Efficacy and Safety Study of Lenalidomide Plus R-CHOP Chemotherapy Versus Placebo Plus R-CHOP Chemotherapy in Untreated ABC Type Diffuse Large B-cell Lymphoma (ROBUST)

• ClinicalTrials.gov Identifier: NCT02285062
• Recruitment Status: Active, not recruiting
• First Posted: November 6, 2014
• Results First Posted: March 30, 2020
• Last Update Posted: March 31, 2020
• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Lymphoma, Large B-Cell, Diffuse
• Interventions: Drug: lenalidomide; Drug: Placebo; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: prednisone; Drug: vincristine
• Enrollment: 570

Participant Flow

Recruitment Details	The study has completed enrollment but is ongoing. 177 community, academic and government sites randomized participants in Australia, Belgium, Canada, China, the Czech Republic, France, Ireland, Israel, Italy, Japan, the Netherlands, New Zealand, Poland, Portugal, Russia, South Korea, Spain, Switzerland, Taiwan, Turkey and the United States.
Pre-assignment Details	Participants were randomized in a 1:1 ratio to either lenalidomide-(R2)CHOP or placebo-R-CHOP, and stratified by International Prognostic Index (IPI) Score 2 or ≥ 3, age: < 65 or ≥ 65 years and presence of bulky disease: diameter of the lesion ≥ 7.0 cm (bulky) or < 7.0 cm (nonbulky). .

Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Period Title: Overall Study
Started	285	285
Received Study Treatment	283	284
Ongoing Study Treatment	0	0
Completed [1]	207	201
Not Completed	78	84
Reason Not Completed
Withdrawal by Subject	12	17
Death	58	62
Lost to Follow-up	8	5
[1] Completed = Ongoing in the Follow-Up Period

Baseline Characteristics

Arm/Group Title		Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP	Total
Arm/Group 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.	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.	Total of all reporting groups
Overall Number of Baseline Participants		285	285	570
Baseline Analysis Population Description		The Intent-to-treat (ITT) population was defined as all participants who were randomized into the trial, regardless of whether they received study treatment or not.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	285 participants	285 participants	570 participants
		62.5 (11.72)	63.9 (9.35)	63.2 (10.62)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	285 participants	285 participants	570 participants
	< 65	138 48.4%	137 48.1%	275 48.2%
	≥ 65	147 51.6%	148 51.9%	295 51.8%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	285 participants	285 participants	570 participants
	Female	121 42.5%	142 49.8%	263 46.1%
	Male	164 57.5%	143 50.2%	307 53.9%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	285 participants	285 participants	570 participants
	Hispanic or Latino	14 4.9%	17 6.0%	31 5.4%
	Not Hispanic or Latino	270 94.7%	267 93.7%	537 94.2%
	Unknown or Not Reported	1 0.4%	1 0.4%	2 0.4%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	285 participants	285 participants	570 participants
	White	173 60.7%	183 64.2%	356 62.5%
	Asian	101 35.4%	89 31.2%	190 33.3%
	Black or African American	2 0.7%	3 1.1%	5 0.9%
	Other	3 1.1%	2 0.7%	5 0.9%
	Not Collected or Reported	6 2.1%	8 2.8%	14 2.5%
Body Surface Area (BSA) [1]; Mean (Standard Deviation); Unit of measure: M^2
	Number Analyzed	285 participants	285 participants	570 participants
		1.780 (0.2167)	1.775 (0.2101)	1.777 (0.2132)
		[1] Measure Description: 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.
Eastern Cooperative Oncology Group (ECOG) Performance Status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	285 participants	285 participants	570 participants
	0 = Fully Active	129 45.3%	111 38.9%	240 42.1%
	1 = Restrictive but ambulatory	104 36.5%	118 41.4%	222 38.9%
	2 = Ambulatory but unable to work	52 18.2%	56 19.6%	108 18.9%
		[1] Measure Description: 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
Creatinine Clearance [1] [2]; Mean (Standard Deviation); Unit of measure: mL/min
	Number Analyzed	285 participants	284 participants	569 participants
		92.08 (35.576)	90.19 (31.040)	91.14 (33.373)
		[1] Measure Description: 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.; [2] Measure Analysis Population Description: One creatinine clearance value is missing.
International Prognostic Index (IPI) Score [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	285 participants	285 participants	570 participants
	= 2	121 42.5%	120 42.1%	241 42.3%
	≥ 3	164 57.5%	165 57.9%	329 57.7%
		[1] Measure Description: 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)
Presence of Bulky Disease; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	285 participants	285 participants	570 participants
	< 7.0 cm (Non-Bulky Disease)	188 66.0%	186 65.3%	374 65.6%
	≥ 7.0 cm (Bulky Disease)	97 34.0%	99 34.7%	196 34.4%
Disease Stage of Diffuse Large B-Cell Lymphoma at Diagnosis [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	285 participants	285 participants	570 participants
	Stage I	0 0.0%	1 0.4%	1 0.2%
	Stage II	37 13.0%	32 11.2%	69 12.1%
	Stage III	80 28.1%	98 34.4%	178 31.2%
	Stage IV	168 58.9%	154 54.0%	322 56.5%
		[1] Measure Description: 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.

