Rituximab and Belimumab for Lupus Nephritis | NCT02260934

ID	Type	Description	Link
CALIBRATE	Other Identifier	Immune Tolerance Network

Name	Class
Immune Tolerance Network (ITN)	NETWORK

Label	Type	Description	Intervention Names
Rituximab/Cyclophosphamide (RC)	Active Comparator	Prednisone taper to 10 mg/day by week 12 and continue prednisone 10 mg/day to week 96.	Biological: Rituximab Drug: Cyclophosphamide Drug: Prednisone Drug: Methylprednisolone Drug: Diphenhydramine Drug: Acetaminophen
Rituximab/Cyclophosphamide/Belimumab (RCB)	Experimental	Belimumab (10 mg/kg IV) at weeks 4, 6, 8, and every 4 weeks to week 48. Prednisone taper to 10 mg/day by week 12, and continue prednisone 10 mg/day to week 96.	Biological: Rituximab Drug: Cyclophosphamide Drug: Prednisone Drug: Methylprednisolone Drug: Diphenhydramine Drug: Acetaminophen Biological: Belimumab

Name	Type	Description	Arm Group Labels	Other Names
Rituximab	Biological	Rituximab 1000mg intravenously (IV) at week 0 and week 2	Rituximab/Cyclophosphamide (RC)

Measure	Description	Time Frame
Percentage of Participants With At Least One Grade 3 or Higher Infectious Adverse Event By Week 24, Week 48 and Week 96	The percentage of participants who experienced at least one Grade 3 or higher treatment-emergent infectious adverse event. The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v4.03:June 14, 2010). Treatment-emergent AEs are those: with an onset date on or after the first dose of study medication, with onset before first dose but that worsened in severity after first dose, and for which the start of the AE in relation to the start of study medication could not be established. AEs were classified by system organ class and preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA) version 17.0. Grade 3 or higher AEs were classified infectious based on the study team's review of the MedDRA body systems and preferred terms of the AEs.	Week 0 to Week 96

Measure	Description	Time Frame
Percentage of Participants With B Cell Reconstitution at Week 24, Week 48 and Week 96	The percentage of participants who achieved B cell reconstitution, defined as a peripheral blood total B cell count ≥ to the baseline count or the lower limit of normal, whichever was lower. Note: B cell depletion was expected to occur in this study between Weeks 0 and 4, after initiation of rituximab and cyclophosphamide. Normal peripheral blood B Cell count: 107 to 698 cells/µL.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Diagnosis of Systemic Lupus Erythematosus (SLE) by American College of Rheumatology (ACR) criteria.
Positive antinuclear antibody (ANA) or positive anti-ds DNA test results at visit -1 or any time within 14 days before visit -1.
Active proliferative lupus nephritis, as defined by either of the following:
- Kidney biopsy documentation within the last 3 months of International Society of Nephrology/Renal Pathology Society (ISN/RPS) proliferative nephritis: Class III, Class IV, or Class V in combination with Class III or IV.
- Active urinary sediment and kidney biopsy documentation within the last 12 months of ISN/RPS proliferative nephritis: Class III, Class IV, or Class V in combination with Class III or IV. Active urinary sediment is defined as any one of the following:
- >5 RBC/hpf in the absence of menses and infection;
- >5 White blood cell per high powered field (WBC/hpf) in the absence of infection; or
- Cellular casts limited to RBC or WBC casts.
Urine protein-to-creatinine ratio (UPCR) >1 at study entry based on a 24-hour collection.
Ability to provide informed consent.

Exclusion Criteria:

