samples were collected from participants who received ofatumumab plus chlorambucil at predose and 0.5 hour after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of the treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.

End point type

Secondary

End point timeframe

Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	0 ^[5]	208
Units: Liters
geometric mean (geometric coefficient of variation)
Vss, Cycle 1 Day 1, n=0, 193	( )	7.78 ( 0.55 )
Vss, Cycle 1 Day 8, n=0, 208	( )	7.77 ( 0.54 )
Vss, Cycle 4 Day 1, n=0, 183	( )	8.06 ( 0.53 )

Notes
[5] - Vss was not collected for this arm/drug.

No statistical analyses for this end point

Secondary: Plasma half life (t1/2) of ofatumumab

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End point title

Plasma half life (t1/2) of ofatumumab

End point description

The terminal half-life (t1/2) of ofatumumab is defined as the time required for the plasma concentration of ofatumumab to reach half of its original concentration. Blood samples were collected to assess the plasma half-life of ofatumumab. Blood samples were collected from participants who received ofatumumab plus chlorambucil pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of the treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.

End point type

Secondary

End point timeframe

Cycle 4 Day 1

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	0 ^[6]	183
Units: hours
geometric mean (geometric coefficient of variation)	( )	445 ( 1.05 )

Notes
[6] - t1/2 was not collected for this arm/drug

No statistical analyses for this end point

Secondary: Dose-normalized Cmax of chlorambucil and phenylacetic acid mustard (PAAM)

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End point title

Dose-normalized Cmax of chlorambucil and phenylacetic acid mustard (PAAM)

End point description

Blood samples for the determination of serum concentrations of chlorambucil and its metabolite PAAM were collected from participants in a substudy on Cycle 3 Day 1. The maximum observed concentration (Cmax) of chlorambucil and PAAM normalized to the administered dose was determined as a measure of exposure and compared to reference data from a prior study (LEUA1001) [No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00].

End point type

Secondary

End point timeframe

Cycle 3 Day 1

End point values	Study OMB110911: Ofatumumab + Chlorambucil	Study LEUA1001: Chlorambucil
Number of subjects analysed	7	12
Units: nanograms per milliliter per milligram
geometric mean (standard deviation)
Chlorambucil Cmax/Dose	27.1 ( 0.32 )	38.4 ( 0.36 )
PAAM Cmax/Dose	19.3 ( 0.23 )	24.3 ( 0.30 )

Dose-normalized Cmax of chlorambucil and PAAM

Comparison groups

Study OMB110911: Ofatumumab + Chlorambucil v Study LEUA1001: Chlorambucil

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[7]

Method

Parameter type

Ratio of Cmax/Dose

Point estimate

0.71

Confidence interval

level

90%

sides

2-sided

lower limit

0.53

upper limit

0.94

Notes
[7] - Comparability of dose-normalized chlorambucil Cmax values with ofatumumab in current study and without ofatumumab in prior study

Dose-normalized Cmax of chlorambucil and PAAM

Comparison groups

Study OMB110911: Ofatumumab + Chlorambucil v Study LEUA1001: Chlorambucil

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[8]

Method

Parameter type

Ratio of Cmax/Dose

Point estimate

0.79

Confidence interval

level

90%

sides

2-sided

lower limit

0.63

upper limit

0.99

Notes
[8] - Comparability of dose-normalized PAAM Cmax values with ofatumumab in current study and without ofatumumab in prior study

Secondary: Dose-normalized AUC(0-6) and AUC(0-inf) of chlorambucil and dose-normalized AUC(0-6) of phenylacetic acid mustard (PAAM)

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End point title

Dose-normalized AUC(0-6) and AUC(0-inf) of chlorambucil and dose-normalized AUC(0-6) of phenylacetic acid mustard (PAAM)

End point description

Blood samples for the determination of serum concentrations of chlorambucil and its metabolite PAAM were collected from participants in a substudy on Cycle 3 Day 1. The area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-inf]) and over 6 hours (AUC[0-6]) of chlorambucil and AUC(0-6) of PAAM normalized to the administered dose was determined as a measure of exposure and compared to reference data from a prior study (LEUA1001) [No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00].

