Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Rituxumab, Rituximab (R), rituximab [MabThera], Rituximab and DexaBEAM, Rituximab IV, Rituximab SC
Rituximab · 55 trials · 21 indications
AARs defined as all related adverse events (AEs) occurring within 24 hours of rituximab SC administration, including infusion/injection-related reactions (IIRRs), injection-site reactions, administration site conditions and all symptoms thereof.
AARs were defined as all adverse events (AEs) occurring within 24 hours of rituximab administration and which were considered related to study drug. AARs included infusion/injection-related reactions (IIRRs), injection-site reactions, administration site conditions and all symptoms thereof. Grading was completed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
Participants who preferred rituximab SC over rituximab IV, along with the corresponding 95% confidence interval (CI), were estimated using the patient preference questionnaire (PPQ) after completing cycle 6.
Participants who preferred rituximab SC over rituximab IV, along with the corresponding 95% confidence interval (CI), were estimated using the patient preference questionnaire (PPQ) after completing Cycle 8.
Tumor response was assessed per criteria published by Cheson et al (1999). According to consensus recommendations, CR was defined as complete disappearance of all clinical and radiographic evidence of disease and disease-related symptoms, regression of lymph nodes to normal size, absence of splenomegaly, and absence of bone marrow involvement. CRu was defined as disappearance of clinical and radiographic evidence of disease and absence of splenomegaly, with regression of lymph nodes by greater than (\>) 75 percent (%) but still \>1.5 centimeters (cm) in size, and indeterminate bone marrow assessment. The percentage of participants with either response at the end of induction (EOI) was determined with corresponding 95% Pearson-Clopper confidence interval (CI).
Progression free survival from randomization (PFSrand) is defined as the time from date of randomization to the date of first documented disease progression or death, whichever occurs first. One participant died in Induction before randomization and one participant died in Maintenance II Observation arm due to an SAE and were not considered in the analysis as no death page was completed. The Observation arm did not include one participant with AE outcome of death reported retrospectively 2 months after discontinuation from study (censored as having no event on Day 456 post-randomization).
The DAS28 was calculated as \[0.28 times (x) the square root of number of swollen joints\] plus (+) \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of erythrocyte sedimentation rate (ESR)\] + \[0.014 x Visual Analog Scale (VAS) patient global assessment of disease activity\]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Remission was defined as a DAS28 score \<2.6 at the assessment visit.
Overall Response comprised complete response (CR), CR unconfirmed (CRu), or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and computed tomography (CT) scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by more than (\>) 75% in the sum of the products of greatest diameters (SPD); PR: Greater than or equal to (≥) 50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper.
PD occurred if any of the following events was observed: appearance of any new lesion, such as enlarged lymph nodes (greater than \[\>\]1.5 centimeters \[cm\]), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of greater than or equal to (\>/=) 50 percent (%) in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by \>/=50%; an increase in the number of blood lymphocytes by \>/=50% with B-lymphocytes \>/=5000 per microliter (/mcL); transformation to a more aggressive histology; occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.
PFS was defined as the time from date of randomization to date of PD, relapse, or death due to any cause. Participants alive with no evidence of PD or relapse were censored at date of last clinical examination. PD occurred if any of the following events was observed: appearance of any new lesion, such as enlarged lymph nodes (\>1.5 cm), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of \>/=50% in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by \>/=50%; an increase in the number of blood lymphocytes by \>/=50% with B-lymphocytes \>/=5000/mcL; transformation to a more aggressive histology; occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.
The percentage of patients who developed Grade 3 or 4 IRRs resulting from faster infusion of rituximab at Cycle 2 was assessed in patients who had previously received rituximab at the standard infusion rate without experiencing a Grade 3 or 4 IRR at Cycle 1. IRRs were a predefined list of Medical Dictionary for Regulatory Activities (MedDRA) terms for infusion-related adverse events occurring on the day of and/or the day after rituximab infusion. The list of IRR terms was compiled based on IRRs observed in the present and previous studies in which rituximab was infused at the standard rate.
The erosion score was determined according to the Outcome Measures in Rheumatology (OMERACT) rheumatoid arthritis MRI scoring (RAMRIS) system in magnetic resonance images with and without gadolinium of 15 anatomical locations in each wrist and 10 locations in each hand in the hand and wrist with the most arthritic activity. If there was no difference in disease activity between the hands, the dominant hand was used. Images were assessed by 2 experienced blinded musculoskeletal radiologists. Each location was scored in 0.5 increments from 0 to 10 with each integer unit increment representing a 10% loss of articular bone using the following scale. 0.0=normal, no erosion; 0.5=1-5% erosion; 1.0=6-10% erosion; 1.5=11-15% erosion; 2.0=16-20% erosion; etc, up to 10.0=96-100% erosion. The individual scores were summed and normalized to a range of 0 to 100 with a higher score indicating more erosion. A negative change score indicates improvement.
DAS28 calculated from the swollen joint count (SJC) and tender joint count (PJC) using the 28 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and Patient Global Asessment of disease activity (participant- rated arthritis activity assessment) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). A clinically meaningful improvement in DAS28 was defined as an improvement of 1.2 units.
The DAS28 consists of swollen joint count (SJC) and tender joint count (TJC) measurements, the erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hr), and the Patient's Global Assessment of Disease Activity (participant-ated rheumatoid arthritis \[RA\] activity assessment) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 less than or equal to (≤)3.2 equals (=) low disease activity, DAS28 greater than (\>)3.2 to 5.1 = moderate to high disease activity.