New onset lupus nephritis, defined as lupus nephritis for which the participant has not yet been treated with either mycophenolate mofetil or cyclophosphamide.
Neutropenia (absolute neutrophil count <1500/mm^3).
Thrombocytopenia (platelets <50,000/mm^3).
Moderately severe anemia (Hgb < mg/dL).
Moderately severe hypogammaglobulinemia (IgG <450 mg/dL) or Immunoglobulin A (IgA) <10mg/dL.
Positive QuantiFERON -Tuberculosis (TB) Gold test results.
Pulmonary fibrotic changes on chest radiograph consistent with prior healed tuberculosis.
Active bacterial, viral, fungal, or opportunistic infections.
Evidence of infection with human immunodeficiency virus (HIV), hepatitis B (as assessed by HBsAg and anti-HBc) or hepatitis C.
Hospitalization for treatment of infections, or parenteral (IV or IM) antibacterials, antivirals, anti-fungals, or anti-parasitic agents within the past 60 days.
Chronic infection that is currently being treated with suppressive antibiotic therapy, including but not limited to tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, and atypical mycobacteria.
History of significant infection or recurrent infection that, in the investigator's opinion, places the participant at risk by participating in this study.
Receipt of a live-attenuated vaccine within 3 months of study enrollment.
End-stage renal disease (eGFR <20 mL/min/1.73m^2).
Concomitant malignancies or a history of malignancy, with the exception of adequately treated basal and squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
History of transplantation.
History of primary immunodeficiency.
Pregnancy.
Breastfeeding.
Unwillingness to use an FDA-approved form of birth control (including but not limited to a diaphragm, an intrauterine device, progesterone implants or injections, oral contraceptives, the double-barrier method, or a condom).
Use of cyclophosphamide within the past 6 months.
Use of anti-Tumor Necrosis Factor (TNF) medication, other biologic medications, or experimental non- biologic therapeutic agents within the past 90 days, or 5 half-lives prior to screening, whichever is greater.
Intravenous immunoglobulin (IVIG), plasmapheresis, or leukopheresis within the past 90 days.
Use of investigational biologic agent within the past 12 months.
Prior treatment with rituximab, belimumab, atacicept, or other biologic B cell therapy.
Liver function test [aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase] results that are >=2 times the upper limit of normal.
Severe, progressive, or uncontrolled renal, hepatic, hematological,gastrointestinal, pulmonary, cardiac, or neurological disease, either related or unrelated to SLE, with the exception of active lupus nephritis (or, in the investigator's opinion, any other concomitant medical condition that places the participant at risk by participating in this study).
Comorbidities requiring corticosteroid therapy, including those which have required three or more courses of systemic corticosteroids within the previous 12 months.
Current substance abuse or history of substance abuse within the past year.
History of severe allergic or anaphylactic reactions to chimeric or fully human monoclonal antibodies.
History of anaphylactic reaction to parenteral administration of contrast agents.
Lack of peripheral venous access.
History of severe depression or severe psychiatric condition.
History of suicidal thoughts within the past 2 months or suicidal behavior within the past 6 months, or a significant suicide risk in the investigator's opinion.
Inability to comply with study and follow-up procedures.

Name	Affiliation	Role
Betty Diamond, M.D.	Feinstein Institute for Medical Research	Study Chair
David Wofsy, M.D.	University of California San Francisco, Department of Medicine	Study Chair
Maria Dall'Era, M.D.	University of California San Francisco, Department of Medicine	Study Chair
Cynthia Aranow, M.D.	Feinstein Institute for Medical Research	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
University of Alabama, Birmingham		Birmingham	Alabama	35294	United States
UCLA Medical Center: Division of Rheumatology

PubMed Identifier	Type	Citation	Retractions
32755035	Result	Atisha-Fregoso Y, Malkiel S, Harris KM, Byron M, Ding L, Kanaparthi S, Barry WT, Gao W, Ryker K, Tosta P, Askanase AD, Boackle SA, Chatham WW, Kamen DL, Karp DR, Kirou KA, Sam Lim S, Marder B, McMahon M, Parikh SV, Pendergraft WF 3rd, Podoll AS, Saxena A, Wofsy D, Diamond B, Smilek DE, Aranow C, Dall'Era M. Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. Arthritis Rheumatol. 2021 Jan;73(1):121-131. doi: 10.1002/art.41466. Epub 2020 Dec 1.
40001033

Label	URL
National Institute of Allergy and Infectious Diseases website	View source

ID	Title	Description
FG000	Rituximab/Cyclophosphamide (RC)	Participants received infusions of Solumedrol 100mg, rituximab 1000mg, and cyclophosphamide 750mg intravenously (IV) at Week 0 and Week 2. Prednisone was administered at 40 mg/day for the first 2 weeks, followed by a guided steroid taper to 10 mg/day by Week 12. Prednisone was continued through to Week 96 at 10 mg/day, with the potential of a taper to a minimum of 5 mg/day.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Oct 9, 2015	Mar 4, 2019

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Week 0 to Week 24

Title	Measurements
	OG0009.1(1.1 to 29.2) OG0014.8(0.1 to 23.8)

Week 0 to Week 48

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Week 0 to Week 24	Regression, Logistic	Treatment group was the independent variable in the logistic regression.	0.58	Two-sided test													Superiority
OG000 OG001

Secondary

Percentage of Participants With B Cell Reconstitution at Week 24, Week 48 and Week 96

The percentage of participants who achieved B cell reconstitution, defined as a peripheral blood total B cell count ≥ to the baseline count or the lower limit of normal, whichever was lower. Note: B cell depletion was expected to occur in this study between Weeks 0 and 4, after initiation of rituximab and cyclophosphamide.

