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Clinical Trial Results:
Phase 3 Randomized, Double-Blind, Placebo Controlled, Multicenter Study to Compare the Efficacy and Safety of Lenalidomide (Cc-5013) Plus R-Chop Chemotherapy (R2-Chop) Versus Placebo Plus R-Chop Chemotherapy in Subjects with Previously Untreated Activated B-Cell Type Diffuse Large

Summary
EudraCT number	2013-004054-21
Trial protocol	ES IE CZ IT PT BE NL
Global end of trial date	25 Jul 2022

Results information
Results version number	v1(current)
This version publication date	07 Jun 2023
First version publication date	07 Jun 2023
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

CC-5013-DLC-002

ISRCTN number

US NCT number

NCT02285062

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussee de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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

26 Sep 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

25 Jul 2022

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study is to compare the efficacy of R2-CHOP versus placebo-RCHOP.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Jan 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Italy: 134

Country: Number of subjects enrolled

Japan: 46

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 23

Country: Number of subjects enrolled

Netherlands: 11

Country: Number of subjects enrolled

New Zealand: 4

Country: Number of subjects enrolled

Poland: 21

Country: Number of subjects enrolled

Portugal: 13

Country: Number of subjects enrolled

Russian Federation: 9

Country: Number of subjects enrolled

Spain: 40

Country: Number of subjects enrolled

Switzerland: 2

Country: Number of subjects enrolled

Taiwan: 12

Country: Number of subjects enrolled

Turkey: 25

Country: Number of subjects enrolled

United States: 40

Country: Number of subjects enrolled

Australia: 13

Country: Number of subjects enrolled

Belgium: 10

Country: Number of subjects enrolled

Canada: 7

Country: Number of subjects enrolled

China: 105

Country: Number of subjects enrolled

Czechia: 23

Country: Number of subjects enrolled

France: 15

Country: Number of subjects enrolled

Ireland: 5

Country: Number of subjects enrolled

Israel: 12

Worldwide total number of subjects

570

EEA total number of subjects

272

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)

275

From 65 to 84 years

295

85 years and over

Subject disposition

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Recruitment details

Screening details

570 participants were randomized (Intent to Treat (ITT) population) and 567 participants were treated (Safety population).

Period 1 title

Pre-Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Lenalidomide Plus R-CHOP (R2-CHOP)

Arm description

Participants received lenalidomide 15 mg capsules on days 1 to 14 of each 21 day treatment cycle followed by R-CHOP: rituximab 375 mg/m^2 by intravenous (IV) administration on Day 1, doxorubicin 50 mg/m^2 IV on Day 1, vincristine 1.4 mg/m^2 IV on Day 1 (maximum dose of 2.0 mg total), cyclophosphamide 750 mg/m^2 IV on Day 1 and oral or IV prednisone/prednisolone 100 mg on Day 1 to Day 5 of each 21 day treatment cycle for 6 cycles. Treatment continued until completed, unless unacceptable toxicity, treatment change, disease progression, or withdrawal of consent, whichever occurred first. An additional two doses (1 dose per 21-day cycle) of single agent rituximab after the 6 cycles of treatment were completed if considered standard of care per local practice.

Arm type

Experimental

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

15 mg capsule (oral administration) PO once daily for 14 days in each 21-day cycle

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Concentrate for solution for infusion

Routes of administration

Oral use, Intravenous use

Dosage and administration details

100 mg PO (oral administration) or intravenously (IV) on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

50 mg/m2 IV on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.4 mg/m2 (max of 2.0 mg total) IV on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

375 mg/m2 IV on Day -1 or Day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

750 mg/m2 IV on Day 1 of each 21-day treatment cycle for up to 6 cycles.

Placebo Plus R-CHOP

Arm description

Participants received identically matching placebo capsules on days 1 to 14 of each 21 day treatment cycle followed by R-CHOP: rituximab 375 mg/m^2 by intravenous (IV) administration on Day 1, doxorubicin 50 mg/m^2 IV on Day 1, vincristine 1.4 mg/m^2 IV on Day 1 (maximum dose of 2.0 mg total), cyclophosphamide 750 mg/m^2 IV on Day 1 and oral or IV prednisone/prednisolone 100 mg on Day 1 to Day 5 of each 21 day treatment cycle for 6 to 8 cycles. Treatment continued until 6-8 cycles were completed, unless unacceptable toxicity, treatment change, disease progression, or withdrawal of consent, occurred first. An additional two doses (1 dose per 21-day cycle) of single agent rituximab after the 6 cycles of treatment were completed if considered standard of care per local practice.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

15 mg capsule (oral administration) PO once daily for 14 days in each 21-day cycle

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

375 mg/m2 IV on Day -1 or Day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Concentrate for solution for infusion

Routes of administration

Oral use, Intravenous use

Dosage and administration details

100 mg PO (oral administration) or intravenously (IV) on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.4 mg/m2 (max of 2.0 mg total) IV on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

50 mg/m2 IV on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

750 mg/m2 IV on Day 1 of each 21-day treatment cycle for up to 6 cycles.