Outcome Measures

1. Primary Outcome

Title	Kaplan-Meier Estimate of Progression Free Survival (PFS)
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.
Time Frame	From the date of randomization up to the data cut off date of 15 March 2019; median follow-up of 24.5 months

Outcome Measure Data

Analysis Population Description

The Intent-to-treat (ITT) population was defined as all participants who were randomized into the trial, regardless of whether they received study treatment or not.

Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed	285	285
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (35.5 to NA)

[1]

Median PFS and the upper and lower 95% confidence interval was not reached due to the low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus R-CHOP (R2-CHOP), Placebo Plus R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2864
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Stratified by: IPI score (2 or ≥ 3), presence or absence of bulky disease (diameter of the lesion ≥ 7 cm or < 7 cm), and age (< 65 or ≥ 65 years).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.849
	Confidence Interval	(2-Sided) 95%; 0.632 to 1.140
	Estimation Comments	Hazard ratio was derived from Cox proportional hazard model adjusting for the 3 stratification factors

2. Secondary Outcome

Title	Kaplan-Meier (K-M) Estimate of Event Free Survival (EFS)
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.
Time Frame	From the date of randomization up to the data cut off date of 15 March 2019; median follow-up was 24.5 months

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized into the trial, regardless of whether they received study treatment or not.

Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed	285	285
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (31.3 to NA)

[1]

Median EFS was not reached due to the low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus R-CHOP (R2-CHOP), Placebo Plus R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7294
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Stratified by: IPI score (2 or ≥ 3), presence or absence of bulky disease (diameter of the lesion ≥ 7 cm or < 7 cm), and age (< 65 or ≥ 65 years).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.038
	Confidence Interval	(2-Sided) 95%; 0.802 to 1.344
	Estimation Comments	Hazard ratio was derived from Cox proportional hazard model adjusting for the 3 stratification factors.

3. Secondary Outcome

Title	K-M Estimate of Overall Survival (OS)
Description	Overall survival was assessed by the IRAC and defined as time from randomization until death of 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.
Time Frame	From the date of randomization up to the data cut off date of 15 March 2019; median follow-up was 24.5 months

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized into the trial, regardless of whether they received study treatment or not.

Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed	285	285
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

K-M estimate median OS was not reached due to low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus R-CHOP (R2-CHOP), Placebo Plus R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6433
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Log-rank test stratified by 3 factors: IPI score (2 or ≥ 3), presence of bulky disease (bulky or nonbulky), and age (< 65 or ≥ 65).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.925
	Confidence Interval	(2-Sided) 95%; 0.646 to 1.323
	Estimation Comments	Hazard ratio was derived from Cox proportional hazard model adjusting for the 3 stratification factors.

4. Secondary Outcome

Title	Percentage of Participants Who Achieved a Complete Response (CR)
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.
Time Frame	From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized into the trial, regardless of whether they received study treatment or not. Participants who had a CR.

Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed	285	285
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	69.1; (63.4 to 74.4)	64.9; (59.1 to 70.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus R-CHOP (R2-CHOP), Placebo Plus R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2933
	Comments	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)
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

5. Secondary Outcome

Title	Percentage of Participants Who Achieved an Objective Response
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Intent-to-treat population was defined as all participants who were randomized into the trial, regardless of whether they received study treatment or not. Participants who had a PR or better.

Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed	285	285
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	90.9; (86.9 to 94.0)	90.9; (86.9 to 94.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus R-CHOP (R2-CHOP), Placebo Plus R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9964
	Comments	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)
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

6. Secondary Outcome

Title	K-M Estimate of Duration of Complete Response
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.
Time Frame	From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months.

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized into the trial, regardless of whether they received study treatment or not. Participants who had a response.

Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed	197	185
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [2]; (NA to NA)

[1]

Median duration of CR could not be estimated due to the low number of events.

[2]

Median duration of CR could not be estimated due to due to the low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus R-CHOP (R2-CHOP), Placebo Plus R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2143
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Stratified by: IPI score (2 or ≥ 3), presence or absence of bulky disease (diameter of the lesion ≥ 7 cm or < 7 cm), and age (< 65 or ≥ 65 years).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.776
	Confidence Interval	(2-Sided) 95%; 0.521 to 1.157
	Estimation Comments	HR was derived from COX model adjusting for the 3 stratification factors mentioned above.

7. Secondary Outcome

Title	K-M Estimate of Time to Next Lymphoma Therapy (TTNLT)
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.
Time Frame	From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months

Outcome Measure Data

Analysis Population Description

The Intent-to-treat (ITT) population was defined as all participants who were randomized into the trial, regardless of whether they received study treatment or not.

Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed	285	285
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Median time to next lymphoma treatment was not reached due to low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus R-CHOP (R2-CHOP), Placebo Plus R-CHOP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3150
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Stratified by: IPI score (2 or ≥ 3), presence or absence of bulky disease (diameter of the lesion ≥ 7 cm or < 7 cm), and age (< 65 or ≥ 65 years).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.167
	Confidence Interval	95%; 0.856 to 1.590
	Estimation Comments	HR is derived from Cox model

8. Secondary Outcome

Title	Number of Participants With a Treatment Emergent Adverse Event (TEAE)
Description	A TEAE was defined as an AE that begins or worsens in intensity or frequency on or after the first dose of study drug through 28 days after last dose of study drug. A serious adverse event (SAE) is any: Death;; Life-threatening event;; Any inpatient hospitalization or prolongation of existing hospitalization;; Persistent or significant disability or incapacity;; Congenital anomaly or birth defect;; Any other important medical event The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death
Time Frame	From the first dose of study treatment up to 28 days after the last dose of LEN/placebo or any component of R-CHOP including the optional 2 additional doses of rituximab if administered; up to 15 March 2019; maximum treatment duration = 29 months

Outcome Measure Data

Analysis Population Description

The safety population was defined as all participants who had received at least one dose of investigational product.

Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed	283	284
Measure Type: Count of Participants; Unit of Measure: Participants
≥ 1 TEAE	281 99.3%	279 98.2%
≥1 TEAE Related to Lenalidomide (LEN)/Placebo	249 88.0%	222 78.2%
≥ 1 TEAE Related to RCHOP	271 95.8%	254 89.4%
≥ 1 Grade (GR) 3 TEAE	203 71.7%	172 60.6%
≥ 1 GR 4 TEAE	154 54.4%	129 45.4%
≥ 1 GR 3 or 4 TEAE	221 78.1%	203 71.5%
≥1 GR 3 or 4 TEAE Related to LEN/Placebo (PBO)	185 65.4%	157 55.3%
≥ 1 GR 3 or 4 TEAE related to R- CHOP	200 70.7%	177 62.3%
≥ 1 GR 5 TEAE (Leading to Death)	6 2.1%	8 2.8%
≥ 1 GR 5 TEAE (Death) Related to LEN/PBO	3 1.1%	4 1.4%
≥ 1 GR 5 TEAE (Death) related to R-CHOP	3 1.1%	3 1.1%
≥ 1 Treatment-Emergent SAE	104 36.7%	88 31.0%
≥ 1 Treatment-Emergent SAE Related to LEN/PBO	69 24.4%	57 20.1%
≥1 Treatment-Emergent SAE Related to R-CHOP	67 23.7%	60 21.1%
≥1 TEAE Leading to Discontinuing (DC) LEN/PBO	49 17.3%	32 11.3%
≥1 TEAE Leading to DC R-CHOP	9 3.2%	9 3.2%
≥1 TEAE Leading to DC of LEN/placebo and R-CHOP	7 2.5%	9 3.2%
≥1 TEAE Lead to Reduction/ Interruption LEN/PBO	159 56.2%	129 45.4%
≥1 TEAE Leading to Dose Reduction of LEN/PBO	68 24.0%	41 14.4%
≥1 TEAE Leading to Dose Interruption of LEN/PBO	144 50.9%	122 43.0%
≥1 TEAE Lead to Dose Reduction/Interruption R-CHOP	97 34.3%	82 28.9%
≥ 1 TEAE Leading to Dose Reduction of R-CHOP	54 19.1%	45 15.8%
≥ 1 TEAE Leading to Dose Interruption of R-CHOP	64 22.6%	53 18.7%

9. Secondary Outcome

Title	Percentage of Participants Who Completed the Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) Questionnaire
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized into the trial, regardless of whether they received study treatment or not.

Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed	285	285
Measure Type: Number; Unit of Measure: Percentage of Participants
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

10. Secondary Outcome

Title	Percentage of Participants Who Completed the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Health Related Quality of Life (HR-QoL) Questionnaire
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'.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized into the trial, regardless of whether they received study treatment or not.

Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed	285	285
Measure Type: Number; Unit of Measure: Percentage of Participants
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

11. Secondary Outcome

Title	Mean Change From Baseline in the FACT-Lym Physical Well-Being Subscale
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The HRQoL evaluable population was defined as all participants in the ITT population who had: at least one baseline and the corresponding post-baseline calculable FACT-Lym score assessment; where post-baseline is any subsequent time excluding unscheduled visits (i.e. at Midcycle, C6D1, EOT or a follow-up visit).

Arm/Group Title		Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed		257	257
Mean (Standard Deviation); Unit of Measure: Units on a Scale
Midcycle	Number Analyzed	246 participants	244 participants
		-0.7 (5.91)	0.2 (5.40)
C6 D1	Number Analyzed	140 participants	137 participants
		-0.0 (6.35)	0.9 (6.02)
EoT = 3-4 weeks after C6	Number Analyzed	214 participants	226 participants
		1.5 (5.53)	0.7 (5.72)
Follow-Up Period: Week 34	Number Analyzed	191 participants	196 participants
		2.8 (5.24)	2.6 (5.55)

12. Secondary Outcome

Title	Mean Change From Baseline in the FACT-Lym Additional Concerns Subscale
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The HRQoL evaluable population was defined as all participants in the ITT population who had: at least one baseline and the corresponding post-baseline calculable FACT-Lym score assessment; where post-baseline is any subsequent time excluding unscheduled visits (i.e. at Midcycle, C6D1, EOT or a follow-up visit).

