GP2013 in the Treatment of RA Patients Refractory to or I... | NCT01274182

ID	Type	Description	Link
2010-021184-32	EudraCT Number
GPN013A2301	Other Identifier	Novartis

Name	Class
Novartis Pharmaceuticals	INDUSTRY

Label	Type	Intervention Names
GP2013	Experimental	Biological: GP2013
MabThera	Active Comparator	Biological: MabThera
Rituxan	Active Comparator	Biological: Rituxan

Name	Type	Description	Arm Group Labels	Other Names
GP2013	Biological	1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)	GP2013

Measure	Description	Time Frame
AUC(0-inf) of GP2013, MabThera and Rituxan Following IV Infusion in Patients With RA	Area under the curve AUC(0-inf) calculated based on serum samples, collected from baseline up to 24 weeks: Day 1, 4, 8, 15, 18, 29, 57, 85,113 and 169	From baseline to 24 weeks

Measure	Description	Time Frame
Maximum Serum Concentration (Cmax) of GP2013, MabThera and Rituxan Following IV Infusion in Patients With RA	Maximum serum concentration (Cmax) after the first infusion of GP2013, MabThera and Rituxan in patients with RA. Samples collected from baseline up to 24 weeks: Day 1, 4, 8, 15, 18, 29, 57, 85,113 and 169.	From baseline to week 24

Measure	Description	Time Frame
Number of Patients With at Least One Anti-Drug-Antibody (ADA) Positive Serum Sample	Number of patients with at least one post-baseline Anti-Drug-Antibody (ADA) positive serum sample until the last study visit. Sampling was at Day 1, 29, 113, 169, 267, 365, optional visit 1 (could be at any time between day 169 - week 24 and day 365 - week 52 for patients, who received a 2nd treatment course) and optional visit 2 (only applicable for patients, who received a 2nd treatment course, 26 weeks thereafter, if this was after day 365 - week 52).

Name	Affiliation	Role
Sandoz Biopharmaceuticals	Sandoz	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Miller Clinical Research		Los Angeles	California	90057	United States
Bluegrass Community Research, Inc.

PubMed Identifier	Type	Citation	Retractions
28637670	Derived	Smolen JS, Cohen SB, Tony HP, Scheinberg M, Kivitz A, Balanescu A, Gomez-Reino J, Cen L, Zhu P, Shisha T. A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis. Ann Rheum Dis. 2017 Sep;76(9):1598-1602. doi: 10.1136/annrheumdis-2017-211281. Epub 2017 Jun 21.

ID	Title	Description
FG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
FG001	MabThera	MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

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
	ParticipantsBG000133 ParticipantsBG00187 ParticipantsBG00292 ParticipantsBG003

Sex: Female, Male

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG000133 ParticipantsBG00187 ParticipantsBG002

Race (NIH/OMB)

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG000133 ParticipantsBG00187 ParticipantsBG002

Region of Enrollment

Number

participants

Title	Denominators	Categories
Argentina	ParticipantsBG000133 ParticipantsBG00187 ParticipantsBG002

Body Mass Index (BMI)

Analysis done on data of BMI available at the baseline visit.

Mean

Standard Deviation

kg/m2

Title	Denominators	Categories
	ParticipantsBG000133 ParticipantsBG00185 ParticipantsBG002

Duration of Rheumatoid Arthritis(RA)

Time in years since initial diagnosis of RA

Analysis done on data of Duration of RA available at the baseline visit

Mean

Standard Deviation

years

Title	Denominators	Categories
	ParticipantsBG000133 ParticipantsBG00186 ParticipantsBG002

Number of patients having received 1, 2 or >2 TNF inhibitor therapies.

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG000133 ParticipantsBG00187 ParticipantsBG002

Disease Activity Score 28 joint count - C-reactive proteine (DAS28-CRP)

In order to calculate the DAS28(CRP) the number of tender joints and swollen joints were assessed using 28-joint count (tender28 and swollen28).The patient's global assessment of disease activity (GH) measured on a Visual Analogue Scale (VAS from 0mm - best to 100mm - worst) was obtained.