Number of subjects in period 1	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Started	285	285
Completed	284	283
Not completed	1	2
Consent withdrawn by subject	1	-
Protocol deviation	-	2

Period 2 title

Treatment Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Lenalidomide Plus R-CHOP (R2-CHOP)

Arm description

Arm type

Experimental

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

15 mg capsule (oral administration) PO once daily for 14 days in each 21-day cycle

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

375 mg/m2 IV on Day -1 or Day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Concentrate for solution for infusion

Routes of administration

Oral use, Intravenous use

Dosage and administration details

100 mg PO (oral administration) or intravenously (IV) on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

50 mg/m2 IV on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.4 mg/m2 (max of 2.0 mg total) IV on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

750 mg/m2 IV on Day 1 of each 21-day treatment cycle for up to 6 cycles.

Placebo Plus R-CHOP

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

15 mg capsule (oral administration) PO once daily for 14 days in each 21-day cycle

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

375 mg/m2 IV on Day -1 or Day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Concentrate for solution for infusion

Routes of administration

Oral use, Intravenous use

Dosage and administration details

100 mg PO (oral administration) or intravenously (IV) on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.4 mg/m2 (max of 2.0 mg total) IV on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

50 mg/m2 IV on day 1 of each 21-day cycle for up to 6 cycles.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

750 mg/m2 IV on Day 1 of each 21-day treatment cycle for up to 6 cycles.

Number of subjects in period 2	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Started	283	284
Completed	211	240
Not completed	72	44
Combined reasons for not completing 6-full cycles.	72	44

Baseline characteristics

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Reporting group title

Lenalidomide Plus R-CHOP (R2-CHOP)

Reporting group description

Reporting group title

Placebo Plus R-CHOP

Reporting group description

Reporting group values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP	Total
Number of subjects	285	285	570
Age Categorical
Units: Participants
< 65	138	137	275
≥ 65	147	148	295
Age Continuous
Units: Years
arithmetic mean (standard deviation)	62.5 ± 11.72	63.9 ± 9.35	-
Sex: Female, Male
Units: Participants
Female	121	142	263
Male	164	143	307
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	14	17	31
Not Hispanic or Latino	270	267	537
Unknown or Not Reported	1	1	2
Race/Ethnicity, Customized
Units: Subjects
White	173	183	356
Asian	101	89	190
Black or African American	2	3	5
Other	3	2	5
Not Collected or Reported	6	8	14
Eastern Cooperative Oncology Group (ECOG) Performance Status
The ECOG performance status is used to describe a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical ability (walking, working, etc.). The scale ranges from 0 to 5: 0 = Fully active, no restrictions; 1 = Restricted activity but ambulatory, able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care but unable to carry out work activities; 3 = Limited self-care, confined to bed or chair more than 50% of waking hours; 4 = Completely disabled, no self-care, confined to bed or chair; 5 = Dead
Units: Subjects
0 = Fully Active	129	111	240
1 = Restrictive but ambulatory	104	118	222
2 = Ambulatory but unable to work	52	56	108
International Prognostic Index (IPI) Score
The IPI score is a clinical tool developed to aid in predicting the prognosis of patients with aggressive non-Hodgkin's lymphoma, including DLBCL. One point is assigned for each of the following risk factors: Age greater than 60 years, Stage III or IV disease, elevated serum lactate dehydrogenase (LDH), ECOG performance status of 2, 3, or 4, more than 1 extranodal site. The sum of the points allotted correlates with the following risk groups: Low risk (0-1 points) Low-intermediate risk (2 points) High-intermediate risk (3 points) High risk (4-5 points)
Units: Subjects
= 2	121	120	241
≥ 3	164	165	329
Presence of Bulky Disease
Units: Subjects
< 7.0 cm (Non-Bulky Disease)	188	186	374
≥ 7.0 cm (Bulky Disease)	97	99	196
Disease Stage of Diffuse Large B-Cell Lymphoma at Diagnosis
The criteria for clinical stage (Ann Arbor staging) are as below: I: involvement of a single nodal region. II: involvement of 2 or more lymph node regions on the same side of the diaphragm. III: involvement of lymph node regions on both sides of the diaphragm. IV: disseminated involvement of 1 or more extra-lymphatic sites with or without associated lymph node involvement.
Units: Subjects
Stage I	0	1	1
Stage II	37	32	69
Stage III	80	98	178
Stage IV	168	154	322
Creatinine Clearance
Creatinine is a waste product from the normal breakdown of muscle tissue. As creatinine is produced, it's filtered through the kidneys and excreted in urine. Doctors measure the blood creatinine level as a test of kidney function.
Units: mL/min
arithmetic mean (standard deviation)	92.08 ± 35.576	90.19 ± 31.040	-
Body Surface Area (BSA)
Body surface area is the calculated surface of a human body. BSA is often considered a more accurate measure of metabolic mass than body weight, since it's less affected by irregular amounts of fat tissue.
Units: m^2
arithmetic mean (standard deviation)	1.780 ± 0.2167	1.775 ± 0.2101	-

End points

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Reporting group title

Lenalidomide Plus R-CHOP (R2-CHOP)