DAS28-CRP was based on joint counts, overall participant assessment, and serum CRP levels (measured in milligrams per liter \[mg/L\]) at each visit. Joint counts included swollen joint count (SJC) and tender joint count (TJC). Total score range was 0 to 9.4; a higher score indicated more disease activity. DAS28-CRP less than or equal to (≤)3.2 implied low disease activity, \>3.2 to 5.1 implied moderate to high disease activity, and less than (\<)2.6 equals (=) remission. The AUC of all DAS28-CRP values between Day 1 and Week 104 (15 values of protocol visits) was calculated using the trapeze method (AUC between t1 and t2=(t2-t1)\*((DAS28-CRP at t1 + DAS28-CRP at t2)/2). The true visit dates were used to calculate the time between 2 DAS28-CRP evaluations. All the AUC were censored at Week 104 (linear extrapolation using the 2 last DAS28-CRP values (Weeks 96 and 104) to obtain the "true" DAS28-CRP value at the "true" Week 104).
DAS28 was calculated from the number of swollen joints and painful joints using the 28 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity (participant-rated arthritis activity assessment using visual analog scale \[VAS\]) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 less than or equal to (≤)3.2 equals (=) low disease activity, DAS28 greater than (\>)3.2 to 5.1 = moderate to high disease activity.
Percentage of participants who reported an AE or serious AE (SAE), a drug-related AE, who had an acute infusion reaction, an AE leading to study drug discontinuation, with an infection or serious infection, or who died.
An Adverse event (AE) was considered any unfavorable medical event in a participant of clinical research who received the study drug and that not necessarily had a causal relationship with this treatment. An AE could, therefore, being any unfavorable sign and non-intentional, symptom or disease temporarily related with the use of a medicinal product, considered or not related to the medicinal product. Pre-existing conditions that worsened during the study were reported as AEs. A serious adverse event (SAE) is any experience that suggested a significant risk, contraindication, caution, and at any dose fulfills at least one of the following criteria: adverse event considered as fatal (resulting in death), life threatening, defect of birth/congenital abnormality, required hospitalization or extension of hospital length of stay, significant medical intervention, resulted in significant disability/impairment.
An AE is any unfavorable sign and non-intentional, symptom or disease temporarily related with the use of a medicinal product, considered or not related to the medicinal product. Pre-existing conditions that worsened during the study were reported as AEs. The Intensity of AEs was classified as Grade 1, Grade 2, Grade 3 and Grade 4. Grade 1: Discomfort was noticed, but the normal daily activity was not interrupted. Grade 2: Discomfort was enough to reduce the normal daily activity. Grade 3: There was disability for work or develop normal daily activities. Grade 4: It represented an immediate threat to life (these events were reported as SAEs).
An AE is any unfavorable sign and non-intentional, symptom or disease temporarily related with the use of a medicinal product, considered or not related to the medicinal product. Pre-existing conditions that worsened during the study were reported as AEs. A SAE is any experience that suggested a significant risk, contraindication, caution, and at any dose, fulfills, at least, one of the following criteria: adverse event considered as fatal (resulting in death), life threatening, defect of birth/congenital abnormality, required hospitalization or extension of hospital length of stay, significant medical intervention, resulted in significant disability/impairment. Relationship between AEs and medication under investigation was evaluated through the classification "Yes" and "No". A relationship classified as "Yes" implied a significant causal relationship with the medication under investigation which was evaluated based on enough evidences, facts or arguments.
Adverse event of special interest during the study treatment and follow up period included infections. The participants with AEs of special interest were reported at Screening, End of treatment (EOT), and End of Follow-up (EOFU) visit.
ACR20 defined as overall score of ≥20 in ACR number (ACRn) calculation. Overall score defined as lowest percent improvement from baseline (BL) of following 3 measures: tender joint count (TJC; 68 joints), swollen joint count (SJC: 66 joints), and the 3rd lowest improvement achieved by at least 3 of 5 remaining ACR core parameters: physician's global assessment of disease activity, participant's global assessment of disease activity, participant's assessment of pain (visual analog assessment \[VAS\]), Health Assessment Questionnaire (HAQ), and C-Reactive Protein (CRP). If CRP missing, erythrocyte sedimentation rate (ESR) was used. In order for improvements in the ACRn score to be expressed as a positive result, rather than the negative changes that improvements represent, the final ACRn results were multiplied by negative 1. Last observation carried forward (LOCF) for TJC/SJC, HAQ, CRP/ESR, VAS. If change in CRP incalculable, change in ESR used. ACR20 set to Non-Responder if ACRn missing
ACR20 response was defined as a ≥ 20% improvement compared with baseline in both tender joint count (TJC) \[68 joints\] and swollen joint count (SJC) \[66 joints\] as well as a ≥ 20% improvement in three of five additional measurements: 1) Physician's Global Assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[visual analog scale: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) erythrocyte sedimentation rate.
A participant had a CRR if they met the following 3 criteria: (1) Normalization of serum creatinine (SC) as evidenced by a SC level ≤ the upper limit of the normal range of central laboratory values or a SC level ≤ 15% greater than Baseline, if Baseline SC was within the normal range of the central laboratory values; (2) Inactive urinary sediment (as evidenced by \< 5 red blood cells/high-power field (RBCs/HPF) and absence of red cell casts; (3) Urinary protein (UP) to creatinine ratio (CR) \< 0.5. A participant had a PRR if they met the following 3 criteria: (1) A SC level ≤ 15% above Baseline; (2) RBCs/HPF ≤ 50% above Baseline and no RBC casts; (3) 50% improvement in the UP to CR, with 1 of the following conditions met: If the Baseline UP to CR was ≤ 3.0, then a UP to CR of \< 1.0 or if the Baseline UP to CR was \> 3.0, then a UP to CR of ≤ 3.0. A participant had a NRR if they did not achieve either a CRR or PRR.
Sustained response defined as a platelet count of greater than or equal to (≥) 50x10\^9/L at 6 months (Week 24) after the initial treatment. Participants failing therapy before Month 6 (Week 24) and treated in other ways were considered failures.