Normal peripheral blood B Cell count: 107 to 698 cells/µL.

Confidence intervals were calculated using Clopper-Pearson method.

Posted

Number

95% Confidence Interval

Percentage of Participants

Week 24, Week 48 and Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	Participants received infusions of Solumedrol 100mg, rituximab 1000mg, and cyclophosphamide 750mg intravenously (IV) at Week 0 and Week 2. Prednisone was administered at 40 mg/day for the first 2 weeks, followed by a guided steroid taper to 10 mg/day by Week 12. Prednisone was continued through to Week 96 at 10 mg/day, with the potential of a taper to a minimum of 5 mg/day.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	Participants received infusions of Solumedrol 100mg, rituximab 1000mg, and cyclophosphamide 750mg intravenously (IV) at Week 0 and Week 2. Prednisone was administered at 40 mg/day for the first 2 weeks, followed by a guided steroid taper to 10 mg/day by Week 12. Prednisone was continued through to Week 96 at 10 mg/day, with the potential of a taper to a minimum of 5 mg/day. In addition, participants received IV belimumab 10mg/kg at Weeks 4, 6, 8, and then every 4 weeks through Week 48 in addition to prednisone.

Secondary

Percentage of Participants With Grade 4 Hypogammaglobulinemia by Week 24, Week 48, and Week 96

The percentage of participants who experienced Grade 4 hypogammaglobulinemia, defined as having a serum Immunoglobulin G (IgG) level < 300 mg/dL. Severity of adverse events (AEs) was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v4.03:June 14, 2010).

Confidence intervals were calculated using Clopper-Pearson method.

Posted

Number

95% Confidence Interval

percentage of participants

Week 24, Week 48 and Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	Participants received infusions of Solumedrol 100mg, rituximab 1000mg, and cyclophosphamide 750mg intravenously (IV) at Week 0 and Week 2. Prednisone was administered at 40 mg/day for the first 2 weeks, followed by a guided steroid taper to 10 mg/day by Week 12. Prednisone was continued through to Week 96 at 10 mg/day, with the potential of a taper to a minimum of 5 mg/day.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	Participants received infusions of Solumedrol 100mg, rituximab 1000mg, and cyclophosphamide 750mg intravenously (IV) at Week 0 and Week 2. Prednisone was administered at 40 mg/day for the first 2 weeks, followed by a guided steroid taper to 10 mg/day by Week 12. Prednisone was continued through to Week 96 at 10 mg/day, with the potential of a taper to a minimum of 5 mg/day.

Secondary

Percentage of Participants With a Complete Response at Week 24, Week 48, and Week 96

The percentage of participants who achieved a complete response, defined as meeting all of the following criteria:

Urine protein-to-creatinine ratio (UPCR) < 0.5, based on a 24-hour collection;
Estimated glomerular filtration rate (eGFR) ≥ 120 ml/min/1.73 m^2 calculated by the CKD-EPI formula or, if < 120 ml/min/1.73 m^2, then > 80% of eGFR at entry; and
Prednisone dose tapered to 10 mg/day and adherence to prednisone dosing provisions.

Confidence intervals were calculated using Clopper-Pearson method.

Posted

Number

95% Confidence Interval

percentage of participants

Week 24, Week 48 and Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.

Secondary

Percentage of Participants With an Overall Response at Week 24, Week 48, and Week 96

The percentage of participants who achieved an overall response, defined as meeting all of the following criteria:

>50% improvement in the urine protein-to-creatinine ratio (UPCR) from study entry, based on a 24-hour collection;
Estimated glomerular filtration rate (eGFR) ≥120 ml/min/1.73 m^2 calculated by the CKD-EPI formula or, if < 120 ml/min/1.73 m^2, then > 80% of eGFR at entry; and
Prednisone dose tapered to 10 mg/day and adherence to prednisone dosing provisions.

Confidence intervals were calculated using Clopper-Pearson method.