Arm/Group Title		Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed		257	255
Mean (Standard Deviation); Unit of Measure: Units on a Scale
Midcycle	Number Analyzed	244 participants	242 participants
		3.8 (10.33)	4.1 (8.88)
C6 D1	Number Analyzed	139 participants	135 participants
		5.8 (11.11)	5.2 (9.40)
EoT = 3-4 weeks after C6	Number Analyzed	212 participants	222 participants
		6.6 (10.11)	4.5 (9.62)
Follow-Up Period: Week 34	Number Analyzed	189 participants	195 participants
		8.3 (10.61)	6.5 (9.20)

13. Secondary Outcome

Title	Mean Change From Baseline in the FACT-Lym Functional Well-Being Subscale
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The HRQoL evaluable population was defined as all participants in the ITT population who had: at least one baseline and the corresponding post-baseline calculable FACT-Lym score assessment; where post-baseline is any subsequent time excluding unscheduled visits (i.e. at Midcycle, C6D1, EOT or a follow-up visit).

Arm/Group Title		Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed		258	256
Mean (Standard Deviation); Unit of Measure: Units on a Scale
Midcycle	Number Analyzed	246 participants	242 participants
		-0.5 (6.12)	0.5 (5.84)
C6 D1	Number Analyzed	139 participants	135 participants
		0.0 (6.24)	1.4 (5.63)
EoT = 3-4 weeks after C6	Number Analyzed	214 participants	224 participants
		1.0 (6.53)	0.7 (6.71)
Follow-Up Period: Week 34	Number Analyzed	191 participants	196 participants
		2.3 (6.65)	3.1 (6.17)

14. Secondary Outcome

Title	Mean Change From Baseline in the FACT-Lym Trial Outcome Index (TOI)
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The HRQoL evaluable population was defined as all participants in the ITT population who had: at least one baseline and the corresponding post-baseline calculable FACT-Lym score assessment; where post-baseline is any subsequent time excluding unscheduled visits (i.e. at Midcycle, C6D1, EOT or a follow-up visit).

Arm/Group Title		Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed		256	254
Mean (Standard Deviation); Unit of Measure: Units on a Scale
Midcycle	Number Analyzed	244 participants	240 participants
		2.6 (18.26)	4.6 (16.49)
C6 D1	Number Analyzed	138 participants	133 participants
		5.9 (19.85)	7.5 (17.40)
EoT = 3-4 weeks after C6	Number Analyzed	212 participants	220 participants
		9.1 (18.51)	5.8 (18.64)
Follow-Up Period: Week 34	Number Analyzed	189 participants	193 participants
		13.5 (18.74)	12.2 (17.97)

15. Secondary Outcome

Title	Mean Change From Baseline in the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Index Score
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').
Time Frame	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

Outcome Measure Data

Analysis Population Description

The HRQoL evaluable population was defined as all participants in the ITT population who had: at least one baseline and the corresponding post-baseline calculable EQ-5D score assessment; where post-baseline is any subsequent time excluding unscheduled visits (i.e. at Midcycle, C6D1, EOT or a follow-up visit).

Arm/Group Title		Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed		257	255
Mean (Standard Deviation); Unit of Measure: Units on a Scale
Midcycle	Number Analyzed	245 participants	241 participants
		0.08 (0.308)	0.08 (0.281)
C6 D1	Number Analyzed	139 participants	135 participants
		0.10 (0.325)	0.14 (0.330)
EoT = 3-4 weeks after C6	Number Analyzed	214 participants	223 participants
		0.10 (0.309)	0.06 (0.319)
Follow-Up Period: Week 34	Number Analyzed	190 participants	195 participants
		0.15 (0.293)	0.09 (0.311)

16. Secondary Outcome

Title	Mean Change From Baseline in the EQ-5D-3L Visual Analogue Scale (VAS)
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".
Time Frame	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

Outcome Measure Data

Analysis Population Description

The HRQoL evaluable population was defined as all participants in the ITT population who had: at least one baseline and the corresponding post-baseline calculable EQ-5D score assessment; where post-baseline is any subsequent time excluding unscheduled visits (i.e. at Midcycle, C6D1, EOT or a follow-up visit).