Event-free survival (EFS) was defined as the time from baseline (Week 0) to the time to progression, relapse, death from any cause, or institution of a new treatment, whichever occurs first. Mean EFS was estimated by the Kaplan-Meier estimation and provided with their 95% confidence interval. ITT population (patients who received at least one maintenance MabThera infusion) was used for this analysis.
An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Number of participants with non-serious AEs was exclusive of SAEs.
PFS from randomization was measured from the date of randomization to the date of documented disease progression, relapse, or death from any cause. PFS function was estimated using Kaplan-Meier product-limit method. Responding participants and participants who were lost to follow up were censored at their last assessment date.
PFS from randomization was measured from the date of randomization to the date of documented disease progression, relapse, or death from any cause. Responding participants and participants who were lost to follow-up were censored at their last assessment date. PFS was estimated using Kaplan-Meier methods.
Progression-free survival (PFS) was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.
Progression-free survival was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.
Treatment failure was defined as an event of any of the following: progressive disease while receiving study treatment, death due to any cause, or the initiation of another type of treatment due to stable disease, progressive disease or relapse, or intolerance to study treatment.
The median time, in months, between randomization and treatment failure event determined using Kaplan-Meier estimates.
CR was defined as a complete remission of all objective medical findings at the time of restaging, with complete resolution of pre-existing swelling of the lymph nodes, as well as a pre-existing hepatomegaly and splenomegaly, for at least 4 weeks. This was in exclusion of persistent lymphoma infiltration of the bone marrow by means of bone marrow biopsy; normalization of blood counts with granulocytes greater than (\>)1.5 giga particles per liter (Gpt/L) (which is the equivalent of 10\^9/L), hemoglobin (Hb) \>7.5 millimoles per liter (mmol/L), and platelets less than (\<) 100 Gpt/L. PR was defined as greater than or equal to (≥)50 percent (%) reduction of all measurable and evaluable lymphoma manifestations (sum of the products of the 2 largest perpendicular diameters) for at least 4 weeks without occurrence of new manifestations and normalization of blood counts.
For this pharmacokinetics (PK) primary outcome measure the serum rituximab Ctrough for SC and IV administrations were measured at Cycle 7, 21 days after study treatment administration for Cycle 7 (pre-dose of Cycle 8). Geometric mean ratio and 90% confidence interval were estimated based on an ANCOVA model adjusted for tumor load at baseline and are reported in the statistical analysis.
An AE is any unfavourable and unintended sign (including abnormal laboratory finding), symptom, or disease temporarily associated with the use of a study drug, whether or not considered related to the study drug. A SAE is any experience that results in death, is life-threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically significant.
CL is a quantitative measure of the rate at which a drug substance is removed from the body. The following allometric scaling equation was used for the estimation of CL in children: CL= qCL X (BSA/1.9) 0.92 X 1.31\*ADA where qCL is a typical value of clearance in millilitres per day (mL/day) for a typical participant (i.e., Body Surface Area (BSA) of 1.9 m\^2 and absence of anti-rituximab antibodies (ADA)) and is equal to 258 mL/day; BSA is in m\^2 and ADA is 1 when anti-rituximab antibodies are present (0 otherwise). The allometric scaling factor was 0.92. CL was calculated in millilitres per day (mL/day).
Vd is defined as the theoretical central volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vd was calculated in millilitres (mL).
Overall response rate was defined as the percentage of participants with a complete response (CR) or a partial response (PR) according to National Cancer Institute - Working Group \[NCI-WG\] guidelines. CR: no clonal B lymphocytes in peripheral blood, no significant lymphadenopathy, liver and spleen normal size, no disease symptoms, blood counts: absolute neutrophil count (ANC) \>1,500/microliter (mcL), platelets \> 100,000/mcL, hemoglobin \> 11.0 grams/deciliter (g/dL), normocellular bone marrow. PR: \>/= 50% decrease in clonal B lymphocyte count, \>/= 50% reduction in lymphadenopathy, \>/= 50% reduction of liver or spleen enlargement and ANC \>1,500/mcL, platelets \> 100,000/mcL, hemoglobin \> 11.0 g/dL OR \>/= 50% increase in ANC, platelets or hemoglobin.
CR defined as: 1) laboratory CR: peripheral blood lymphocytes (PBL) less than (\<) 4000/microliter (μL), neutrophils (PMN) greater than (\>) 1500/μL, platelets \>100,000/μL, and hemoglobin (Hb) \>11 grams per deciliter (g/dL); 2) clinical CR: lymph nodes (LN) \<1.5 centimeter (cm), and no constitutional symptoms, hepatomegaly (HM) or splenomegaly (SM); 3) instrumental CR: LN \<1.5 cm and no HM/SM, and 4) bone marrow (BM) CR: normocellular aspirate/biopsy for participant age \<30 percent (%) lymphocytes, and no B cell lymphoid nodules. CRi was defined as CR with anemia, thrombocytopenia, or neutropenia not related to chronic lymphocytic leukemia (CLL), with no clonal infiltrate in aspirate or biopsy. PR defined as: a 50% decrease in PBL, a 50% decrease in LN size, no increase in LN size, no new enlarged LN, a 50% reduction from baseline (BL) in the HM/SM, and 1 of the following: PMN \>1500/μL, platelets \>100,000/μL or \>50% improvement from BL, and Hb \>11.0 g/dL or \>50% improvement from BL.
CR was defined as no adenopathies (ADPs) and visceromegalies (VSMs) in physical examination (PE); no general symptoms (Sx); lymphocytes (Lymph) in peripheral blood less than (\<) 4000 per cubic millimeter (mm\^3); normalization of peripheral blood parameters: neutrophils (Neut) greater than (\>) 1500/mm\^3, platelets (Plt) \>100,000/mm\^3, hemoglobin (Hb) \>11 grams per deciliter (g/dL) without transfusion; normocellular bone marrow (BM) with \<30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules.