Reporting group description

Reporting group title

Placebo Plus R-CHOP

Reporting group description

Reporting group title

Lenalidomide Plus R-CHOP (R2-CHOP)

Reporting group description

Reporting group title

Placebo Plus R-CHOP

Reporting group description

Primary: Kaplan-Meier Estimate of Progression Free Survival (PFS)

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End point title

Kaplan-Meier Estimate of Progression Free Survival (PFS)

End point description

Progression free survival was defined as the time (months) from the date of randomization to the date of disease progression or death (any cause), whichever occurred earlier and was assessed by the Independent Response Adjudication Committee (IRAC). Relapse from complete response (CR) was considered as disease progression throughout the study. Disease progression was determined based on the Revised Response Criteria for Malignant Lymphoma. The PFS analysis was based on the censoring rules using the Food and Drug Administration (FDA) Guidance. Participants who did not experience disease progression and who did not die before the clinical data cutoff date were censored at the date of last adequate response assessment. "99999" = Not Applicable/Not Available.

End point type

Primary

End point timeframe

From the date of randomization up to the data cut off date of 15 March 2019; median follow-up of 24.5 months

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	285	285
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (35.5 to 99999)

PFS Hazard Ratio

Comparison groups

Lenalidomide Plus R-CHOP (R2-CHOP) v Placebo Plus R-CHOP

Number of subjects included in analysis

570

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2864

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.849

Confidence interval

level

95%

sides

2-sided

lower limit

0.632

upper limit

1.14

Secondary: Percentage of Participants who Achieved a Complete Response (CR)

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End point title

Percentage of Participants who Achieved a Complete Response (CR)

End point description

The percentage of participants who achieved a CR after initiation of the study treatment and prior to initiation of subsequent systemic antilymphoma therapy as assessed by the IRAC. A CR = complete metabolic response; target nodes/nodal masses regressed on computed tomography to (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy. Regressed to normal size by imaging, and absence of nodules related to lymphoma. If bone marrow was involved prior to therapy, no evidence of fluorodeoxyglucose avid disease in marrow per International Working Group (IWG) 2014 for Non-Hodgkin's Lymphoma (NHL). Participants who did not have any adequate response assessments during this period were not considered as responders.

End point type

Secondary

End point timeframe

From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	285	285
Units: Percentage of Participants
number (confidence interval 95%)	69.1 (63.4 to 74.4)	64.9 (59.1 to 70.4)

Complete Response

Comparison groups

Lenalidomide Plus R-CHOP (R2-CHOP) v Placebo Plus R-CHOP

Number of subjects included in analysis

570

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2933 ^[1]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[1] - Obtained from CMH test adjusting for stratification factors: IPI score (2 or ≥ 3), presence of bulky disease (bulky or nonbulky), and age (< 65 or ≥ 65)

Secondary: K-M Estimate of Overall Survival (OS)

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End point title

K-M Estimate of Overall Survival (OS)

End point description

Overall survival was assessed by the IRAC (Independent Response Adjudication Committee) and defined as time from randomization until death due to any cause. Participants who withdrew consent were censored at the time of withdrawal. Participants who were still alive before the clinical data cutoff date and participants who were lost to follow-up were censored at date last known alive. "99999" = Not Applicable/Not Available

End point type

Secondary

End point timeframe

From randomization until death due to any cause (up to approximately 86 months)

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	285	285
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

OS Hazard Ratio

Comparison groups

Lenalidomide Plus R-CHOP (R2-CHOP) v Placebo Plus R-CHOP

Number of subjects included in analysis

570

Analysis specification

Pre-specified

Analysis type

P-value

= 0.876

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.965

Confidence interval

level

95%

sides

2-sided

lower limit

0.716

upper limit

1.3

Secondary: Kaplan-Meier (K-M) Estimate of Event Free Survival (EFS)

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End point title

Kaplan-Meier (K-M) Estimate of Event Free Survival (EFS)

End point description

EFS was defined as the time (months) from randomization until occurrence of one of the following events, whichever occurred first: • Disease progression • Initiation of subsequent systemic anti-lymphoma therapy • Death due to any cause The assessment of EFS was conducted by the IRAC using the International Working Group (IWG) criteria for NHL. Pre-specified optional therapies such as the extra 2 doses of single agent rituximab after Cycle 6 or consolidation radiotherapy did not count as an EFS event (initiation of subsequent systemic anti-lymphoma therapy) if the decision to treat and the location to be treated was determined prior to randomization. Participants who did not experience any of the events defined in the categories above before the clinical data cutoff date were censored at date last known alive. "99999" = Not Applicable/Not Available

End point type

Secondary

End point timeframe

From the date of randomization up to the data cut off date of 15 March 2019; median follow-up was 24.5 months

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	285	285
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (31.3 to 99999)

EFS Hazard Ratio

Comparison groups

Lenalidomide Plus R-CHOP (R2-CHOP) v Placebo Plus R-CHOP

Number of subjects included in analysis

570

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7294

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.038

Confidence interval

level

95%

sides

2-sided

lower limit

0.802

upper limit

1.344

Secondary: K-M Estimate of Time to Next Lymphoma Therapy (TTNLT)