Posted

Number

95% Confidence Interval

percentage of participants

Week 24, Week 48 and Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.

Secondary

Percentage of Participants With a Sustained Complete Response

The percentage of participants who achieved a sustained complete response, defined as a complete response achieved at Week 48 and Week 96.

Complete response was defined as meeting all of the following criteria:

Urine protein-to-creatinine ratio (UPCR) < 0.5, based on a 24-hour collection;
Estimated glomerular filtration rate (eGFR) ≥120 ml/min/1.73 m^2 calculated by the CKD-EPI formula or, if < 120 ml/min/1.73 m^2, then > 80% of eGFR at entry; and
Prednisone dose tapered to 10 mg/day and adherence to prednisone dosing provisions.

Confidence intervals were calculated using Clopper-Pearson method.

Posted

Number

95% Confidence Interval

percentage of participants

Week 48, Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.

Secondary

Percentage of Participants With Treatment Failure by Week 24, Week 48, and Week 96

The percentage of participants who met the criteria for treatment failure, defined by withdrawal from the protocol treatment regimen due to worsening nephritis, infection, or study medication toxicity.

Confidence intervals were calculated using Clopper-Pearson method.

Posted

Number

95% Confidence Interval

percentage of participants

Week 24, Week 48 and Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.

Secondary

Count of Participants: Frequency of Non-renal Flares by Week 24

Count of participants who experienced non-renal flares, defined as any new "A" finding in a non-renal organ system in the British Isles Lupus Assessment Group (BILAG) assessment. A BILAG "A" finding represents a significant increase in, or a new manifestation of, disease activity.

Posted

Count of Participants

Participants

Week 24

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.

Secondary

Count of Participants: Frequency of Non-renal Flares by Week 48

Posted

Count of Participants

Participants

Week 48

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.

Secondary

Count of Participants: Frequency of Non-renal Flares by Week 96

Posted

Count of Participants

Participants

Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.

Secondary

Percentage of Participants With an Negative Anti-dsDNA Result at Week 24, Week 48, and Week 96

The percentage of participants who were anti-double stranded DNA (anti-dsDNA) negative, defined as having anti-dsDNA levels <30 IU/mL.

Anti-dsDNA levels are associated with systemic lupus erythematosus disease activity.

Confidence intervals were calculated using Clopper-Pearson method.

Posted

Number

95% Confidence Interval

percentage of participants

Week 24, Week 48 and Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.

Secondary

Percentage of Participants Hypocomplementemic for Complement Component C3 at Week 24, Week 48, and Week 96

The percentage of participants who were hypocomplementemic for complement component, C3, defined as a C3 level <90 mg/dL.

Serum C3 complement is a protein which can be measured in the blood. Low blood levels of C3 are common in those with active lupus.

Confidence intervals were calculated using Clopper-Pearson method.

Posted

Number

95% Confidence Interval

percentage of participants

Week 24, Week 48 and Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.

Secondary

Percentage of Participants Hypocomplementemic for Complement Component C4 at Week 24, Week 48, and Week 96

The percentage of participants who were hypocomplementemic for complemen component C4, defined as a C4 level <10 mg/dL.

Serum C4 complement is a protein which can be measured in the blood. Low blood levels of C4 are common in those with active lupus.

Confidence intervals were calculated using Clopper-Pearson method.

Posted

Number

95% Confidence Interval

percentage of participants

Week 24, Week 48 and Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The modified intent to treat population includes all randomized participants who received 1 dose of Solumedrol, 1 dose of rituximab, 1 dose of cyclophosphamide, and, if in the Rituximab/Cyclophosphamide/Belimumab (RCB) arm, 1 dose of belimumab.

Secondary

Frequency of Specific Adverse Events of Interest By Event by Week 96

Number of ≥ Grade 2 specific treatment-emergent adverse events (AEs) of interest. Grade 2 or higher AEs were classified according to the listed categories of interest based on the study team's review of the AEs.

Treatment-emergent AEs are those:

with an onset date on or after the first dose of study medication,
with onset before first dose but that worsened in severity after first dose, and
for which the start of the AE in relation to the start of study medication could not be established.

The severity of AEs was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v4.03: June 14, 2010). AEs were classified by system organ class and preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA) version 17.0.

The safety population includes all participants who received at least one dose of study treatment.

Posted

Number

Events

Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The safety population includes all participants who received at least one dose of study treatment.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The safety population includes all participants who received at least one dose of study treatment.