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 56 days from the beginning of the last treatment cycle that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs as well as non-serious AEs.
CR was defined by: a) disappearance of clinical/radiographic evidence of disease, disease-related symptoms, and biochemical abnormalities; b) decrease in lymph nodes (LNs) greater than (\>) 1.5 centimeters (cm) in greatest transverse diameter (GTD) to less than (\<) 1.5 cm, a decrease in LNs 1.1 - 1.5 cm to 1 cm or 75 percent (%) decrease in sum of the products of GTD (SPD); c) non-palpable spleen, decreased size of enlarged organs, and disappearance of nodules; and d) disappearance of bone marrow (BM) infiltrate. CR(u) was defined as fulfilling a) and c), above, with greater than or equal to (≥) 1 of the following: a) \> 75% decrease in SPD of LNs \> 1.5 cm, and \> 75% decrease in SPD of previously confluent LNs; b) indeterminate BM, or c) confirmed CR. PR was defined by: a) 50% decrease in SPD of the 6 largest LNs; b) no increase in LNs, liver, or spleen size; c) ≥ 50% decrease in splenic and hepatic nodule SPDs; d) no measurable disease in other organs; and e) no new sites of disease.
Percentage of participants with an overall response at Week 8 achieving a CR or PR as evaluated by platelets, new or increased Idiopathic Thrombocytopenic Purpura (ITP)-related treatments and corticosteroids given for Adverse Events (AEs). CR was defined as a platelet count of greater than (\>) 150x10\^9/ liters (L) over at least 2 consecutive measurements at least 2 weeks apart, but no more than 60 days apart, with no increase in concomitant ITP therapy or initiation of new ITP therapy. PR was defined as platelet count of \>50x10\^9/L over at least 2 consecutive measurements at least \<2 weeks apart, but no more than 60 days apart, with no increase in concomitant ITP therapy or initiation of new ITP therapy. Overall response rate (participants who achieved CR or confirmed PR) was evaluated using platelets, new or increased ITP related treatments, and corticosteroids given for AEs.
Treatment response was monitored throughout the study and assessed using standardized criteria. Disease progression was defined as the occurrence of at least one of the following: greater than or equal to (≥) 50 percent (%) increase in the longest diameter of at least two enlarged lymph nodes, increase in spleen and/or liver size by at least 2 centimeters (cm) from Baseline as determined by measurement below the costal margin, or ≥50% increase in the number of circulating lymphocytes. The percentage of participants with death or documented disease progression at any time during the study was calculated.
Participants were followed for survival throughout the study. The percentage of participants who died of any cause during the study was calculated.
Participants were followed for survival throughout the study. OS was defined as the time from study inclusion until death from any cause and was estimated using Kaplan-Meier analysis
Treatment response was monitored throughout the study and assessed using standardized criteria. CR was defined as hemoglobin ≥11 grams per deciliter (g/dL), lymphocytes less than (\<) 4000 cells per cubic millimeter (cells/mm\^3), neutrophils greater than (\>) 1500 cells/mm\^3, platelets \>100,000 cells/mm\^3, bone marrow (BM) biopsy with \<30% lymphocytes with no lymphocytic infiltrates, no evidence of lymphoid nodules on physical exam, and performance status of 0. PR was defined as \>50% decrease in size of enlarged lymph nodes, hepatomegaly, and splenomegaly, with peripheral counts meeting the same criteria as CR or ≥50% improvement from pre-treatment values. Participants with lymphoid nodules on BM biopsy who otherwise met CR criteria were considered nPR. The percentage of participants with each level of best overall response was calculated.
The immune response to tetanus toxoid adsorbed booster vaccine was measured in serum samples immediately prior to and 4 weeks after vaccine administration. The tetanus antibody test was an ELISA that used tetanus toxoid as a capturing reagent and alkaline phosphatase-conjugated anti-human IgG (γ) for detection. For patients with pre-vaccination tetanus antibody titers \< 0.1 IU/mL, a positive immune response was defined as an antibody titer ≥ 0.2 IU/mL. For patients with pre-vaccination tetanus antibody titers ≥ 0.1 IU/mL, a positive immune response to the booster immunization was defined as a 4-fold increase in antibody titer.
Best clinical response was determined according to the National Cancer Institute (NCI) Clinical and Clinical plus (+) Radiological evaluations by central response assessment. Assessment of response was performed according to the NCI revised guidelines for the diagnosis and treatment of chronic lymphocytic lymphoma (CLL) with additional computerized tomography (CT) scan evaluation of lymphadenopathy. Per NCI guidelines, CR requires all of the following criteria at least 2 months after the last treatment: no lymphadenopathy (Ly)/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils greater than (\>)1500 per microliter (/µL), platelets (PL) \>100,000/µL, hemoglobin (Hb) \>11.0 grams per deciliter (g/dL), lymphocytes (LC) (less than) \<4000/µL, bone marrow (BM) sample must be normocellular for age, \<30% LC.
Percentage of participants who at 2 years from the start of treatment remained free from documented disease progression, relapse, or death. Failure status was based on tumor evaluation performed on Month 28. Participants who did not have a tumor evaluation at Month 28 were counted as failures.
The BILAG Index measures clinical disease activity in Systemic Lupus Erythematosus (SLE). A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24; PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+\>=2Bs, or\>=2 As, or\>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6.
Disease progression was assessed using the Expanded Disability Status Scale (EDSS), a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of greater than or equal to (≥) 1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score greater than (\>) 5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. Those who did not meet criteria for CDP, completed treatment with only initial progression, or received an exclusionary therapy were censored at last EDSS assessment. Time to CDP was the time from randomization to initial disease progression, estimated using Kaplan-Meier (KM) analysis.
Disease progression was assessed using the EDSS, a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of ≥1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score \>5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. The percentage of participants with CDP was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.