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End point title

K-M Estimate of Time to Next Lymphoma Therapy (TTNLT)

End point description

Time to next lymphoma therapy was defined as the time from randomization to the time of treatment change for the next lymphoma treatment. Participants without treatment change were censored at date last known alive. Pre-specified optional therapies such as the extra 2 doses of single agent rituximab after Cycle 6 or consolidation radiotherapy did not count as treatment change for the next lymphoma therapy if the decision to treat and the location to be treated were determined prior to randomization. "99999" = Not Applicable/Not Available

End point type

Secondary

End point timeframe

From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	285	285
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

TTNLT

Comparison groups

Lenalidomide Plus R-CHOP (R2-CHOP) v Placebo Plus R-CHOP

Number of subjects included in analysis

570

Analysis specification

Pre-specified

Analysis type

P-value

= 0.315

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.167

Confidence interval

level

95%

sides

2-sided

lower limit

0.856

upper limit

1.59

Secondary: K-M Estimate of Duration of Complete Response

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End point title

K-M Estimate of Duration of Complete Response

End point description

Duration of complete response was calculated for complete responders only and was defined as the time from documented initial complete response prior to initiation of subsequent systemic antilymphoma therapy until documented disease progression or death, whichever occurred earlier. Participants who had not progressed or died at the time of the analysis were censored at the date of last response assessment demonstrating no disease progression. Participants who changed treatment without evidence of disease progression were censored at the last assessment showing no progression prior to treatment change. "99999" = Not Applicable/Not Available

End point type

Secondary

End point timeframe

From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months.

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	197	185
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

DOCR

Comparison groups

Lenalidomide Plus R-CHOP (R2-CHOP) v Placebo Plus R-CHOP

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2143

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.776

Confidence interval

level

95%

sides

2-sided

lower limit

0.521

upper limit

1.157

Secondary: Percentage of Participants who Achieved an Objective Response

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End point title

Percentage of Participants who Achieved an Objective Response

End point description

An objective response = percentage of participants who achieved a complete response or partial response after initiation of the treatment and prior to initiation of subsequent systemic anti-lymphoma therapy. A CR = complete metabolic response; Target nodes/nodal masses regressed on computed tomography to (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy. Regressed to normal size by imaging, and absence of nodules related to lymphoma. If bone marrow was involved prior to therapy, no evidence of fluorodeoxyglucose avid disease in marrow. PR = ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. No increase in other nodes, liver, or spleen. Splenic nodules regressed by ≥ 50% in their SPD or for single nodules, in the greatest transverse diameter; no new lesions. Participants who did not have any adequate response assessments during this period were not considered as responders.

End point type

Secondary

End point timeframe

From randomization date up to the data cut off date of 15 March 2019; median total treatment duration was 18.10 weeks for both treatment arms; range = 1.6 to 29.0 weeks for R2-CHOP arm and 0.3 to 22.9 weeks for placebo-R-CHOP arm

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	285	285
Units: Percentage of Participants
number (confidence interval 95%)	90.9 (86.9 to 94.0)	90.9 (86.9 to 94.0)

Objective Response

Comparison groups

Lenalidomide Plus R-CHOP (R2-CHOP) v Placebo Plus R-CHOP

Number of subjects included in analysis

570

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9964 ^[2]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[2] - Obtained from CMH test adjusting for stratification factors: IPI score (2 or ≥ 3), presence of bulky disease (bulky or nonbulky), and age (< 65 or ≥ 65)

Secondary: Percentage of Participants who Completed the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Health Related Quality of Life (HR-QoL) Questionnaire

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End point title

Percentage of Participants who Completed the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Health Related Quality of Life (HR-QoL) Questionnaire

End point description

The completion rate for EQ-5D assessments was judged by looking at the number of completed assessments at each time point. Completion rates were calculated as the number and percentage of participants out of the total number of patients in the ITT population and summarized by visit/cycle and treatment group. The EQ-5D-3L is a generic, self-reported preference-based measure of health across five dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has three levels of ‘severity’ corresponding to “no problems”, “some problems” and “extreme problems”. The instrument is scored using the United Kingdom (UK) index ranges from -0.594 – 1, where 0 equates to death and 1 equates to full health -0.594 is considered ‘worse than death’.

End point type

Secondary

End point timeframe

Screening, Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	285	285
Units: Percentage of Participants
number (not applicable)
Screening	98.9	97.9
Midcycle	87.0	86.3
End of Treatment (EoT)	76.5	79.6
Follow-Up Period: Week 34	68.1	69.1

No statistical analyses for this end point

Secondary: Percentage of Participants who Completed the Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) Questionnaire

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End point title

Percentage of Participants who Completed the Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) Questionnaire

End point description

The completion rate for FACT-Lym assessments was judged by looking at the number of completed FACT-Lym assessments at each time point. The FACT-Lym was considered completed if at least 1 calculable score was present. Completion rates were calculated as the number and percentage of participants out of the total number of patients in the ITT population and summarized by visit/cycle and treatment group. The FACT-Lym is a health related quality of life (HRQoL) questionnaire targeted to the management of chronic illness, predominantly within oncology and is considered an extension of the FACT-General questionnaire.