DAS28(CRP) = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * GH + 0.96 The DAS28(CRP) provides a number on a scale from 0 to 10 indicating the current activity of the RA, while lower values correspond with less disease activity. A decrease in DAS28 signifies a clinical improvement

Analysis done on data of DAS28-CRP available at the baseline visit

Mean

Standard Deviation

units on a scale

Title	Denominators	Categories
	ParticipantsBG000132 ParticipantsBG001

Dose of methotrexate at baseline

Analysis done on data of Methotrexate use available at the baseline visit

Mean

Standard Deviation

mg/week

Title	Denominators	Categories
	ParticipantsBG000131 ParticipantsBG00184 ParticipantsBG002

Anti-drug antibodies (ADA)

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG000133 ParticipantsBG00187 ParticipantsBG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

AUC(0-inf) of GP2013, MabThera and Rituxan Following IV Infusion in Patients With RA

Area under the curve AUC(0-inf) calculated based on serum samples, collected from baseline up to 24 weeks: Day 1, 4, 8, 15, 18, 29, 57, 85,113 and 169

PK Analysis Set

Posted

Geometric Mean

Geometric Coefficient of Variation

day*mcg/mL

From baseline to 24 weeks

ID	Title	Description
OG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG001	MabThera	MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG002	Rituxan	Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

Units	Counts
Participants	OG000124 OG00179 OG00280

Title

Denominators

Categories

Title	Measurements
	OG0007627.44± 38.60 OG0016896.97± 40.56 OG0027536.89± 40.28

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	PK bioequivalence is defined as AUC(0-inf) of the drugs being comparable, i.e. the two-sided 90% CI for the ratio of the geometric means (GP2013/MabThera) is within the predefined bioequivalence limits of 0.8 to 1.25.					Geometric mean ratio	1.106			2-Sided	90	1.010	1.210			GP2013 arm is the numerator and MabThera arm is the denominator		Equivalence	The PK parameters were transformed prior to analysis using a logarithmic transformation. An analysis of variance (ANOVA) was used to analyze the transformed data including treatment group only as a factor in the model. The confidence interval for the difference between the two products on the transformed scale was obtained from the ANOVA model, which was then be back-transformed (exp base e) to obtain the confidence interval for the ratio on the original scale.

Secondary

Maximum Serum Concentration (Cmax) of GP2013, MabThera and Rituxan Following IV Infusion in Patients With RA

Maximum serum concentration (Cmax) after the first infusion of GP2013, MabThera and Rituxan in patients with RA. Samples collected from baseline up to 24 weeks: Day 1, 4, 8, 15, 18, 29, 57, 85,113 and 169.

PK Analysis Set

Posted

Geometric Mean

Geometric Coefficient of Variation

mcg/mL

From baseline to week 24

ID	Title	Description
OG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG001	MabThera	MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG002	Rituxan	Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

Units	Counts
Participants

Secondary

Area Under the Effect Curve From Baseline to Day 14 (AUEC(0-14d)) of Percent B-cells of GP2013, MabThera and Rituxan in Patients With RA

Area under the effect curve of percent change of peripheral B-cell count from baseline to Day 14 (AUEC(0-14d)) of GP2013, MabThera and Rituxan in patients with RA

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

% * day

14 days

ID	Title	Description
OG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG001	MabThera	MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG002	Rituxan	Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

Units	Counts
Participants

Secondary

Change From Baseline in DAS28(CRP) at Week 24

Change from baseline in Disease Activity Score 28 joint count - C-reactive proteine DAS28(CRP) at Week 24.

PP analysis set

Posted

Least Squares Mean

Standard Error

units on a scale

24 weeks

ID	Title	Description
OG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG001	MabThera	MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG002	Rituxan	Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

Secondary

Number of Patients With ACR20 (CRP) Response

A patient will be considered as improved according the ACR20 criteria

at least 20 % improvement from baseline in tender joint count, using the 68-joint count
at least 20 % improvement from baseline in swollen joint count, using the 66-joint count
and at least 20% improvement from baseline in a least 3 of the following 5 measures:
Patient's assessment of RA pain (VAS 100 mm)
Patient's global assessment of disease activity (VAS 100 mm)
Physician's global assessment of disease activity (VAS 100 mm)
Patient self-assessed disability (Health Assessment Questionnaire disability index)
Acute phase reactant (C-reactive protein or erythrocyte sedimentation rate)

PP analysis set

Posted

Count of Participants

Participants

24 weeks

ID	Title	Description
OG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG001	MabThera	MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG002	Rituxan	Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

Secondary

Summary of Disease Activity According to CDAI

In order to calculate the Clinical Disease Activity Index (CDAI) the number of tender and swollen joints were assessed using the 28 -joint count (tender28 and swollen28). The patient's global assessment of disease activity and the physician's global assessment of disease activity were measured using a Visual Analogue Scale (VAS) of 10 cm (from 0=best to 10=worst).