A participant had an ACR20 response if there was at least a 20 percent (%) improvement, ie, reduction from Baseline, in tender joint count (TJC) and swollen joint count (SJC) (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[visual analog scale (VAS): 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either C-reactive protein \[CRP\] or erythrocyte sedimentation rate \[ESR\]). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
PFS at 5 years in patients * completing the entire protocol (PPP) * intention to treat population (IIT)
Percentage of participants with a CR, PR at the end of the first cycle of treatment (Week 4). CR was defined as the complete disappearance of all objective disease findings, including enlarged lymph nodes, hepatomegaly, and splenomegaly for at least 4 weeks, and a normalization of blood counts with granulocytes \>1.500/ microliter (µL), hemoglobin (Hb) \>12 grams per deciliter (g/dL), and platelets \>100,000/µL. PR was defined as a less than (\<) 50% regression of all measurable and evaluable lymphoma manifestations (sum of the products of the 2 largest diameters vertical to each other) for at least 4 weeks without the appearance of new manifestations, and normalization of blood counts.
Ctrough is defined as the trough or minimum serum concentration. Pharmacokinetic parameters for rituximab were assessed during Cycles 5 (IV rituximab) and 6 (SC rituximab). Rituximab pharmacokinetic (PK) data from Part 1 were integrated into a population PK model using parametric, nonlinear, mixed-effects modelling. Rituximab IV 500 mg/m\^2 administered once every 4 weeks was compared to fixed doses of rituximab SC between 1400 mg and 1870 mg. The dose selection was performed on Ctrough concentrations at Cycle 5 (pre-dose Cycle 6). A test of the probability of success was applied to each of the 100 replicates, and the percentage of replicates with a positive test corresponded to the probability of success of the trial.
Ctrough is defined as the trough or minimum serum concentration in a given cycle of treatment. The objective of Part 2 was to demonstrate the comparability of the observed Ctrough of rituximab SC 1600 mg and rituximab IV 500 mg/m2 at Cycle 5, as assessed by a non-inferiority test with a lower boundary of at least 0.8 for the 90% CI.
| Arm | Type | Description |
|---|---|---|
| Rituximab | EXPERIMENTAL | Participants with FL and DLBCL will receive rituximab SC 1400 milligrams (mg) once a month for a minimum of 4 cycles as induction therapy. Participants with FL will continue to receive rituximab once in 2 months for a minimum of 6 cycles as maintenance therapy according to local standards of care. Participants will also receive standard chemotherapy regimen (CHOP \[cyclophosphamide+doxorubicin+vincristine+prednisone\], CVP \[cyclophosphamide+vincristine+prednisone\] or FC \[fludarabine+cyclophosphamide\]) during induction. |
| Subcutaneous Rituximab | EXPERIMENTAL | Participants with CD20+ non-Hodgkin's follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), who had already received at least one full dose of intravenous (IV) rituximab will be treated with subcutaneous (SC) rituximab. Participants with FL will be administered 1400 mg rituximab during induction therapy (once monthly for 4-7 cycles) and maintenance therapy (once every 2 months for 6-12 cycles). Participants with DLBCL will be administered 1400 mg SC of rituximab once monthly for 4-7 cycles. Treatment duration is expected to last up to 7 months for participants with DLBCL and up to 32 months for participants with FL. |
| Arm A | EXPERIMENTAL | Participants in Arm A received one cycle of rituximab 375 mg/m\^2 intravenously (IV), then three cycles of rituximab 1400mg subcutaneously (SC), followed by four cycles of rituximab 375 mg/m\^2 IV in combination with a standard chemotherapy of cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone/prednisolone (CHOP), cyclophosphamide, vincristine, prednisone/prednisolone (CVP), or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. |
| Arm B | EXPERIMENTAL | Participants in Arm B received four cycles of rituximab 375 mg/m\^2 IV followed by four cycles of rituximab 1400mg SC in combination with a standard chemotherapy of CHOP, CVP, or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. |
| A: Rituximab SC | EXPERIMENTAL | - |
| B: Rituximab IV | ACTIVE_COMPARATOR | - |
| Maintenance II Period Observation Only | OTHER | Participants will receive standard chemotherapy regimen in combination with 375 mg/m\^2 rituximab IV in Cycle 1 (3-4 week-cycles), followed by 1400 mg rituximab SC every 3-4 weeks for 8 cycles (induction period); 1400 mg rituximab SC every 8 weeks for 24 months (Maintenance I period); no treatment in Maintenance II period until disease progression or end of study, whichever occurs first. |
| Maintenance II Period Rituximab | EXPERIMENTAL | Participants will receive standard chemotherapy regimen in combination with 375 mg/m\^2 rituximab IV in Cycle 1 (3-4 week-cycles), followed by 1400 mg rituximab SC every 3-4 weeks for 8 cycles (induction period); 1400 mg rituximab SC every 8 weeks for 24 months (Maintenance I period); 1400 mg rituximab SC every 8 weeks until disease progression or end of study, whichever occurs first (Maintenance II period). |
| 1 | EXPERIMENTAL | - |
| 2 | EXPERIMENTAL | - |
| Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) | ACTIVE_COMPARATOR | Eight cycles of rituximab IV infusion (375 mg/m\^2; rituximab induction) in combination with up to 8 cycles of cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) or cyclophosphamide, vincristine, prednisolone (CVP) chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m\^2) once every 8 weeks for 24 months. |
| Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP) | EXPERIMENTAL | First cycle of rituximab IV infusion (375 mg/m\^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months. |
| Induction: Rituximab, Cladribine, Cyclophosphamide | EXPERIMENTAL | Participants will receive rituximab at a dose of 375 milligrams per meter squared (mg/m\^2) as intravenous (IV) infusion on Day 1, cladribine at a dose of 0.12 milligrams per kilogram per day (mg/kg/day) as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m\^2/day as IV infusion over 15-30 minutes on Days 2-4 in Cycle 1. Then, rituximab at a dose of 500 mg/m\^2 as IV infusion on Day 1, cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m\^2/day as IV infusion over 15-30 minutes on Days 2-4 will be administered in Cycles 2-6. Each cycle will be of 28 days in duration. |
| Maintenance Arm: Rituximab | EXPERIMENTAL | Participants with PR or CR after induction phase who will be randomized to maintenance arm will receive rituximab treatment for 8 cycles. Twelve weeks after the last induction cycle, participants will receive rituximab at a dose of 375 mg/m\^2 as IV infusion on Day 1 of each 12-week cycle until disease progression (up to approximately 96 weeks). |
| Observation Arm: No Intervention | NO_INTERVENTION | Participants with PR or CR after induction phase who will be randomized to observation arm will not receive any intervention. Participants will be assessed every 4-weeks for the first 12 weeks and every 12-weeks afterwards up to 96 weeks. |
| Rituximab 375 mg/m^2 | EXPERIMENTAL | Patients received 6 or 8 21-day cycles of CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone) or CVP (cyclophosphamide, vincristine, prednisone) in combination with rituximab 375 mg/m\^2 administered by intravenous (IV) infusion on Day 1 of each cycle. |
| Rituximab 500 mg | EXPERIMENTAL | Participants received rituximab 500 mg iv on Day 1 and Day 15 of the main study. Participants received a second course of treatment on Day 1 and Day 15 after Week 24 of the main study, if they met eligibility criteria (see the Detailed Description). Participants received further treatment courses on Day 1 and Day 15 at intervals of ≥ 6 months after Week 52 in the study extension phase, if they met eligibility criteria (see the Detailed Description). Throughout the study, participants received methylprednisolone 100 mg iv prior to infusion of the investigational drug, methotrexate 7.5 to 25 mg/week orally or parenterally, and folic acid or folate ≥ 5 mg/week orally. |
| Rituximab 1000 mg | EXPERIMENTAL | Participants received rituximab 1000 mg iv on Day 1 and Day 15 of the main study. Participants received a second course of treatment on Day 1 and Day 15 after Week 24 of the main study, if they met eligibility criteria (see the Detailed Description). Participants received further treatment courses on Day 1 and Day 15 at intervals of ≥ 6 months after Week 52 in the study extension phase, if they met eligibility criteria (see the Detailed Description). Throughout the study, participants received methylprednisolone 100 mg iv prior to infusion of the investigational drug, methotrexate 7.5 to 25 mg/week orally or parenterally, and folic acid or folate ≥ 5 mg/week orally. |
| Placebo | PLACEBO_COMPARATOR | Participants received placebo intravenously (iv) on Day 1 and Day 15 of the main study. Participants received a second course of treatment on Day 1 and Day 15 after Week 24 of the main study, if they met eligibility criteria (see the Detailed Description). Participants were switched to receive rituximab 1000 mg iv on Day 1 and Day 15 at intervals of ≥ 6 months after Week 52 in the study extension phase, if they met eligibility criteria (see the Detailed Description). Throughout the study, participants received methylprednisolone 100 mg iv prior to infusion of the investigational drug, methotrexate 7.5 to 25 mg/week orally or parenterally, and folic acid or folate ≥ 5 mg/week orally. |
| MabThera (Rituximab) | EXPERIMENTAL | - |
| A | EXPERIMENTAL | 1000 mg IV rituximab |
| B | EXPERIMENTAL | 2 x 1000 mg IV rituximab |
| MabThera/Rituxan | EXPERIMENTAL | - |
| Single arm | EXPERIMENTAL | - |
| 3 | EXPERIMENTAL | - |
| Arm A: Rituximab Retreatment | EXPERIMENTAL | 1000 mg rituximab intravenous initial treatment on day 1 and day 15 plus 10-25 mg/week methotrexate followed by re-treatment during weeks 24 -40 consisting of two additional doses of 1000 mg rituximab 14 days apart plus 10-25 mg/week methotrexate. |
| Arm B: Placebo Retreatment | PLACEBO_COMPARATOR | 1000 mg rituximab intravenous initial treatment on day 1 and day 15 plus 10-25 mg/week methotrexate followed by retreatment during weeks 24 -40 consisting of two doses of placebo 14 days apart plus 10-25 mg/week methotrexate. |
| Dexamethasone | ACTIVE_COMPARATOR | Participants received 40 milligrams (mg) dexamethasone, orally, once per day for 4 consecutive days (Days 1, 2, 3, and 4). Participants in this treatment arm who failed to achieve a sustained response and had a platelet count of less than or equal to (≤)20 x 10\^9 platelets per liter (L; from Day 30 up to end of 6 months) were treated with salvage treatment of dexamethasone 40 mg, orally, once per day for 4 consecutive days (Days 1, 2, 3, and 4) and rituximab 375 mg per square meter (mg/m\^2), intravenously (IV), with premedication of oral acetaminophen 500 mg and chlorpheniramine 10 mg IV on Days 7, 14, 21, and 28. |