End point type

Secondary

End point timeframe

Screening, Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	285	285
Units: Percentage of Participants
number (not applicable)
Screening	98.6	98.2
Midcycle = After Cycle 3, but before Cycle 4	87.0	86.3
End of Treatment (EoT) = 3-4 weeks after C6	76.1	79.6
Follow-Up Period: Week 34	67.7	69.5

No statistical analyses for this end point

Secondary: Mean Change from Baseline in the FACT-Lym Physical Well-Being Subscale

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End point title

Mean Change from Baseline in the FACT-Lym Physical Well-Being Subscale

End point description

The FACT-Lym questionnaire is a validated instrument for assessing the impact of lymphoma on HRQL and contains 42 questions covering HRQL and common lymphoma symptoms and treatment side-effects. It begins with the Functional Assessment of Cancer Therapy - General (FACT-G), which contains 27 questions covering four core subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 questions) used to assess NHL-related symptoms and concerns. All questions are answered on a 5-point scale ranging from “not at all” (0) to “very much” (4). The physical well-being subscale ranges from 0 to 28, where higher scores reflect better HRQoL.

End point type

Secondary

End point timeframe

Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	257	257
Units: Units on a Scale
arithmetic mean (standard deviation)
Midcycle	-0.7 ± 5.91	0.2 ± 5.40
C6 D1	-0.0 ± 6.35	0.9 ± 6.02
EoT = 3-4 weeks after C6	1.5 ± 5.53	0.7 ± 5.72
Follow-Up Period: Week 34	2.8 ± 5.24	2.6 ± 5.55

No statistical analyses for this end point

Secondary: Mean Change from Baseline in the FACT-Lym Functional Well-Being Subscale

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End point title

Mean Change from Baseline in the FACT-Lym Functional Well-Being Subscale

End point description

The FACT-Lym questionnaire is a validated instrument for assessing the impact of lymphoma on HRQL and contains 42 questions covering HRQL and common lymphoma symptoms and treatment side-effects. It begins with the Functional Assessment of Cancer Therapy - General (FACT-G), which contains 27 questions covering four core subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 questions) used to assess NHL-related symptoms and concerns. All questions are answered on a 5-point scale ranging from “not at all” (0) to “very much” (4). The functional well-being subscale ranges from 0 to 28, where higher scores reflect better HRQoL.

End point type

Secondary

End point timeframe

Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	258	256
Units: Units on a Scale
arithmetic mean (standard deviation)
Midcycle	-0.5 ± 6.12	0.5 ± 5.84
C6 D1	0.0 ± 6.24	1.4 ± 5.63
EoT = 3-4 weeks after C6	1.0 ± 6.53	0.7 ± 6.71
Follow-Up Period: Week 34	2.3 ± 6.65	3.1 ± 6.17

No statistical analyses for this end point

Secondary: Mean Change from Baseline in the FACT-Lym Additional Concerns Subscale

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End point title

Mean Change from Baseline in the FACT-Lym Additional Concerns Subscale

End point description

The FACT-Lym questionnaire is a validated instrument for assessing the impact of lymphoma on HRQL and contains 42 questions covering HRQL and common lymphoma symptoms and treatment side-effects. It begins with the Functional Assessment of Cancer Therapy - General (FACT-G), which contains 27 questions covering four core subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 questions) used to assess NHL-related symptoms such as pain, itching, night sweats,trouble sleeping, fatigue and trouble concentrating and concerns regarding lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. All questions are answered on a 5-point scale ranging from “not at all” (0) to “very much” (4). The Additional Concerns subscale ranges from 0 to 60, where higher scores reflect better HRQoL.

End point type

Secondary

End point timeframe

Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	257	255
Units: Units on a Scale
arithmetic mean (standard deviation)
Midcycle	3.8 ± 10.33	4.1 ± 8.88
C6 D1	5.8 ± 11.11	5.2 ± 9.40
EoT = 3-4 weeks after C6	6.6 ± 10.11	4.5 ± 9.62
Follow-Up Period: Week 34	8.3 ± 10.61	6.5 ± 9.20

No statistical analyses for this end point

Secondary: Mean Change from Baseline in the FACT-Lym Trial Outcome Index (TOI)

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End point title

Mean Change from Baseline in the FACT-Lym Trial Outcome Index (TOI)

End point description

The FACT-Lym questionnaire is a validated instrument for assessing the impact of lymphoma on HRQL and contains 42 questions covering HRQL and common lymphoma symptoms and treatment side-effects. It begins with the Functional Assessment of Cancer Therapy - General (FACT-G), which contains 27 questions covering four core subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 questions) used to assess NHL-related symptoms and concerns. All questions are answered on a 5-point scale ranging from “not at all” (0) to “very much” (4). The FACT-Lym TOI is calculated by summing the Physical Well-being, Functional Well-being and Additional Concerns scores and has a range of 0 to 116. Higher scores reflect better HRQoL or fewer symptoms.