End point type

Secondary

End point timeframe

Cycle 3 Day 1

End point values	Study OMB110911: Ofatumumab + Chlorambucil	Study LEUA1001: Chlorambucil
Number of subjects analysed	7	12
Units: Hours*nanogram/milliliter/milligram
geometric mean (standard deviation)
Chlorambucil AUC(0-6)/Dose	67.84 ( 0.24 )	65.43 ( 0.44 )
Chlorambucil AUC(0-inf)/Dose	74.42 ( 0.23 )	67.10 ( 0.45 )
PAAM AUC(0-6)/Dose	71.52 ( 0.26 )	80.32 ( 0.26 )

Dose-normalized AUC of PAAM

Comparison groups

Study OMB110911: Ofatumumab + Chlorambucil v Study LEUA1001: Chlorambucil

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[9]

Method

Parameter type

Ratio of AUC(0-6)/Dose

Point estimate

1.04

Confidence interval

level

90%

sides

2-sided

lower limit

0.77

upper limit

1.4

Notes
[9] - Comparability of dose-normalized chlorambucil AUC(0-6) values with ofatumumab in current study and without ofatumumab in prior study

Dose-normalized AUC of PAAM

Comparison groups

Study OMB110911: Ofatumumab + Chlorambucil v Study LEUA1001: Chlorambucil

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[10]

Method

Parameter type

Ratio of AUC(0-inf)/Dose

Point estimate

1.11

Confidence interval

level

90%

sides

2-sided

lower limit

0.82

upper limit

1.5

Notes
[10] - Comparability of dose-normalized chlorambucil AUC(0-inf) values with ofatumumab in current study and without ofatumumab in prior study

Dose-normalized AUC of PAAM

Comparison groups

Study OMB110911: Ofatumumab + Chlorambucil v Study LEUA1001: Chlorambucil

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[11]

Method

Parameter type

Ratio of AUC(0-6)/Dose

Point estimate

0.89

Confidence interval

level

90%

sides

2-sided

lower limit

0.72

upper limit

1.1

Notes
[11] - Comparability of dose-normalized PAAM AUC(0-6) values with ofatumumab in current study and without ofatumumab in prior study

Secondary: Change from Baseline in health related quality of life (HRQOL)

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End point title

Change from Baseline in health related quality of life (HRQOL)

End point description

HRQOL was assessed using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTCQLQC30), Chronic Lymphocytic Leukemia module (EORTC QLQ-CLL16), EuorQoL-Five Dimension (EQ-5D), and HCQ. Period (P)1 (Day 85, Day 169, Day 253) and P2 (scheduled follow-up (FU) and withdrawal visits) analysis were considered. Baseline (BL) for P1 was defined as score from screening visit and BL for P2 was defined as the last on-treatment score. The 2 principal QoL outcomes were pre-specified as the Global Health scale (GHS/QOL) of the EORTC QLQ-C30 and fatigue scale of the EORTC QLQ-CLL16. For EORTC QLQ-C30,GHS/Qol, the possible scale range was 0-100 (with 100 being 'best') and a positive difference from BL is indicative of better functioning (range -100 to +100). For the EORTC QLQ-CLL16 fatigue scale, the possible scale range was 0-100 (with 0 being 'best') and a negative difference from BL represents an improvement in fatigue (range -100 to +100).