Arm/Group Title		Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
Overall Number of Participants Analyzed		256	255
Mean (Standard Deviation); Unit of Measure: Units on a Scale
Midcycle	Number Analyzed	245 participants	242 participants
		4.0 (20.5)	3.0 (18.2)
C6 D1	Number Analyzed	138 participants	135 participants
		6.0 (23.5)	9.0 (24.5)
EoT = 3-4 weeks after C6	Number Analyzed	213 participants	224 participants
		8.0 (18.7)	6.0 (21.5)
Follow-Up Period: Week 34	Number Analyzed	190 participants	195 participants
		12.0 (20.2)	9 (21.4)

Adverse Events

Time Frame	AEs were monitored from the first dose of study treatment up to 28 days after the last dose of LEN/PBO or any component of R-CHOP including the optional 2 additional doses of rituximab; median total treatment duration was 18.10 weeks for both arms; up to 15 March 2019
Adverse Event Reporting Description	All-Cause Mortality is reported for the entire duration of the study including follow-up. (ITT Population)
Arm/Group Title	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
Arm/Group 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.	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.
All-Cause Mortality
	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
	Affected / at Risk (%)	Affected / at Risk (%)
Total	58/285 (20.35%)	62/285 (21.75%)
Serious Adverse Events
	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
	Affected / at Risk (%)	Affected / at Risk (%)
Total	104/283 (36.75%)	88/284 (30.99%)
Blood and lymphatic system disorders
Agranulocytosis † 1	1/283 (0.35%)	1/284 (0.35%)
Anaemia † 1	6/283 (2.12%)	6/284 (2.11%)
Cytopenia † 1	1/283 (0.35%)	0/284 (0.00%)
Febrile neutropenia † 1	31/283 (10.95%)	14/284 (4.93%)
Leukopenia † 1	2/283 (0.71%)	0/284 (0.00%)
Lymphadenopathy † 1	0/283 (0.00%)	1/284 (0.35%)
Neutropenia † 1	19/283 (6.71%)	13/284 (4.58%)
Splenic necrosis † 1	0/283 (0.00%)	1/284 (0.35%)
Thrombocytopenia † 1	16/283 (5.65%)	1/284 (0.35%)
Cardiac disorders
Acute coronary syndrome † 1	1/283 (0.35%)	0/284 (0.00%)
Acute myocardial infarction † 1	2/283 (0.71%)	0/284 (0.00%)
Arrhythmia supraventricular † 1	1/283 (0.35%)	0/284 (0.00%)
Atrial fibrillation † 1	2/283 (0.71%)	4/284 (1.41%)
Atrial flutter † 1	0/283 (0.00%)	1/284 (0.35%)
Cardiac arrest † 1	0/283 (0.00%)	1/284 (0.35%)
Cardiac disorder † 1	0/283 (0.00%)	1/284 (0.35%)
Cardiac failure † 1	0/283 (0.00%)	3/284 (1.06%)
Cardiac failure congestive † 1	0/283 (0.00%)	1/284 (0.35%)
Coronary artery disease † 1	0/283 (0.00%)	1/284 (0.35%)
Sinus tachycardia † 1	0/283 (0.00%)	1/284 (0.35%)
Gastrointestinal disorders
Abdominal distension † 1	1/283 (0.35%)	0/284 (0.00%)
Abdominal pain † 1	4/283 (1.41%)	0/284 (0.00%)
Dental caries † 1	0/283 (0.00%)	1/284 (0.35%)
Diarrhoea † 1	6/283 (2.12%)	4/284 (1.41%)
Diverticular perforation † 1	0/283 (0.00%)	1/284 (0.35%)
Enterocutaneous fistula † 1	0/283 (0.00%)	1/284 (0.35%)
Flatulence † 1	1/283 (0.35%)	0/284 (0.00%)
Gastric haemorrhage † 1	2/283 (0.71%)	1/284 (0.35%)
Gastroduodenal haemorrhage † 1	0/283 (0.00%)	1/284 (0.35%)
Gastrointestinal haemorrhage † 1	1/283 (0.35%)	0/284 (0.00%)
Haematochezia † 1	1/283 (0.35%)	0/284 (0.00%)
Intestinal obstruction † 1	1/283 (0.35%)	0/284 (0.00%)
Large intestine perforation † 1	0/283 (0.00%)	1/284 (0.35%)
Nausea † 1	2/283 (0.71%)	2/284 (0.70%)
Neutropenic colitis † 1	0/283 (0.00%)	1/284 (0.35%)
Stomatitis † 1	2/283 (0.71%)	0/284 (0.00%)
Vomiting † 1	3/283 (1.06%)	1/284 (0.35%)
General disorders
Asthenia † 1	2/283 (0.71%)	1/284 (0.35%)
Death † 1	1/283 (0.35%)	0/284 (0.00%)