End point type

Secondary

End point timeframe

Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	256	254
Units: Units on a Scale
arithmetic mean (standard deviation)
Midcycle	2.6 ± 18.26	4.6 ± 16.49
C6 D1	5.9 ± 19.85	7.5 ± 17.40
EoT = 3-4 weeks after C6	9.1 ± 18.51	5.8 ± 18.64
Follow-Up Period: Week 34	13.5 ± 18.74	12.2 ± 17.97

No statistical analyses for this end point

Secondary: Mean Change from Baseline in the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Index Score

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End point title

Mean Change from Baseline in the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Index Score

End point description

The EQ-5D-3L is a generic, self-reported preference-based measure of health across five dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has three levels of ‘severity’ corresponding to “no problems”, “some problems” and “extreme problems”. The instrument is scored as a single summary index using one of the available EQ-5D-3L value sets; in this study the UK scoring weights 9 were used. The UK index ranges from -0.594 to 1, where 0 equates to death and 1 equates to full health (-0.594 is considered ‘worse than death’).

End point type

Secondary

End point timeframe

Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	257	255
Units: Units on a Scale
arithmetic mean (standard deviation)
Midcycle	0.08 ± 0.308	0.08 ± 0.281
C6 D1	0.10 ± 0.325	0.14 ± 0.330
EoT = 3-4 weeks after C6	0.10 ± 0.309	0.06 ± 0.319
Follow-Up Period: Week 34	0.15 ± 0.293	0.09 ± 0.311

No statistical analyses for this end point

Secondary: Mean Change from Baseline in the EQ-5D-3L Visual Analogue Scale (VAS)

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End point title

Mean Change from Baseline in the EQ-5D-3L Visual Analogue Scale (VAS)

End point description

The EQ-5D-3L questionnaire includes a visual analogue scale which records the respondent’s self-rated health on a vertical, 0–100 scale where 100 = “Best imaginable health state” and 0 = “Worst imaginable health state”. Higher scores again indicate better HRQoL and positive change scores indicate that post screening values were higher than those observed at screening. The EQ-5D-3L is a generic, self-reported preference-based measure of health across five dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has three levels of ‘severity’ corresponding to “no problems”, “some problems” and “extreme problems”.

End point type

Secondary

End point timeframe

Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34

End point values	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Number of subjects analysed	256	255
Units: Units on a Scale
arithmetic mean (standard deviation)
Midcycle	4.0 ± 20.5	3.0 ± 18.2
C6 D1	6.0 ± 23.5	9.0 ± 24.5
EoT = 3-4 weeks after C6	8.0 ± 18.7	6.0 ± 21.5
Follow-Up Period: Week 34	12.0 ± 20.2	9 ± 21.4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

SAEs and NSAEs were monitored from the participant's first dose of study treatment up to 28 days after their last dose; measured up to approximately 33 weeks.

Adverse event reporting additional description

Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication (Safety Population).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Placebo Plus R-CHOP

Reporting group description

Reporting group title

Lenalidomide Plus R-CHOP (R2-CHOP)