CDAI = tender28 + swollen28 + patient's global assessment (in cm) + physician's global assessment (in cm)

PP analysis set

Posted

Count of Participants

Participants

At week 24

ID	Title	Description
OG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG001	Rituxan	Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG002	GP2013 Part I	This is the subgroup of patients in the GP2013 treatment arm, who were enrolled in the study Part I. Efficacy comparisons between GP2013 and MabThera were done in the study Part I on patients enrolled only in the study Part I

Secondary

Summary of Disease Activity According to SDAI

In order to calculate the Simplified Disease Activity Index (SDAI) the number of tender and swollen joints were assessed using the 28 -joint count (tender28 and swollen28). The patient's global assessment of disease activity and the physician's global assessment of disease activity were measured using a Visual Analogue Scale (VAS) of 10 cm (from 0=best to 10=worst).

SDAI = CDAI + CRP (in mg/dL)

(CDAI = tender28 + swollen28 + patient's global assessment (in cm) + physician's global assessment (in cm))

PP analysis set

Posted

Count of Participants

Participants

At week 24

ID	Title	Description
OG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG001	Rituxan	Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG002	GP2013 Part I	This is the subgroup of patients in the GP2013 treatment arm, who were enrolled in the study Part I. Efficacy comparisons between GP2013 and MabThera were done in the study Part I on patients enrolled only in the study Part I

Secondary

Participant Response as Assessed by EULAR Response Criteria

Present DAS28 ≤ 3.2 (low): good response (if improvement > 1.2), moderate response (if improvement >0.6 and ≤ 1.2), no response (if improvement ≤ 0.6).

Present DAS28 > 3.2 to ≤ 5.1 (moderate): moderate response (if improvement > 1.2), moderate response (if improvement >0.6 and ≤ 1.2), no response (if improvement ≤ 0.6).

Present DAS28 > 5.1 (high): moderate response (if improvement > 1.2), no response (if improvement >0.6 and ≤ 1.2), no response (if improvement ≤ 0.6).

PP analysis set

Posted

Count of Participants

Participants

At week 24

ID	Title	Description
OG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG001	Rituxan	Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG002	GP2013 Part I	This is the subgroup of patients in the GP2013 treatment arm, who were enrolled in the study Part I. Efficacy comparisons between GP2013 and MabThera were done in the study Part I on patients enrolled only in the study Part I

Other Pre-specified

Number of Patients With at Least One Anti-Drug-Antibody (ADA) Positive Serum Sample

Number of patients with at least one post-baseline Anti-Drug-Antibody (ADA) positive serum sample until the last study visit. Sampling was at Day 1, 29, 113, 169, 267, 365, optional visit 1 (could be at any time between day 169 - week 24 and day 365 - week 52 for patients, who received a 2nd treatment course) and optional visit 2 (only applicable for patients, who received a 2nd treatment course, 26 weeks thereafter, if this was after day 365 - week 52).