End point type

Secondary

End point timeframe

Baseline, Cycle 4 day 1, cycle 7 day 1, 1 month follow-up, 6 month follow-up, 12 month follow-up

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	226	221
Units: Scores on a scale
arithmetic mean (standard deviation)
P1, Cycle 4 Day 1, QLQC30 GHS/QoL score, n=139,159	1.92 ( 21.22 )	6.08 ( 21.08 )
P1, Cycle 7 Day 1, QLQC30 GHS/QoL score, n=52, 55	8.01 ( 22.20 )	6.97 ( 17.55 )
P1,Cycle 4 Day 1,QLQCLL16 fatigue score, n=145,163	-4.71 ( 27.48 )	-4.60 ( 24.23 )
P1, Cycle 7 Day 1,QLQCLL16 fatigue score, n=55,57	-1.21 ( 25.43 )	-9.36 ( 22.93 )
P2,1 month FU, QLQC30 GHS/QoL score, n=118, 150	4.79 ( 23.13 )	0.56 ( 18.31 )
P2, 6 month FU, QLQC30 GHS/QoL score, n=83, 129	3.01 ( 22.07 )	3.75 ( 20.83 )
P2, 12 month FU, QLQC30 GHS/QoL score, n=48, 96	3.82 ( 18.27 )	1.22 ( 17.69 )
P2, 1 month FU, QLQCLL16 fatigue score, n=121, 152	-1.24 ( 21.75 )	-0.33 ( 19.13 )
P2, 6 month FU, QLQCLL16 fatigue score, n=85, 131	-7.06 ( 18.96 )	-2.93 ( 19.34 )
P2, 12 month FU, QLQCLL16 fatigue score, n=51, 95	-2.94 ( 17.86 )	0.88 ( 16.91 )

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

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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.

End point type

Secondary

End point timeframe

From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	227	217
Units: Participants
Any AE	205	208
Any SAE	84	97

No statistical analyses for this end point

Secondary: Number of participants with AEs and SAEs of maximum severity of grade 3 or higher

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End point title

Number of participants with AEs and SAEs of maximum severity of grade 3 or higher

End point description

End point type

Secondary

End point timeframe

From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	227	217
Units: Participants
Any AE, Grade 3	54	67
Any AE, Grade 4	31	36
Any AE, Grade 5	25	36
Any SAE, Grade 3	36	34
Any SAE, Grade 4	13	19
Any SAE, Grade 5	25	36

No statistical analyses for this end point

Secondary: Number of participants with at least one Grade 3/Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia)

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End point title

Number of participants with at least one Grade 3/Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia)

End point description

Participants with a Grade 3 or Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented by treatment cycle. 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

From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	227	217
Units: Participants	92	83

No statistical analyses for this end point

Secondary: Number of participants with autoimmune hemolytic anaemia (AIHA) disease

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End point title

Number of participants with autoimmune hemolytic anaemia (AIHA) disease

End point description

AIHA is a disease 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 diagnosed with AIHA are presented.

End point type

Secondary

End point timeframe

From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	227	217
Units: Participants	6	4

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 are counted in this table.

End point type

Secondary

End point timeframe

From start of treatment to the last study visit/withdrawal visit (Median follow-up approximately 28.9 months)

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	227	217
Units: Participants
No transfusions	159	168
At least one transfusion	68	49

No statistical analyses for this end point

Secondary: Mean change from Baseline in the Immunoglobulin (Ig) antibodies IgA, IgG, and IgM

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End point title

Mean change from Baseline in the 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. IgA, IgG, and IgM were measured in the blood samples of the participants. Baseline IgA, IgG, and IgM values are the last pre-dose assessment values performed on Cycle 1 Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

End point type

Secondary

End point timeframe

From start of treatment up to 30 days after last treatment

End point values	Chlorambucil	Ofatumumab + Chlorambucil
Number of subjects analysed	227	217
Units: Gram per liter
arithmetic mean (standard deviation)
IgA, n=175, 186	0.047 ( 0.5706 )	0.048 ( 0.4257 )
IgG, n=175, 186	-0.458 ( 3.6177 )	-0.268 ( 2.5430 )
IgM n=175, 186	-0.398 ( 4.7864 )	-0.031 ( 0.2507 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events and Serious Adverse Events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 111 months

Adverse event reporting additional description

All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 111 months.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Chlorambucil

Reporting group description

Reporting group title

Ofatumumab 1000 mg + Chlorambucil

Reporting group description

Reporting group title

Total

Reporting group description

All patients.