Reporting group description

Serious adverse events	Placebo Plus R-CHOP	Lenalidomide Plus R-CHOP (R2-CHOP)
Total subjects affected by serious adverse events
subjects affected / exposed	88 / 284 (30.99%)	104 / 283 (36.75%)
number of deaths (all causes)	87	85
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Central nervous system lymphoma
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diffuse large B-cell lymphoma
subjects affected / exposed	0 / 284 (0.00%)	3 / 283 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Lung adenocarcinoma
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant melanoma in situ
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 284 (0.35%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 284 (0.35%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jugular vein thrombosis
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombophlebitis superficial
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 284 (0.35%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Extravasation
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Face oedema
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypothermia
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Pyrexia
subjects affected / exposed	9 / 284 (3.17%)	7 / 283 (2.47%)
occurrences causally related to treatment / all	4 / 9	3 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (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 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Contrast media allergy
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	4 / 284 (1.41%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	5 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 284 (1.06%)	5 / 283 (1.77%)
occurrences causally related to treatment / all	3 / 3	5 / 5
deaths causally related to treatment / all	1 / 1	0 / 0
Pulmonary oedema
subjects affected / exposed	2 / 284 (0.70%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	3 / 284 (1.06%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Dyspnoea
subjects affected / exposed	2 / 284 (0.70%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tic
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Neutrophil count decreased
subjects affected / exposed	2 / 284 (0.70%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Craniofacial fracture
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	3 / 284 (1.06%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural headache
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural nausea
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural vomiting
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
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	1 / 284 (0.35%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 284 (0.00%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia supraventricular
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	4 / 284 (1.41%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	1 / 4	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	3 / 284 (1.06%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Cardiac disorder
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Nervous system disorders
Cognitive disorder
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Altered state of consciousness
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Amnesia
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aphasia
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	2 / 284 (0.70%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	2 / 284 (0.70%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lethargy
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Memory impairment
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 284 (0.70%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vocal cord paralysis
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	1 / 284 (0.35%)	16 / 283 (5.65%)
occurrences causally related to treatment / all	1 / 1	20 / 20
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic necrosis
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	13 / 284 (4.58%)	19 / 283 (6.71%)
occurrences causally related to treatment / all	14 / 14	23 / 23
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	14 / 284 (4.93%)	31 / 283 (10.95%)
occurrences causally related to treatment / all	15 / 15	41 / 42
deaths causally related to treatment / all	0 / 0	0 / 0
Cytopenia
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	6 / 284 (2.11%)	6 / 283 (2.12%)
occurrences causally related to treatment / all	6 / 7	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Agranulocytosis
subjects affected / exposed	1 / 284 (0.35%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 284 (0.00%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diverticular perforation
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Diarrhoea
subjects affected / exposed	4 / 284 (1.41%)	6 / 283 (2.12%)
occurrences causally related to treatment / all	3 / 4	3 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Dental caries
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 284 (0.00%)	4 / 283 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocutaneous fistula
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroduodenal haemorrhage
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 284 (0.35%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Flatulence
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 284 (0.70%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	1 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 284 (0.00%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 284 (0.35%)	3 / 283 (1.06%)
occurrences causally related to treatment / all	1 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic colitis
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (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 function abnormal
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Liver injury
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Decubitus ulcer
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug eruption
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 284 (0.35%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 284 (0.35%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Cytomegalovirus infection
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	2 / 284 (0.70%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 284 (0.00%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal infection
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 284 (0.35%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
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 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Campylobacter gastroenteritis
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 284 (0.00%)	3 / 283 (1.06%)
occurrences causally related to treatment / all	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 284 (0.35%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Groin abscess
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella infection
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection bacterial
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	9 / 284 (3.17%)	15 / 283 (5.30%)
occurrences causally related to treatment / all	9 / 9	13 / 17
deaths causally related to treatment / all	1 / 1	0 / 1
Pulmonary sepsis
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 284 (0.70%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Septic shock
subjects affected / exposed	1 / 284 (0.35%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	4 / 284 (1.41%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	2 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicella
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 284 (0.35%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia cytomegaloviral
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	2 / 284 (0.70%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 284 (0.35%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 284 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 284 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	1 / 284 (0.35%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Hypercalcaemia
subjects affected / exposed	0 / 284 (0.00%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Placebo Plus R-CHOP	Lenalidomide Plus R-CHOP (R2-CHOP)
Total subjects affected by non serious adverse events
subjects affected / exposed	270 / 284 (95.07%)	272 / 283 (96.11%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	27 / 284 (9.51%)	32 / 283 (11.31%)
occurrences all number	40	46
Aspartate aminotransferase increased
subjects affected / exposed	20 / 284 (7.04%)	22 / 283 (7.77%)
occurrences all number	34	33
Lymphocyte count decreased
subjects affected / exposed	12 / 284 (4.23%)	16 / 283 (5.65%)
occurrences all number	22	36
Platelet count decreased
subjects affected / exposed	10 / 284 (3.52%)	21 / 283 (7.42%)
occurrences all number	14	37
Weight decreased
subjects affected / exposed	10 / 284 (3.52%)	21 / 283 (7.42%)
occurrences all number	10	23
White blood cell count decreased
subjects affected / exposed	19 / 284 (6.69%)	35 / 283 (12.37%)
occurrences all number	63	79
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	30 / 284 (10.56%)	27 / 283 (9.54%)
occurrences all number	30	28
Nervous system disorders
Peripheral sensory neuropathy
subjects affected / exposed	51 / 284 (17.96%)	51 / 283 (18.02%)
occurrences all number	52	53
Paraesthesia
subjects affected / exposed	27 / 284 (9.51%)	26 / 283 (9.19%)
occurrences all number	28	27
Neuropathy peripheral
subjects affected / exposed	12 / 284 (4.23%)	19 / 283 (6.71%)
occurrences all number	12	22
Headache
subjects affected / exposed	28 / 284 (9.86%)	26 / 283 (9.19%)
occurrences all number	29	29
Dizziness
subjects affected / exposed	16 / 284 (5.63%)	16 / 283 (5.65%)
occurrences all number	20	18
Dysgeusia
subjects affected / exposed	15 / 284 (5.28%)	10 / 283 (3.53%)
occurrences all number	15	10
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	55 / 284 (19.37%)	68 / 283 (24.03%)
occurrences all number	130	167
Neutropenia
subjects affected / exposed	150 / 284 (52.82%)	183 / 283 (64.66%)
occurrences all number	366	505
Lymphopenia
subjects affected / exposed	31 / 284 (10.92%)	35 / 283 (12.37%)
occurrences all number	86	104
Anaemia
subjects affected / exposed	95 / 284 (33.45%)	127 / 283 (44.88%)
occurrences all number	161	222
Leukopenia
subjects affected / exposed	50 / 284 (17.61%)	50 / 283 (17.67%)
occurrences all number	151	196
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	40 / 284 (14.08%)	52 / 283 (18.37%)
occurrences all number	57	83
Oedema peripheral
subjects affected / exposed	32 / 284 (11.27%)	33 / 283 (11.66%)
occurrences all number	32	49
Fatigue
subjects affected / exposed	50 / 284 (17.61%)	40 / 283 (14.13%)
occurrences all number	61	43
Asthenia
subjects affected / exposed	28 / 284 (9.86%)	39 / 283 (13.78%)
occurrences all number	32	44
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	18 / 284 (6.34%)	11 / 283 (3.89%)
occurrences all number	24	15
Abdominal pain
subjects affected / exposed	16 / 284 (5.63%)	18 / 283 (6.36%)
occurrences all number	18	21
Vomiting
subjects affected / exposed	26 / 284 (9.15%)	32 / 283 (11.31%)
occurrences all number	30	46
Constipation
subjects affected / exposed	81 / 284 (28.52%)	92 / 283 (32.51%)
occurrences all number	109	115
Diarrhoea
subjects affected / exposed	40 / 284 (14.08%)	49 / 283 (17.31%)
occurrences all number	51	61
Nausea
subjects affected / exposed	66 / 284 (23.24%)	64 / 283 (22.61%)
occurrences all number	97	92
Stomatitis
subjects affected / exposed	37 / 284 (13.03%)	33 / 283 (11.66%)
occurrences all number	41	41
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	10 / 284 (3.52%)	16 / 283 (5.65%)
occurrences all number	11	17
Dyspnoea
subjects affected / exposed	15 / 284 (5.28%)	11 / 283 (3.89%)
occurrences all number	18	13
Cough
subjects affected / exposed	20 / 284 (7.04%)	31 / 283 (10.95%)
occurrences all number	23	38
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	43 / 284 (15.14%)	48 / 283 (16.96%)
occurrences all number	43	48
Psychiatric disorders
Insomnia
subjects affected / exposed	32 / 284 (11.27%)	23 / 283 (8.13%)
occurrences all number	47	24
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	13 / 284 (4.58%)	18 / 283 (6.36%)
occurrences all number	13	18
Back pain
subjects affected / exposed	22 / 284 (7.75%)	15 / 283 (5.30%)
occurrences all number	26	15
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	18 / 284 (6.34%)	23 / 283 (8.13%)
occurrences all number	21	29
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	32 / 284 (11.27%)	29 / 283 (10.25%)
occurrences all number	41	38
Hyperglycaemia
subjects affected / exposed	19 / 284 (6.69%)	18 / 283 (6.36%)
occurrences all number	24	24
Hypokalaemia
subjects affected / exposed	28 / 284 (9.86%)	41 / 283 (14.49%)
occurrences all number	42	74