Patients with positive ADA results at randomization were excluded from analysis

Posted

Number

participants

through study completion, an average of 1 year

ID	Title	Description
OG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG001	MabThera	MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
OG002	Rituxan	Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Bone marrow failure	Blood and lymphatic system disorders	MedDRA Version 19.1	Systematic Assessment	SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.	EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Microcytic anaemia	Blood and lymphatic system disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0012 events1 affected87 at risk EG0020 events0 affected92 at risk
Pancytopenia	Blood and lymphatic system disorders	MedDRA Version 19.1	Systematic Assessment	SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.	EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Angina pectoris	Cardiac disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0012 events2 affected87 at risk EG0020 events0 affected92 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Myocardial infarction	Cardiac disorders	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Sinus tachycardia	Cardiac disorders	MedDRA Version 19.1	Systematic Assessment	SAEs chest pain and sinus tachycardia were diagnosed in same patient at the same time	EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Chest pain	General disorders	MedDRA Version 19.1	Systematic Assessment	SAEs chest pain and sinus tachycardia were diagnosed in same patient at the same time	EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Lipogranuloma	General disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Multiple organ dysfunction syndrome	General disorders	MedDRA Version 19.1	Systematic Assessment	SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.	EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Pyrexia	General disorders	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Drug hypersensitivity	Immune system disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0020 events0 affected92 at risk
Abscess	Infections and infestations	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Atypical pneumonia	Infections and infestations	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0020 events0 affected92 at risk
Gastroenteritis	Infections and infestations	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0020 events0 affected92 at risk
Groin abscess	Infections and infestations	MedDRA Version 19.1	Systematic Assessment	SAEs Fistula, Groin Abscess and Pilonidal cyst occurred in same patient as a sequence of events	EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Klebsiella sepsis	Infections and infestations	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Lyme disease	Infections and infestations	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Pilonidal cyst	Infections and infestations	MedDRA Version 19.1	Systematic Assessment	SAEs Fistula, Groin Abscess and Pilonidal cyst occurred in same patient as a sequence of events	EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Pneumonia	Infections and infestations	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Pneumonia haemophilus	Infections and infestations	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0020 events0 affected92 at risk
Purulent pericarditis	Infections and infestations	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Pyelonephritis	Infections and infestations	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0020 events0 affected92 at risk
Sepsis	Infections and infestations	MedDRA Version 19.1	Systematic Assessment	SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.	EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Septic shock	Infections and infestations	MedDRA Version 19.1	Systematic Assessment	SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.	EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Soft tissue infection	Infections and infestations	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Infusion related reaction	Injury, poisoning and procedural complications	MedDRA Version 19.1	Systematic Assessment		EG0002 events2 affected133 at risk EG0011 events1 affected87 at risk EG0022 events2 affected92 at risk
Rib fracture	Injury, poisoning and procedural complications	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0022 events2 affected92 at risk
Spinal fracture	Injury, poisoning and procedural complications	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0021 events1 affected92 at risk
Bone fissure	Injury, poisoning and procedural complications	MedDRA Version 19.1	Systematic Assessment	SAEs: Bone fissure, Vitamid D defficiency and Fractured sacrum occurred in same patient as a sequence of events	EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Femoral neck fracture	Injury, poisoning and procedural complications	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0020 events0 affected92 at risk
Fractured sacrum	Injury, poisoning and procedural complications	MedDRA Version 19.1	Systematic Assessment	SAEs: Bone fissure, Vitamid D defficiency and Fractured sacrum occurred in same patient as a sequence of events	EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Overdose	Injury, poisoning and procedural complications	MedDRA Version 19.1	Systematic Assessment	SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.	EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Radius fracture	Injury, poisoning and procedural complications	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0020 events0 affected92 at risk
Synovial rupture	Injury, poisoning and procedural complications	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Tibia fracture	Injury, poisoning and procedural complications	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Vitamin D deficiency	Metabolism and nutrition disorders	MedDRA Version 19.1	Systematic Assessment	SAEs: Bone fissure, Vitamid D defficiency and Fractured sacrum occurred in same patient as a sequence of events	EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Fistula	Musculoskeletal and connective tissue disorders	MedDRA Version 19.1	Systematic Assessment	SAEs Fistula, Groin Abscess and Pilonidal cyst occurred in same patient as a sequence of events	EG0002 events2 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0012 events2 affected87 at risk EG0020 events0 affected92 at risk