Extravasation † 1	1/283 (0.35%)	0/284 (0.00%)
Face oedema † 1	1/283 (0.35%)	0/284 (0.00%)
General physical health deterioration † 1	1/283 (0.35%)	0/284 (0.00%)
Hypothermia † 1	1/283 (0.35%)	0/284 (0.00%)
Malaise † 1	1/283 (0.35%)	0/284 (0.00%)
Non-cardiac chest pain † 1	0/283 (0.00%)	1/284 (0.35%)
Oedema peripheral † 1	1/283 (0.35%)	0/284 (0.00%)
Pyrexia † 1	7/283 (2.47%)	9/284 (3.17%)
Sudden cardiac death † 1	1/283 (0.35%)	0/284 (0.00%)
Hepatobiliary disorders
Bile duct stone † 1	1/283 (0.35%)	0/284 (0.00%)
Drug-induced liver injury † 1	1/283 (0.35%)	0/284 (0.00%)
Hepatic function abnormal † 1	0/283 (0.00%)	1/284 (0.35%)
Hepatitis † 1	0/283 (0.00%)	1/284 (0.35%)
Jaundice cholestatic † 1	1/283 (0.35%)	0/284 (0.00%)
Liver injury † 1	0/283 (0.00%)	1/284 (0.35%)
Immune system disorders
Contrast media allergy † 1	0/283 (0.00%)	1/284 (0.35%)
Infections and infestations
Abdominal infection † 1	0/283 (0.00%)	1/284 (0.35%)
Anal abscess † 1	1/283 (0.35%)	0/284 (0.00%)
Appendicitis † 1	1/283 (0.35%)	1/284 (0.35%)
Arthritis bacterial † 1	1/283 (0.35%)	0/284 (0.00%)
Bacterial infection † 1	1/283 (0.35%)	0/284 (0.00%)
Bronchitis † 1	0/283 (0.00%)	1/284 (0.35%)
Campylobacter gastroenteritis † 1	1/283 (0.35%)	0/284 (0.00%)
Cellulitis † 1	3/283 (1.06%)	0/284 (0.00%)
Clostridium difficile colitis † 1	1/283 (0.35%)	1/284 (0.35%)
Cytomegalovirus infection † 1	1/283 (0.35%)	1/284 (0.35%)
Device related infection † 1	1/283 (0.35%)	2/284 (0.70%)
Device related sepsis † 1	2/283 (0.71%)	0/284 (0.00%)
Escherichia sepsis † 1	1/283 (0.35%)	0/284 (0.00%)
Escherichia urinary tract infection † 1	1/283 (0.35%)	0/284 (0.00%)
Groin abscess † 1	1/283 (0.35%)	0/284 (0.00%)
Hepatitis B † 1	0/283 (0.00%)	1/284 (0.35%)
Herpes zoster † 1	0/283 (0.00%)	1/284 (0.35%)
Influenza † 1	1/283 (0.35%)	0/284 (0.00%)
Klebsiella infection † 1	1/283 (0.35%)	0/284 (0.00%)
Lower respiratory tract infection † 1	0/283 (0.00%)	1/284 (0.35%)
Lower respiratory tract infection bacterial † 1	1/283 (0.35%)	0/284 (0.00%)
Lung infection † 1	4/283 (1.41%)	2/284 (0.70%)
Neutropenic sepsis † 1	1/283 (0.35%)	0/284 (0.00%)
Osteomyelitis † 1	0/283 (0.00%)	1/284 (0.35%)
Parainfluenzae virus infection † 1	1/283 (0.35%)	0/284 (0.00%)
Pharyngitis † 1	0/283 (0.00%)	1/284 (0.35%)
Pneumocystis jirovecii pneumonia † 1	0/283 (0.00%)	1/284 (0.35%)
Pneumonia † 1	11/283 (3.89%)	7/284 (2.46%)
Pulmonary sepsis † 1	1/283 (0.35%)	0/284 (0.00%)
Salmonellosis † 1	1/283 (0.35%)	0/284 (0.00%)
Sepsis † 1	2/283 (0.71%)	2/284 (0.70%)
Septic shock † 1	2/283 (0.71%)	1/284 (0.35%)
Soft tissue infection † 1	0/283 (0.00%)	1/284 (0.35%)
Tracheobronchitis † 1	0/283 (0.00%)	1/284 (0.35%)
Upper respiratory tract infection † 1	2/283 (0.71%)	1/284 (0.35%)
Urinary tract infection † 1	0/283 (0.00%)	4/284 (1.41%)
Varicella † 1	1/283 (0.35%)	0/284 (0.00%)
Injury, poisoning and procedural complications
Craniofacial fracture † 1	0/283 (0.00%)	1/284 (0.35%)
Femur fracture † 1	0/283 (0.00%)	1/284 (0.35%)
Infusion related reaction † 1	1/283 (0.35%)	3/284 (1.06%)
Lower limb fracture † 1	1/283 (0.35%)	0/284 (0.00%)
Lumbar vertebral fracture † 1	1/283 (0.35%)	0/284 (0.00%)
Procedural headache † 1	1/283 (0.35%)	0/284 (0.00%)
Procedural nausea † 1	1/283 (0.35%)	0/284 (0.00%)
Procedural vomiting † 1	1/283 (0.35%)	0/284 (0.00%)
Spinal compression fracture † 1	1/283 (0.35%)	1/284 (0.35%)
Spinal fracture † 1	0/283 (0.00%)	1/284 (0.35%)
Traumatic intracranial haemorrhage † 1	0/283 (0.00%)	1/284 (0.35%)
Investigations
Neutrophil count decreased † 1	0/283 (0.00%)	2/284 (0.70%)