Serious adverse events	Chlorambucil	Ofatumumab 1000 mg + Chlorambucil	Total
Total subjects affected by serious adverse events
subjects affected / exposed	57 / 227 (25.11%)	53 / 217 (24.42%)	110 / 444 (24.77%)
number of deaths (all causes)	99	84	183
number of deaths resulting from adverse events	2	3	5
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma pancreas
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Prostate cancer
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Peripheral artery stenosis
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Inflammation
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 227 (0.44%)	5 / 217 (2.30%)	6 / 444 (1.35%)
occurrences causally related to treatment / all	1 / 1	5 / 5	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular stent restenosis
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiectasis
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 227 (0.88%)	2 / 217 (0.92%)	4 / 444 (0.90%)
occurrences causally related to treatment / all	2 / 2	2 / 2	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	4 / 227 (1.76%)	2 / 217 (0.92%)	6 / 444 (1.35%)
occurrences causally related to treatment / all	5 / 5	2 / 2	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 227 (0.00%)	2 / 217 (0.92%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 227 (0.00%)	4 / 217 (1.84%)	4 / 444 (0.90%)
occurrences causally related to treatment / all	0 / 0	4 / 4	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 2
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Haemoglobin decreased
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mycobacterium test
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Traumatic ulcer
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 227 (0.00%)	2 / 217 (0.92%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	0 / 227 (0.00%)	2 / 217 (0.92%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 2	1 / 2
Cardio-respiratory arrest
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Supraventricular tachycardia
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Central nervous system haemorrhage
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebellar ischaemia
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Cognitive disorder
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 227 (0.44%)	1 / 217 (0.46%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	1 / 1	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Extrapyramidal disorder
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 227 (0.00%)	2 / 217 (0.92%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intracranial haematoma
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 227 (0.00%)	2 / 217 (0.92%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	1 / 227 (0.44%)	1 / 217 (0.46%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	1 / 1	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 227 (2.20%)	3 / 217 (1.38%)	8 / 444 (1.80%)
occurrences causally related to treatment / all	6 / 6	4 / 4	10 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Autoimmune haemolytic anaemia
subjects affected / exposed	3 / 227 (1.32%)	0 / 217 (0.00%)	3 / 444 (0.68%)
occurrences causally related to treatment / all	4 / 4	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eosinophilia
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	5 / 227 (2.20%)	3 / 217 (1.38%)	8 / 444 (1.80%)
occurrences causally related to treatment / all	5 / 5	3 / 3	8 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemolysis
subjects affected / exposed	1 / 227 (0.44%)	1 / 217 (0.46%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	1 / 1	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	2 / 227 (0.88%)	0 / 217 (0.00%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	2 / 2	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	4 / 227 (1.76%)	6 / 217 (2.76%)	10 / 444 (2.25%)