| Dexamethasone plus Rituximab | EXPERIMENTAL | Participants received dexamethasone 40 mg, orally, once per day for 4 consecutive days (Days 1, 2, 3, and 4) and rituximab 375 mg/m\^2, IV, with premedication of oral acetaminophen 500 mg and chlorpheniramine 10 mg IV on Days 7, 14, 21, and 28. Nonresponsive participants with platelets less than (\<) 20 x10\^9/L or with active bleeding could have also received an additional treatment course of dexamethasone 40 mg, orally, once per day for 4 consecutive days (Days 1, 2, 3, and 4) and rituximab 375 mg/m\^2, IV on Days 7, 14, 21, and 28 administered with immunoglobulin (IgG) IV (at investigator discretion) and/or low/medium dose steroids (at investigator discretion) on Days 7, 14, 21, and 28. |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | EXPERIMENTAL | - |
| Fludarabine+Cyclophosphamide (FC) | ACTIVE_COMPARATOR | - |
| Rituximab Monotherapy | ACTIVE_COMPARATOR | Participants received 375 milligrams per square meter (mg/m2) rituximab intravenously (i.v.) weekly for 4 weeks. Participants achieving minor response (MR), partial response (PR), or completer response (CR) received a second cycle of treatment. |
| Rituximab, Interferon | EXPERIMENTAL | Participants received 375 mg/m2 rituximab i.v. weekly for 4 weeks; and 3 million international units per day (MIU/day) interferon-a2a subcutaneously (s.c.) during Week 1, and 4.5 MIU/day s.c. 6 days per week during Weeks 2 through 5. Interferon-a2a was not administered on days of rituximab administration. Participants achieving MR, PR, or CR received a second cycle of treatment. |
| Rituximab IV+CHOP | ACTIVE_COMPARATOR | Participants will receive 8 cycles of IV rituximab in combination with 6 or 8 cycles of CHOP chemotherapy administered every 3 weeks. |
| Rituximab SC+CHOP | EXPERIMENTAL | Participants will receive 1 cycle of IV plus 7 cycles of SC rituximab in combination with 6 or 8 cycles of CHOP chemotherapy administered every 3 weeks. |
| Rituximab plus Fludarabine and Cyclophosphamide | EXPERIMENTAL | Elderly participants with chronic lymphocytic leukemia (CLL) will receive combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment is followed by a follow up period of 36 months. |
| Rituximab + Fludarabine + Cyclophosphamide | EXPERIMENTAL | Participants will receive 6 cycles (cycle length = 28 days) of treatment with rituximab (375 milligrams per square meter \[mg/m\^2\] as intravenous \[IV\] infusion on Day 0 of Cycle 1 and 500 mg/m\^2 as IV infusion on Day 1 of Cycles 2-6); fludarabine (25 mg/m\^2 on Days 1-3) and cyclophosphamide (250 mg/m\^2 on Days 1-3). Participants with a partial or complete response and appropriate neutrophil conditions will receive maintenance treatment with rituximab (375 mg/m\^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6. |
| Rituximab plus Chlorambucil | EXPERIMENTAL | Participants will receive combination therapy of rituximab plus chlorambucil for first 6 cycles and then chlorambucil alone for a maximum of 6 additional cycles. |
| Rituximab + methotrexate (Group A) | EXPERIMENTAL | Patients received 2 intravenous infusions of rituximab 1000 mg, 14 days apart + methotrexate 10-25 mg/wk orally or subcutaneously during the Treatment Period. |
| Methotrexate (Group B) | ACTIVE_COMPARATOR | Patients received methotrexate 10-25 mg/wk orally or subcutaneously during the Treatment Period. |
| Rituximab 1000 mg + prednisone | EXPERIMENTAL | Participants will receive rituximab 1000 mg intravenously on Days 1, 15, 168, and 182. Participants will also receive an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants will also receive acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion. |
| Placebo + prednisone | PLACEBO_COMPARATOR | Participants will receive placebo intravenously on Days 1, 15, 168, and 182. Participants will also receive an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants will also receive acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion. |
| 4 | EXPERIMENTAL | - |
| 5 | EXPERIMENTAL | - |
| 6 | EXPERIMENTAL | - |
| 7 | PLACEBO_COMPARATOR | - |
| 8 | PLACEBO_COMPARATOR | - |
| 9 | PLACEBO_COMPARATOR | - |
| VAD Clorambucil Rituximab | EXPERIMENTAL | - |
| Rituximab and DexaBEAM | EXPERIMENTAL | Rituximab and DexaBEAM |
| Group A: Methotrexate | ACTIVE_COMPARATOR | Participants will receive methotrexate at dosage \>=10 milligrams per week (mg/week) orally as determined by the investigator. They also receive placebo infusion on days 1 and 15 in place of rituximab and on Days 3 and 17 in place of cyclophosphamide. |
| Group B: Rituximab Monotherapy | EXPERIMENTAL | Participants will receive 1 g intravenous infusions of rituximab on Days 1 and 15. They also receive Weekly placebo orally instead of methotrexate and placebo infusion in place of cyclophosphamide on Days 3 and 17. |
| Group C: Rituximab and Cyclophosphamide | EXPERIMENTAL | Participants will receive 1g IV infusion of rituximab on Days 1 and 15 and 750 mg infusion of Cyclophosphamide on Days 3 and 17. They also receive weekly oral placebo in place of methotrexate. |
| Group D: Methotrexate and Rituximab | EXPERIMENTAL | Participants will receive \>=10 mg/week methotrexate orally along with 2 times 1 gram (g) rituximab IV infusions on Days 1 and 15. Participants will also receive placebo infusions on Days 3 and 17 in place of cyclophosphamide. |
| Rituximab IV 375 mg/m^2 (Stage 1: Cohort A) | ACTIVE_COMPARATOR | - |
| Rituximab IV 375 mg/m^2 (Stage 2: Cohort E) | ACTIVE_COMPARATOR | - |
| Rituximab SC 1400 mg (Stage 2: Cohort F) | EXPERIMENTAL | - |
| Rituximab SC 375 mg/m^2 (Stage 1: Cohort B) | EXPERIMENTAL | - |
| Rituximab SC 625 mg/m^2 (Stage 1: Cohort C) | EXPERIMENTAL | - |
| Rituximab SC 800 mg/m^2 (Stage 1: Cohort D) | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| Rituximab | DRUG | Rituximab SC 1400 mg |