Platelet count decreased † 1	0/283 (0.00%)	1/284 (0.35%)
White blood cell count decreased † 1	1/283 (0.35%)	0/284 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	0/283 (0.00%)	2/284 (0.70%)
Electrolyte imbalance † 1	1/283 (0.35%)	0/284 (0.00%)
Hypercalcaemia † 1	2/283 (0.71%)	0/284 (0.00%)
Hyperglycaemia † 1	1/283 (0.35%)	1/284 (0.35%)
Hypokalaemia † 1	0/283 (0.00%)	1/284 (0.35%)
Hyponatraemia † 1	1/283 (0.35%)	0/284 (0.00%)
Tumour lysis syndrome † 1	1/283 (0.35%)	1/284 (0.35%)
Musculoskeletal and connective tissue disorders
Back pain † 1	1/283 (0.35%)	1/284 (0.35%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma † 1	0/283 (0.00%)	1/284 (0.35%)
Central nervous system lymphoma † 1	1/283 (0.35%)	0/284 (0.00%)
Diffuse large B-cell lymphoma † 1	3/283 (1.06%)	0/284 (0.00%)
Lung adenocarcinoma † 1	0/283 (0.00%)	1/284 (0.35%)
Malignant melanoma in situ † 1	1/283 (0.35%)	0/284 (0.00%)
Tumour haemorrhage † 1	0/283 (0.00%)	1/284 (0.35%)
Nervous system disorders
Altered state of consciousness † 1	1/283 (0.35%)	0/284 (0.00%)
Amnesia † 1	1/283 (0.35%)	0/284 (0.00%)
Aphasia † 1	1/283 (0.35%)	0/284 (0.00%)
Cerebrovascular accident † 1	0/283 (0.00%)	2/284 (0.70%)
Cognitive disorder † 1	1/283 (0.35%)	0/284 (0.00%)
Dizziness † 1	1/283 (0.35%)	0/284 (0.00%)
Dysarthria † 1	1/283 (0.35%)	0/284 (0.00%)
Epilepsy † 1	1/283 (0.35%)	0/284 (0.00%)
Guillain-Barre syndrome † 1	0/283 (0.00%)	1/284 (0.35%)
Haemorrhage intracranial † 1	0/283 (0.00%)	1/284 (0.35%)
Hemiparesis † 1	1/283 (0.35%)	2/284 (0.70%)
Lethargy † 1	0/283 (0.00%)	1/284 (0.35%)
Memory impairment † 1	1/283 (0.35%)	0/284 (0.00%)
Nervous system disorder † 1	1/283 (0.35%)	0/284 (0.00%)
Neuralgia † 1	0/283 (0.00%)	1/284 (0.35%)
Presyncope † 1	1/283 (0.35%)	0/284 (0.00%)
Syncope † 1	2/283 (0.71%)	2/284 (0.70%)
Vocal cord paralysis † 1	1/283 (0.35%)	0/284 (0.00%)
Psychiatric disorders
Confusional state † 1	1/283 (0.35%)	0/284 (0.00%)
Psychotic disorder † 1	1/283 (0.35%)	0/284 (0.00%)
Tic † 1	0/283 (0.00%)	1/284 (0.35%)
Renal and urinary disorders
Acute kidney injury † 1	2/283 (0.71%)	1/284 (0.35%)
Urinary retention † 1	1/283 (0.35%)	0/284 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	0/283 (0.00%)	1/284 (0.35%)
Cough † 1	1/283 (0.35%)	0/284 (0.00%)
Dyspnoea † 1	0/283 (0.00%)	2/284 (0.70%)
Interstitial lung disease † 1	1/283 (0.35%)	4/284 (1.41%)
Pleural effusion † 1	1/283 (0.35%)	0/284 (0.00%)
Pleuritic pain † 1	1/283 (0.35%)	0/284 (0.00%)
Pneumonitis † 1	0/283 (0.00%)	1/284 (0.35%)
Pulmonary embolism † 1	5/283 (1.77%)	3/284 (1.06%)
Pulmonary oedema † 1	0/283 (0.00%)	2/284 (0.70%)
Respiratory failure † 1	1/283 (0.35%)	3/284 (1.06%)
Skin and subcutaneous tissue disorders
Decubitus ulcer † 1	1/283 (0.35%)	0/284 (0.00%)
Drug eruption † 1	1/283 (0.35%)	0/284 (0.00%)
Rash generalised † 1	1/283 (0.35%)	0/284 (0.00%)
Vascular disorders
Deep vein thrombosis † 1	2/283 (0.71%)	1/284 (0.35%)
Hypertension † 1	1/283 (0.35%)	1/284 (0.35%)
Hypotension † 1	0/283 (0.00%)	1/284 (0.35%)
Jugular vein thrombosis † 1	1/283 (0.35%)	0/284 (0.00%)
Thrombophlebitis superficial † 1	0/283 (0.00%)	1/284 (0.35%)
1 Term from vocabulary, MedDRA 21.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Lenalidomide Plus R-CHOP (R2-CHOP)	Placebo Plus R-CHOP
	Affected / at Risk (%)	Affected / at Risk (%)
Total	272/283 (96.11%)	270/284 (95.07%)
Blood and lymphatic system disorders
Anaemia † 1	127/283 (44.88%)	95/284 (33.45%)
Leukopenia † 1	50/283 (17.67%)	50/284 (17.61%)
Lymphopenia † 1	35/283 (12.37%)	31/284 (10.92%)
Neutropenia † 1	183/283 (64.66%)	150/284 (52.82%)