occurrences causally related to treatment / all	4 / 4	7 / 7	11 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	3 / 227 (1.32%)	1 / 217 (0.46%)	4 / 444 (0.90%)
occurrences causally related to treatment / all	3 / 3	1 / 1	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Aphthous ulcer
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatitis cholestatic
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dermatitis allergic
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	2 / 227 (0.88%)	1 / 217 (0.46%)	3 / 444 (0.68%)
occurrences causally related to treatment / all	2 / 2	1 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 227 (0.00%)	2 / 217 (0.92%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Flank pain
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Anal abscess
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Empyema
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 227 (0.44%)	1 / 217 (0.46%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	1 / 1	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemophilus infection
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 227 (0.44%)	3 / 217 (1.38%)	4 / 444 (0.90%)
occurrences causally related to treatment / all	1 / 1	3 / 3	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	3 / 227 (1.32%)	2 / 217 (0.92%)	5 / 444 (1.13%)
occurrences causally related to treatment / all	3 / 3	2 / 2	5 / 5
deaths causally related to treatment / all	0 / 0	1 / 1	1 / 1
Oral herpes
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	1 / 227 (0.44%)	1 / 217 (0.46%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	1 / 1	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngitis bacterial
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	1 / 1
Pneumonia
subjects affected / exposed	11 / 227 (4.85%)	8 / 217 (3.69%)	19 / 444 (4.28%)
occurrences causally related to treatment / all	12 / 12	8 / 8	20 / 20
deaths causally related to treatment / all	1 / 2	1 / 1	2 / 3
Pneumonia legionella
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Pneumonia staphylococcal
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 227 (0.00%)	2 / 217 (0.92%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Septic shock
subjects affected / exposed	1 / 227 (0.44%)	1 / 217 (0.46%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	1 / 1	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 227 (0.44%)	0 / 217 (0.00%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 227 (0.00%)	1 / 217 (0.46%)	1 / 444 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	0 / 227 (0.00%)	2 / 217 (0.92%)	2 / 444 (0.45%)
occurrences causally related to treatment / all	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Chlorambucil	Ofatumumab 1000 mg + Chlorambucil	Total
Total subjects affected by non serious adverse events
subjects affected / exposed	175 / 227 (77.09%)	183 / 217 (84.33%)	358 / 444 (80.63%)
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	0 / 227 (0.00%)	17 / 217 (7.83%)	17 / 444 (3.83%)
occurrences all number	0	29	1
Vascular disorders
Flushing
subjects affected / exposed	1 / 227 (0.44%)	11 / 217 (5.07%)	12 / 444 (2.70%)
occurrences all number	1	11	2
Hypertension
subjects affected / exposed	1 / 227 (0.44%)	11 / 217 (5.07%)	12 / 444 (2.70%)
occurrences all number	1	12	6
Hypotension
subjects affected / exposed	2 / 227 (0.88%)	12 / 217 (5.53%)	14 / 444 (3.15%)
occurrences all number	3	16	3
Nervous system disorders
Dizziness
subjects affected / exposed	15 / 227 (6.61%)	10 / 217 (4.61%)	25 / 444 (5.63%)
occurrences all number	21	13	29
Headache