Secondary

Frequency of Specific Adverse Events of Interest By Participant, By Week 96

Number of participants who experienced ≥Grade 2 specific treatment-emergent adverse events (AEs) of interest. Grade 2 or higher AEs were classified according to the listed categories of interest based on the study team's review of the AEs.

Treatment-emergent AEs are those:

with an onset date on or after the first dose of study medication,
with onset before first dose but that worsened in severity after first dose, and
for which the start of the AE in relation to the start of study medication could not be established.

The safety population includes all participants who received at least one dose of study treatment.

Posted

Count of Participants

Participants

Week 96

ID	Title	Description
OG000	Rituximab/Cyclophosphamide (RC)	The safety population includes all participants who received at least one dose of study treatment.
OG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	The safety population includes all participants who received at least one dose of study treatment.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	17.0	Systematic Assessment	EG0001 events1 affected22 at risk EG0010 events0 affected21 at risk EG0022 events1 affected22 at risk EG0030 events0 affected21 at risk
Pancytopenia	Blood and lymphatic system disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Aortic valve incompetence	Cardiac disorders	17.0	Systematic Assessment	EG0001 events1 affected22 at risk EG0010 events0 affected21 at risk EG0020 events0 affected22 at risk EG003
Atrial fibrillation	Cardiac disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Myocardial ischaemia	Cardiac disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Blindness transient	Eye disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Serum sickness	Immune system disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0011 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Abscess soft tissue	Infections and infestations	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0011 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Cellulitis	Infections and infestations	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Infective myositis	Infections and infestations	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0020 events0 affected22 at risk EG003
Mediastinitis	Infections and infestations	17.0	Systematic Assessment	EG0001 events1 affected22 at risk EG0010 events0 affected21 at risk EG0020 events0 affected22 at risk EG003
Pneumonia	Infections and infestations	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Pneumonia respiratory syncytial viral	Infections and infestations	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Pseudomonal bacteraemia	Infections and infestations	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Sepsis	Infections and infestations	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Staphylococcal bacteraemia	Infections and infestations	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Urinary tract infection	Infections and infestations	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0011 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Tendon rupture	Injury, poisoning and procedural complications	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0011 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Blood creatinine increased	Investigations	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Hypocalcaemia	Metabolism and nutrition disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Intervertebral disc protrusion	Musculoskeletal and connective tissue disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Osteonecrosis	Musculoskeletal and connective tissue disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Systemic lupus erythematosus	Musculoskeletal and connective tissue disorders	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0010 events0 affected21 at risk EG0023 events2 affected22 at risk EG003
Grand mal convulsion	Nervous system disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Posterior reversible encephalopathy syndrome	Nervous system disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0022 events1 affected22 at risk EG003
Lupus nephritis	Renal and urinary disorders	17.0	Systematic Assessment	EG0001 events1 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Renal failure	Renal and urinary disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0022 events2 affected22 at risk EG003
Renal failure acute	Renal and urinary disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0022 events1 affected22 at risk EG003
Pulmonary alveolar haemorrhage	Respiratory, thoracic and mediastinal disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0021 events1 affected22 at risk EG003
Axillary vein thrombosis	Vascular disorders	17.0	Systematic Assessment	EG0001 events1 affected22 at risk EG0010 events0 affected21 at risk EG0020 events0 affected22 at risk EG003
Hypertensive emergency	Vascular disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0010 events0 affected21 at risk EG0022 events1 affected22 at risk EG003
Subclavian vein thrombosis	Vascular disorders	17.0	Systematic Assessment	EG0001 events1 affected22 at risk EG0010 events0 affected21 at risk EG0020 events0 affected22 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	17.0	Systematic Assessment	EG00017 events10 affected22 at risk EG00120 events13 affected21 at risk EG0023 events3 affected22 at risk EG0031 events1 affected21 at risk