Thrombocytopenia † 1	68/283 (24.03%)	55/284 (19.37%)
Gastrointestinal disorders
Abdominal pain † 1	18/283 (6.36%)	16/284 (5.63%)
Abdominal pain upper † 1	11/283 (3.89%)	18/284 (6.34%)
Constipation † 1	92/283 (32.51%)	81/284 (28.52%)
Diarrhoea † 1	49/283 (17.31%)	40/284 (14.08%)
Nausea † 1	64/283 (22.61%)	66/284 (23.24%)
Stomatitis † 1	33/283 (11.66%)	37/284 (13.03%)
Vomiting † 1	32/283 (11.31%)	26/284 (9.15%)
General disorders
Asthenia † 1	39/283 (13.78%)	28/284 (9.86%)
Fatigue † 1	40/283 (14.13%)	50/284 (17.61%)
Oedema peripheral † 1	33/283 (11.66%)	32/284 (11.27%)
Pyrexia † 1	52/283 (18.37%)	40/284 (14.08%)
Infections and infestations
Upper respiratory tract infection † 1	23/283 (8.13%)	18/284 (6.34%)
Injury, poisoning and procedural complications
Infusion related reaction † 1	27/283 (9.54%)	30/284 (10.56%)
Investigations
Alanine aminotransferase increased † 1	32/283 (11.31%)	27/284 (9.51%)
Aspartate aminotransferase increased † 1	22/283 (7.77%)	20/284 (7.04%)
Lymphocyte count decreased † 1	16/283 (5.65%)	12/284 (4.23%)
Platelet count decreased † 1	21/283 (7.42%)	10/284 (3.52%)
Weight decreased † 1	21/283 (7.42%)	10/284 (3.52%)
White blood cell count decreased † 1	35/283 (12.37%)	19/284 (6.69%)
Metabolism and nutrition disorders
Decreased appetite † 1	29/283 (10.25%)	32/284 (11.27%)
Hyperglycaemia † 1	18/283 (6.36%)	19/284 (6.69%)
Hypokalaemia † 1	41/283 (14.49%)	28/284 (9.86%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	18/283 (6.36%)	13/284 (4.58%)
Back pain † 1	15/283 (5.30%)	22/284 (7.75%)
Nervous system disorders
Dizziness † 1	16/283 (5.65%)	16/284 (5.63%)
Dysgeusia † 1	13/283 (4.59%)	16/284 (5.63%)
Headache † 1	26/283 (9.19%)	28/284 (9.86%)
Neuropathy peripheral † 1	19/283 (6.71%)	12/284 (4.23%)
Paraesthesia † 1	25/283 (8.83%)	27/284 (9.51%)
Peripheral sensory neuropathy † 1	51/283 (18.02%)	51/284 (17.96%)
Psychiatric disorders
Insomnia † 1	23/283 (8.13%)	32/284 (11.27%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	31/283 (10.95%)	20/284 (7.04%)
Dyspnoea † 1	12/283 (4.24%)	15/284 (5.28%)
Oropharyngeal pain † 1	16/283 (5.65%)	10/284 (3.52%)
Skin and subcutaneous tissue disorders
Alopecia † 1	48/283 (16.96%)	43/284 (15.14%)
1 Term from vocabulary, MedDRA 21.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results from a center cannot be submitted for publication before results of multicenter study are published unless it is > 1 year since study completion. Then, Investigator can publish if manuscript is submitted to Celgene 60 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to 90 additional days. Investigator must delete confidential information before submission and defer publication to permit patent applications.

Results Point of Contact

• Name/Title: Anne McClain, Senior Manager, Clinical Trial Disclosure
• Organization: Celgene Corporation
• Phone: 888-260-1599
• EMail: ClinicalTrialDisclosure@Celgene.com

Publications:

Nowakowski GS, Chiappella A, Witzig TE, Spina M, Gascoyne RD, Zhang L, Flament J, Repici J, Vitolo U. ROBUST: Lenalidomide-R-CHOP versus placebo-R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Future Oncol. 2016 Jul;12(13):1553-63. doi: 10.2217/fon-2016-0130. Epub 2016 Apr 18.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT02285062
• Other Study ID Numbers: CC-5013-DLC-002; 2013-004054-21 ( EudraCT Number )
• First Submitted: November 4, 2014
• First Posted: November 6, 2014
• Results First Submitted: March 13, 2020
• Results First Posted: March 30, 2020
• Last Update Posted: March 31, 2020