subjects affected / exposed	7 / 227 (3.08%)	18 / 217 (8.29%)	25 / 444 (5.63%)
occurrences all number	7	30	26
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	27 / 227 (11.89%)	16 / 217 (7.37%)	43 / 444 (9.68%)
occurrences all number	31	25	58
Leukopenia
subjects affected / exposed	4 / 227 (1.76%)	14 / 217 (6.45%)	18 / 444 (4.05%)
occurrences all number	4	22	27
Neutropenia
subjects affected / exposed	36 / 227 (15.86%)	57 / 217 (26.27%)	93 / 444 (20.95%)
occurrences all number	55	103	161
Thrombocytopenia
subjects affected / exposed	56 / 227 (24.67%)	30 / 217 (13.82%)	86 / 444 (19.37%)
occurrences all number	69	41	114
General disorders and administration site conditions
Asthenia
subjects affected / exposed	11 / 227 (4.85%)	18 / 217 (8.29%)	29 / 444 (6.53%)
occurrences all number	11	19	28
Chills
subjects affected / exposed	1 / 227 (0.44%)	18 / 217 (8.29%)	19 / 444 (4.28%)
occurrences all number	1	20	3
Fatigue
subjects affected / exposed	40 / 227 (17.62%)	35 / 217 (16.13%)	75 / 444 (16.89%)
occurrences all number	46	36	85
Oedema peripheral
subjects affected / exposed	12 / 227 (5.29%)	15 / 217 (6.91%)	27 / 444 (6.08%)
occurrences all number	13	17	30
Pyrexia
subjects affected / exposed	18 / 227 (7.93%)	36 / 217 (16.59%)	54 / 444 (12.16%)
occurrences all number	26	45	41
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	5 / 227 (2.20%)	11 / 217 (5.07%)	16 / 444 (3.60%)
occurrences all number	5	12	10
Constipation
subjects affected / exposed	13 / 227 (5.73%)	10 / 217 (4.61%)	23 / 444 (5.18%)
occurrences all number	14	11	25
Diarrhoea
subjects affected / exposed	31 / 227 (13.66%)	38 / 217 (17.51%)	69 / 444 (15.54%)
occurrences all number	37	44	70
Nausea
subjects affected / exposed	57 / 227 (25.11%)	43 / 217 (19.82%)	100 / 444 (22.52%)
occurrences all number	72	66	105
Vomiting
subjects affected / exposed	24 / 227 (10.57%)	23 / 217 (10.60%)	47 / 444 (10.59%)
occurrences all number	30	26	25
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	25 / 227 (11.01%)	33 / 217 (15.21%)	58 / 444 (13.06%)
occurrences all number	29	38	65
Dyspnoea
subjects affected / exposed	10 / 227 (4.41%)	25 / 217 (11.52%)	35 / 444 (7.88%)
occurrences all number	10	32	23
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	2 / 227 (0.88%)	11 / 217 (5.07%)	13 / 444 (2.93%)
occurrences all number	2	14	5
Hyperhidrosis
subjects affected / exposed	5 / 227 (2.20%)	12 / 217 (5.53%)	17 / 444 (3.83%)
occurrences all number	6	13	14
Pruritus
subjects affected / exposed	11 / 227 (4.85%)	26 / 217 (11.98%)	37 / 444 (8.33%)
occurrences all number	11	33	28
Rash
subjects affected / exposed	21 / 227 (9.25%)	53 / 217 (24.42%)	74 / 444 (16.67%)
occurrences all number	25	67	44
Urticaria
subjects affected / exposed	2 / 227 (0.88%)	22 / 217 (10.14%)	24 / 444 (5.41%)
occurrences all number	2	30	7
Psychiatric disorders
Insomnia
subjects affected / exposed	17 / 227 (7.49%)	12 / 217 (5.53%)	29 / 444 (6.53%)
occurrences all number	17	13	27
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	8 / 227 (3.52%)	11 / 217 (5.07%)	19 / 444 (4.28%)
occurrences all number	8	11	18
Back pain
subjects affected / exposed	12 / 227 (5.29%)	11 / 217 (5.07%)	23 / 444 (5.18%)
occurrences all number	13	13	18
Infections and infestations
Bronchitis
subjects affected / exposed	10 / 227 (4.41%)	11 / 217 (5.07%)	21 / 444 (4.73%)
occurrences all number	11	11	22
Nasopharyngitis
subjects affected / exposed	19 / 227 (8.37%)	9 / 217 (4.15%)	28 / 444 (6.31%)
occurrences all number	21	9	30
Upper respiratory tract infection
subjects affected / exposed	16 / 227 (7.05%)	12 / 217 (5.53%)	28 / 444 (6.31%)
occurrences all number	17	13	30
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	20 / 227 (8.81%)	13 / 217 (5.99%)	33 / 444 (7.43%)
occurrences all number	20	15	34