Leukopenia	Blood and lymphatic system disorders	17.0	Systematic Assessment	EG00010 events5 affected22 at risk EG00115 events6 affected21 at risk EG0022 events2 affected22 at risk EG003
Lymphopenia	Blood and lymphatic system disorders	17.0	Systematic Assessment	EG00033 events17 affected22 at risk EG00119 events11 affected21 at risk EG00211 events9 affected22 at risk EG003
Neutropenia	Blood and lymphatic system disorders	17.0	Systematic Assessment	EG0005 events3 affected22 at risk EG0018 events5 affected21 at risk EG0022 events2 affected22 at risk EG003
Cushingoid	Endocrine disorders	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0010 events0 affected21 at risk EG0020 events0 affected22 at risk EG003
Diarrhoea	Gastrointestinal disorders	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0013 events2 affected21 at risk EG0021 events1 affected22 at risk EG003
Dyspepsia	Gastrointestinal disorders	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0011 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Nausea	Gastrointestinal disorders	17.0	Systematic Assessment	EG0006 events5 affected22 at risk EG0011 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Vomiting	Gastrointestinal disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0013 events2 affected21 at risk EG0020 events0 affected22 at risk EG003
Fatigue	General disorders	17.0	Systematic Assessment	EG0004 events2 affected22 at risk EG0011 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Local swelling	General disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0012 events2 affected21 at risk EG0020 events0 affected22 at risk EG003
Oedema peripheral	General disorders	17.0	Systematic Assessment	EG0003 events3 affected22 at risk EG0011 events1 affected21 at risk EG0021 events1 affected22 at risk EG003
Hypogammaglobulinaemia	Immune system disorders	17.0	Systematic Assessment	EG00012 events9 affected22 at risk EG00118 events11 affected21 at risk EG0025 events4 affected22 at risk EG003
Herpes zoster	Infections and infestations	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0013 events3 affected21 at risk EG0020 events0 affected22 at risk EG003
Nasopharyngitis	Infections and infestations	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0013 events2 affected21 at risk EG0020 events0 affected22 at risk EG003
Oral candidiasis	Infections and infestations	17.0	Systematic Assessment	EG0003 events2 affected22 at risk EG0013 events2 affected21 at risk EG0020 events0 affected22 at risk EG003
Upper respiratory tract infection	Infections and infestations	17.0	Systematic Assessment	EG0006 events3 affected22 at risk EG0014 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Urinary tract infection	Infections and infestations	17.0	Systematic Assessment	EG0007 events3 affected22 at risk EG0012 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Viral upper respiratory tract infection	Infections and infestations	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0010 events0 affected21 at risk EG0020 events0 affected22 at risk EG003
Infusion related reaction	Injury, poisoning and procedural complications	17.0	Systematic Assessment	EG0001 events1 affected22 at risk EG0012 events2 affected21 at risk EG0020 events0 affected22 at risk EG003
Maternal exposure during pregnancy	Injury, poisoning and procedural complications	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0014 events3 affected21 at risk EG0020 events0 affected22 at risk EG003
Blood creatinine increased	Investigations	17.0	Systematic Assessment	EG0009 events6 affected22 at risk EG00111 events8 affected21 at risk EG0021 events1 affected22 at risk EG003
Hypoalbuminaemia	Metabolism and nutrition disorders	17.0	Systematic Assessment	EG00015 events10 affected22 at risk EG00110 events8 affected21 at risk EG0022 events2 affected22 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0011 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	17.0	Systematic Assessment	EG0003 events3 affected22 at risk EG0011 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Headache	Nervous system disorders	17.0	Systematic Assessment	EG0000 events0 affected22 at risk EG0012 events2 affected21 at risk EG0021 events1 affected22 at risk EG003
Insomnia	Psychiatric disorders	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0010 events0 affected21 at risk EG0020 events0 affected22 at risk EG003
Lupus nephritis	Renal and urinary disorders	17.0	Systematic Assessment	EG0004 events4 affected22 at risk EG0016 events6 affected21 at risk EG0021 events1 affected22 at risk EG003
Proteinuria	Renal and urinary disorders	17.0	Systematic Assessment	EG0007 events7 affected22 at risk EG0018 events6 affected21 at risk EG0023 events3 affected22 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0012 events2 affected21 at risk EG0020 events0 affected22 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0011 events1 affected21 at risk EG0020 events0 affected22 at risk EG003
Alopecia	Skin and subcutaneous tissue disorders	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0010 events0 affected21 at risk EG0020 events0 affected22 at risk EG003
Hypertension	Vascular disorders	17.0	Systematic Assessment	EG0002 events2 affected22 at risk EG0011 events1 affected21 at risk EG0022 events1 affected22 at risk EG003