| Cyclophosphamide | DRUG | Cyclophosphamide will be administered as per standard local practice. |
| Doxorubicin | DRUG | Doxorubicin will be administered as per standard local practice. |
| Vincristine | DRUG | Vincristine will be administered as per standard local practice. |
| Prednisone | DRUG | Prednisone will be administered as per standard local practice. |
| Fludarabine | DRUG | Fludarabine will be administered as per standard local practice. |
| Bendamustine | DRUG | Bendamustine will be administered as per standard local practice as a part of standard chemotherapy regimen. |
| Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone/Prednisolone (CHOP) | DRUG | Standard chemotherapy |
| Cyclophosphamide, Vincristine, Prednisone/Prednisolone (CVP) | DRUG | Standard chemotherapy |
| CHOP | DRUG | CHOP chemotherapy: cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone; 6 or 8 cycles |
| rituximab [MabThera/Rituxan] | DRUG | The first rituximab dose will be administered intravenously on Day of Cycle 1 at a dose of 375 mg/m2. Subsequent doses of 1400 mg are administered subcutaneously on Day 1 of each cycle, for a further 7 cycles |
| Chemotherapy (Induction Period) | DRUG | Participants will receive standard combination chemotherapy every 3-4 weeks for 6 to 8 months. The chemotherapy regimen will be selected at Investigator's discretion, for individual participant. Study protocol does not enforce any particular chemotherapy regimen. |
| tocilizumab [RoActemra/Actemra] | DRUG | 8 mg/kg intravenously every 4 weeks for 12 weeks. |
| Rituximab SC | DRUG | First cycle of rituximab IV infusion (375 mg/m\^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months. |
| Rituximab IV | DRUG | Eight cycles of rituximab IV infusion (375 mg/m\^2; rituximab induction) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m\^2) once every 8 weeks for 24 months. |
| Prednisone/Prednisolone | DRUG | Eight cycles of prednisone/prednisolone (100 mg/day or 40 mg/m\^2/day IV/orally) administered Days 1 to 5 of every 21 days cycle. |
| Cladribine | DRUG | Cladribine will be adminiatered at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4 of each 28-day cycle during induction phase. |
| CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone) | DRUG | Commercial preparations of CHOP were used. Prednisone was administered prior to rituximab infusion. |
| CVP (cyclophosphamide, vincristine, prednisone) | DRUG | Commercial preparations of CVP were used. Prednisone was administered prior to rituximab infusion. |
| Analgesic/antipyretic and antihistamine drugs | DRUG | An analgesic/antipyretic (eg, acetaminophen) and an antihistamine (eg, diphenhydramine) were administered 30 minutes before each infusion of rituximab. |
| Placebo | DRUG | Placebo was supplied as a sterile liquid in single-use vials for iv administration. |
| Methylprednisolone | DRUG | - |
| Methotrexate | DRUG | - |
| Folic acid or folate | DRUG | - |
| rituximab [MabThera] | DRUG | 1 g was given by intravenous infusion on Days 1 and 15 |
| folate | DRUG | Intravenous repeating dose |
| Mycophenolate mofetil | DRUG | - |
| Diphenhydramine | DRUG | - |
| Acetaminophen | DRUG | - |
| Dexamethasone | DRUG | - |
| Fludarabine Phosphate | DRUG | Intravenous repeating dose |
| interferon-a-2a | DRUG | 3 MIU/day interferon-a2a s.c. during Week 1, and 4.5 MIU/day s.c. 6 days per week during Weeks 2 through 5 |
| Standard chemotherapy | DRUG | As prescribed |
| Paracetamol | DRUG | All participants are required to receive 1000 mg oral paracetamol as premedication prior to starting each infusion of rituximab |
| Diphenhydramine hydrochloride or alternative antihistamine | DRUG | All participants are required to receive 50-100 mg oral diphenhydramine hydrochloride or alternative antihistamine as premedication prior to starting each infusion of rituximab |
| chlorambucil | DRUG | 8mg/m2 po on days 1-7 of courses 1-8 |
| First line chemotherapy | DRUG | As prescribed |
| Methylprednisone | DRUG | Patients received methylprednisolone 100 mg intravenously before each infusion of rituximab. |
| C. albicans | BIOLOGICAL | Patients received an intradermal injection of C. albicans (0.1 mL) on the volar surface of the forearm. |
| Tetanus toxoid adsorbed booster vaccine | BIOLOGICAL | Patients received an intramuscular injection of the tetanus toxoid adsorbed booster vaccine (1 mg in 0.5 mL) in the deltoid muscle. |
| 23-valent pneumococcal polysaccharide vaccine | BIOLOGICAL | Patients received an intramuscular injection of the 23-valent pneumococcal polysaccharide vaccine (0.5 mL) in the deltoid muscle. |
| Keyhole limpet hemocyanin | BIOLOGICAL | Patients received a subcutaneous injection of keyhole limpet hemocyanin (1 mg) |
| corticosteroids | DRUG | Intravenous repeating dose |
| Folic Acid | DRUG | Participants will receive folic acid \>= 5 mg/week or equivalent. |
| Adriblastin | DRUG | - |
| alkeran | DRUG | - |
| Total body irradiation (8Gy/4fr) | PROCEDURE | - |
| Rituximab and DexaBEAM | DRUG | combination treatment |
| Placebo Cyclophosphamide | OTHER | Participants will receive placebo in place of cyclophosphamide on Days 3 and 17 |
| Placebo Methotrexate | OTHER | Participants will receive weekly oral placebo in place of Methotrexate |
| Placebo Rituximab | OTHER | Participants will receive placebo in place of rituximab on days 1 and 15 |
| SGN-40 | DRUG | Escalating intravenous repeating dose |
Inclusion Criteria: * Histologically confirmed, cluster of differentiation (CD)20+ DLBCL or CD20+ follicular NHL grade 1 to 3a, according to the world health organization (WHO) classification system * Currently being treated with rituximab IV in the Induction or Maintenance setting, having received...