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Fracture pain	Musculoskeletal and connective tissue disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Rheumatoid arthritis	Musculoskeletal and connective tissue disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Spinal osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA Version 19.1	Systematic Assessment		EG0002 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Synovial cyst	Musculoskeletal and connective tissue disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0020 events0 affected92 at risk
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Syncope	Nervous system disorders	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0020 events0 affected92 at risk
Ischaemic stroke	Nervous system disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0020 events0 affected92 at risk
Meningoradiculitis	Nervous system disorders	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Seizure	Nervous system disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Depression	Psychiatric disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Dissociative disorder	Psychiatric disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Urogenital prolapse	Reproductive system and breast disorders	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0013 events1 affected87 at risk EG0020 events0 affected92 at risk
Pulmonary fibrosis	Respiratory, thoracic and mediastinal disorders	MedDRA Version 19.1	Systematic Assessment		EG0001 events1 affected133 at risk EG0010 events0 affected87 at risk EG0020 events0 affected92 at risk
Vasculitis	Vascular disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0020 events0 affected92 at risk
Venous thrombosis	Vascular disorders	MedDRA Version 19.1	Systematic Assessment		EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Leukopenia	Blood and lymphatic system disorders	MedDRA Version 19.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0011 events1 affected87 at risk EG0023 events3 affected92 at risk
Nausea	Gastrointestinal disorders	MedDRA Version 19.1	Systematic Assessment	EG0009 events9 affected133 at risk EG0013 events3 affected87 at risk EG00210 events5 affected92 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA Version 19.1	Systematic Assessment	EG0004 events4 affected133 at risk EG0013 events3 affected87 at risk EG0021 events1 affected92 at risk
Fatigue	General disorders	MedDRA Version 19.1	Systematic Assessment	EG0006 events6 affected133 at risk EG0010 events0 affected87 at risk EG0021 events1 affected92 at risk
Pyrexia	General disorders	MedDRA Version 19.1	Systematic Assessment	EG0003 events2 affected133 at risk EG0013 events3 affected87 at risk EG0021 events1 affected92 at risk
Nasopharyngitis	Infections and infestations	MedDRA Version 19.1	Systematic Assessment	EG00012 events9 affected133 at risk EG0016 events5 affected87 at risk EG00211 events9 affected92 at risk
Urinary tract infection	Infections and infestations	MedDRA Version 19.1	Systematic Assessment	EG00012 events11 affected133 at risk EG0017 events5 affected87 at risk EG0022 events2 affected92 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA Version 19.1	Systematic Assessment	EG0007 events6 affected133 at risk EG0015 events5 affected87 at risk EG0026 events6 affected92 at risk
Bronchitis	Infections and infestations	MedDRA Version 19.1	Systematic Assessment	EG0006 events5 affected133 at risk EG0016 events5 affected87 at risk EG0021 events1 affected92 at risk
Oral herpes	Infections and infestations	MedDRA Version 19.1	Systematic Assessment	EG0006 events5 affected133 at risk EG0012 events2 affected87 at risk EG0021 events1 affected92 at risk
Sinusitis	Infections and infestations	MedDRA Version 19.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected87 at risk EG0025 events5 affected92 at risk
Respiratory tract infection	Infections and infestations	MedDRA Version 19.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0014 events3 affected87 at risk EG0021 events1 affected92 at risk
Infusion related reaction	Injury, poisoning and procedural complications	MedDRA Version 19.1	Systematic Assessment	EG0004 events4 affected133 at risk EG0016 events3 affected87 at risk EG0022 events2 affected92 at risk
Alanine aminotransferase increased	Investigations	MedDRA Version 19.1	Systematic Assessment	EG0004 events3 affected133 at risk EG0011 events1 affected87 at risk EG0024 events3 affected92 at risk
Dyslipidaemia	Metabolism and nutrition disorders	MedDRA Version 19.1	Systematic Assessment	EG0003 events2 affected133 at risk EG0012 events2 affected87 at risk EG0025 events5 affected92 at risk
Rheumatoid arthritis	Musculoskeletal and connective tissue disorders	MedDRA Version 19.1	Systematic Assessment	EG0006 events6 affected133 at risk EG0015 events5 affected87 at risk EG00214 events8 affected92 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA Version 19.1	Systematic Assessment	EG0004 events4 affected133 at risk EG0015 events4 affected87 at risk EG0023 events3 affected92 at risk
Headache	Nervous system disorders	MedDRA Version 19.1	Systematic Assessment	EG0006 events6 affected133 at risk EG0017 events5 affected87 at risk EG00210 events6 affected92 at risk
Depression	Psychiatric disorders	MedDRA Version 19.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0010 events0 affected87 at risk EG0023 events3 affected92 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA Version 19.1	Systematic Assessment	EG0005 events5 affected133 at risk EG0014 events4 affected87 at risk EG0027 events7 affected92 at risk
Throat irritation	Respiratory, thoracic and mediastinal disorders	MedDRA Version 19.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0012 events2 affected87 at risk EG0024 events3 affected92 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA Version 19.1	Systematic Assessment	EG0005 events5 affected133 at risk EG0015 events4 affected87 at risk EG0021 events1 affected92 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA Version 19.1	Systematic Assessment	EG0003 events2 affected133 at risk EG0016 events6 affected87 at risk EG0022 events1 affected92 at risk
Hypertension	Vascular disorders	MedDRA Version 19.1	Systematic Assessment	EG0005 events5 affected133 at risk EG0018 events5 affected87 at risk EG0023 events3 affected92 at risk

ID	Term
D001168	Arthritis
D007592	Joint Diseases
D009140	Musculoskeletal Diseases
D012216	Rheumatic Diseases
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

ID	Title	Description
BG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
BG001	MabThera	MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
BG002	Rituxan	Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
BG003	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	GP2013	GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)	1	133	16	133	87	133
EG001	MabThera	MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)	0	87	14	87	56	87
EG002	Rituxan	Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)	1	92	9	92	60	92