ID	Term
D005921	Glomerulonephritis
D009393	Nephritis
D007674	Kidney Diseases
D014570	Urologic Diseases
D052776	Female Urogenital Diseases
D005261	Female Urogenital Diseases and Pregnancy Complications
D000091642	Urogenital Diseases
D052801	Male Urogenital Diseases
D008180	Lupus Erythematosus, Systemic
D003240	Connective Tissue Diseases
D017437	Skin and Connective Tissue Diseases
D001327	Autoimmune Diseases
D007154	Immune System Diseases

ID	Term
D058846	Antibodies, Monoclonal, Murine-Derived
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins
D010752	Phosphoramide Mustards
D009588	Nitrogen Mustard Compounds
D009150	Mustard Compounds
D006846	Hydrocarbons, Halogenated
D006838	Hydrocarbons
D009930	Organic Chemicals
D063088	Phosphoramides
D009943	Organophosphorus Compounds
D011244	Pregnadienediols
D011245	Pregnadienes
D011278	Pregnanes
D013256	Steroids
D000072473	Fused-Ring Compounds
D011083	Polycyclic Compounds
D011239	Prednisolone
D011246	Pregnadienetriols
D005021	Ethylamines
D000588	Amines
D001559	Benzhydryl Compounds
D001555	Benzene Derivatives
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D000083	Acetanilides
D000813	Anilides
D000577	Amides
D000814	Aniline Compounds

ID	Title	Description
BG000	Rituximab/Cyclophosphamide (RC)	Participants received infusions of Solumedrol 100mg, rituximab 1000mg, and cyclophosphamide 750mg intravenously (IV) at Week 0 and Week 2. Prednisone was administered at 40 mg/day for the first 2 weeks, followed by a guided steroid taper to 10 mg/day by Week 12. Prednisone was continued through to Week 96 at 10 mg/day, with the potential of a taper to a minimum of 5 mg/day.
BG001	Rituximab/Cyclophosphamide/Belimumab (RCB)	Participants received infusions of Solumedrol 100mg, rituximab 1000mg, and cyclophosphamide 750mg intravenously (IV) at Week 0 and Week 2. Prednisone was administered at 40 mg/day for the first 2 weeks, followed by a guided steroid taper to 10 mg/day by Week 12. Prednisone was continued through to Week 96 at 10 mg/day, with the potential of a taper to a minimum of 5 mg/day. In addition, participants received IV belimumab 10mg/kg at Weeks 4, 6, 8, and then every 4 weeks through Week 48 in addition to prednisone.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	RC Group on Treatment	Participants received infusions of Solumedrol 100mg, rituximab 1000mg, and cyclophosphamide 750mg intravenously (IV) at Week 0 and Week 2. Prednisone 40 mg per day was administered for the first 2 weeks, with a guided steroid taper to 10mg per day by Week 12 and continued treatment until Week 96.	22	6	22	22	22
EG001	RCB Group on Treatment	Participants received infusions of Solumedrol 100mg, rituximab 1000mg, and cyclophosphamide 750mg intravenously (IV) at Week 0 and Week 2. Prednisone 40 mg per day was administered for the first 2 weeks, with a guided steroid taper to 10mg per day by Week 12 and continued treatment until Week 96. In addition, participants received IV belimumab 10mg/kg at Weeks 4, 6, 8, and then every 4 weeks through Week 48 in addition to prednisone.	21	4	21	21	21
EG002	RC Group After Treatment Discontinuation	Participants received infusions of Solumedrol 100mg, rituximab 1000mg, and cyclophosphamide 750mg intravenously (IV) at Week 0 and Week 2. Prednisone 40 mg per day was administered for the first 2 weeks, with a guided steroid taper to 10mg per day by Week 12 and continued treatment until Week 96.	22	8	22	11	22
EG003	RCB Group After Treatment Discontinuation	Participants received infusions of Solumedrol 100mg, rituximab 1000mg, and cyclophosphamide 750mg intravenously (IV) at Week 0 and Week 2. Prednisone 40 mg per day was administered for the first 2 weeks, with a guided steroid taper to 10mg per day by Week 12 and continued treatment until Week 96. In addition, participants received IV belimumab 10mg/kg at Weeks 4, 6, 8, and then every 4 weeks through Week 48 in addition to prednisone.	21	1	21	6	21

ID	Term
D000069283	Rituximab
D003520	Cyclophosphamide
D011241	Prednisone
D008775	Methylprednisolone
D008776	Methylprednisolone Hemisuccinate
D004155	Diphenhydramine
D000082	Acetaminophen
C511911	belimumab