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Were there any global substantial amendments to the protocol? Yes

11 Aug 2008

1) Clarification of translational research and consent language to comply with local Institutional Review Board / Ethics Committee requirements. 2) The steroid pre-infusion schedule was modified to allow dose reduction for patients where steroid administration was not medically indicated (U.S. FDA request). 3) DoR and PROs were removed as inferential secondary endpoints because a formal comparison of these endpoints was not considered feasible with the proposed study design. Instead, OS was added as an inferential secondary endpoint (U.S. FDA/EMA request).

10 Aug 2009

1) Addition of inclusion criterion, ‘considered inappropriate for fludarabine-based therapy, for reasons that include, but not limited to, advanced age or presence of comorbidities’ to further define patient population (U.S. FDA request). 2) Addition of a CT scan at time of progression to provide the IRC a means of objective assessment of progressive disease by lymphadenopathy, for sensitivity analysis (U.S. FDA request). 3) Update of CLL diagnosis definition and response assessment criteria in alignment with the IWCLL updated (NCI-WG) guidelines.

25 Nov 2009

1) Implementation of Hepatitis B virus DNA monitoring for HBcAb-positive patients to monitor for potential hepatitis reactivation. 2) Addition of a drug-drug interaction and ECG substudy to evaluate potential ofatumumab/chlorambucil interaction and any effect of ofatumumab on QTc intervals (FDA request).

23 May 2014

1) Change of Medical Monitor. 2) Removal of CT scan at time of progression 3) Extension of follow-up period from 5 to up to 10 years 4) Clarification of data collection period for concomitant medication in follow-up 5) Update Data Disclosure information

24 Sep 2015

1) Delete or replace references to GSK or its staff with that of Novartis/Novartis and its authorized agents. 2) 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.

The study was terminated early because the majority of patients (62%) had been treated with next line therapies, including new highly effective therapies confounding the interpretation of the OS 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: Number of participants with the best overall response (OR), as assessed by the IRC

Secondary: Number of participants with the best overall response (OR), as assessed by the IRC

Secondary: Number of participants who were negative for minimal residual disease (MRD)

Secondary: Number of participants who were negative for minimal residual disease (MRD)

Secondary: Overall Survival

Secondary: Overall Survival

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 ECOG performance status of 0 or 1

Secondary: Number of participants with improvement in ECOG performance status of 0 or 1

Secondary: Number of participants with improvement in constitutional symptoms (CS)

Secondary: Number of participants with improvement in constitutional symptoms (CS)

Secondary: Number of participants with a human anti-human antibody (HAHA) positive result

Secondary: Number of participants with a human anti-human antibody (HAHA) positive result

Secondary: Cmax and Ctrough of ofatumumab

Secondary: Cmax and Ctrough of ofatumumab

Secondary: Total plasma clearance (CL) of ofatumumab

Secondary: Total plasma clearance (CL) of ofatumumab

Secondary: AUC(0-tau) of ofatumumab

Secondary: AUC(0-tau) of ofatumumab

Secondary: Volume of distribution at steady state (Vss) of ofatumumab

Secondary: Volume of distribution at steady state (Vss) of ofatumumab

Secondary: Plasma half life (t1/2) of ofatumumab

Secondary: Plasma half life (t1/2) of ofatumumab

Secondary: Dose-normalized Cmax of chlorambucil and phenylacetic acid mustard (PAAM)

Secondary: Dose-normalized Cmax of chlorambucil and phenylacetic acid mustard (PAAM)

Secondary: Dose-normalized AUC(0-6) and AUC(0-inf) of chlorambucil and dose-normalized AUC(0-6) of phenylacetic acid mustard (PAAM)

Secondary: Dose-normalized AUC(0-6) and AUC(0-inf) of chlorambucil and dose-normalized AUC(0-6) of phenylacetic acid mustard (PAAM)

Secondary: Change from Baseline in health related quality of life (HRQOL)

Secondary: Change from Baseline in health related quality of life (HRQOL)

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 AEs and SAEs of maximum severity of grade 3 or higher

Secondary: Number of participants with AEs and SAEs of maximum severity of grade 3 or higher

Secondary: Number of participants with at least one Grade 3/Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia)

Secondary: Number of participants with at least one Grade 3/Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia)

Secondary: Number of participants with autoimmune hemolytic anaemia (AIHA) disease

Secondary: Number of participants with autoimmune hemolytic anaemia (AIHA) disease

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: Mean change from Baseline in the Immunoglobulin (Ig) antibodies IgA, IgG, and IgM

Secondary: Mean change from Baseline in the Immunoglobulin (Ig) antibodies IgA, IgG, and IgM

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information