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Were there any global substantial amendments to the protocol? Yes

24 Jan 2017

Revised lenalidomide / placebo dose modification rules for neutropenia and thrombocytopenia toxicities.

12 Jun 2019

Protocol Amendment 4 removes the requirement of follow-up assessments for subjects continuing in the study except for overall survival (OS) and second primary malignancy (SPM) follow-up.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Kaplan-Meier Estimate of Progression Free Survival (PFS)

Primary: Kaplan-Meier Estimate of Progression Free Survival (PFS)

Secondary: Percentage of Participants who Achieved a Complete Response (CR)

Secondary: Percentage of Participants who Achieved a Complete Response (CR)

Secondary: K-M Estimate of Overall Survival (OS)

Secondary: K-M Estimate of Overall Survival (OS)

Secondary: Kaplan-Meier (K-M) Estimate of Event Free Survival (EFS)

Secondary: Kaplan-Meier (K-M) Estimate of Event Free Survival (EFS)

Secondary: K-M Estimate of Time to Next Lymphoma Therapy (TTNLT)

Secondary: K-M Estimate of Time to Next Lymphoma Therapy (TTNLT)

Secondary: K-M Estimate of Duration of Complete Response

Secondary: K-M Estimate of Duration of Complete Response

Secondary: Percentage of Participants who Achieved an Objective Response

Secondary: Percentage of Participants who Achieved an Objective Response

Secondary: Percentage of Participants who Completed the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Health Related Quality of Life (HR-QoL) Questionnaire

Secondary: Percentage of Participants who Completed the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Health Related Quality of Life (HR-QoL) Questionnaire

Secondary: Percentage of Participants who Completed the Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) Questionnaire

Secondary: Percentage of Participants who Completed the Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) Questionnaire

Secondary: Mean Change from Baseline in the FACT-Lym Physical Well-Being Subscale

Secondary: Mean Change from Baseline in the FACT-Lym Physical Well-Being Subscale

Secondary: Mean Change from Baseline in the FACT-Lym Functional Well-Being Subscale

Secondary: Mean Change from Baseline in the FACT-Lym Functional Well-Being Subscale

Secondary: Mean Change from Baseline in the FACT-Lym Additional Concerns Subscale

Secondary: Mean Change from Baseline in the FACT-Lym Additional Concerns Subscale

Secondary: Mean Change from Baseline in the FACT-Lym Trial Outcome Index (TOI)

Secondary: Mean Change from Baseline in the FACT-Lym Trial Outcome Index (TOI)

Secondary: Mean Change from Baseline in the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Index Score

Secondary: Mean Change from Baseline in the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Index Score

Secondary: Mean Change from Baseline in the EQ-5D-3L Visual Analogue Scale (VAS)

Secondary: Mean Change from Baseline in the EQ-5D-3L Visual Analogue Scale (VAS)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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