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GP2013 in the Treatment of RA Patients Refractory to or Intolerant of Standard Therapy

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ClinicalTrials.gov Identifier: NCT01274182
Recruitment Status : Completed
First Posted : January 11, 2011
Results First Posted : January 24, 2018
Last Update Posted : January 24, 2018
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Sandoz

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Rheumatoid Arthritis
Interventions Biological: GP2013
Biological: MabThera
Biological: Rituxan
Enrollment 312
Recruitment Details  
Pre-assignment Details  
Arm/Group Title GP2013 MabThera Rituxan
Hide Arm/Group Description GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15) MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15) Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Period Title: Overall Study
Started 133 87 92
24 Weeks 123 83 84
Completed 112 69 80
Not Completed 21 18 12
Reason Not Completed
Unsatisfactory therapeutic effect             6             3             4
Adverse Event             4             5             3
Withdrawal by Subject             5             5             3
Lost to Follow-up             2             3             1
Protocol Violation             3             2             0
Death             1             0             1
Arm/Group Title GP2013 MabThera Rituxan Total
Hide Arm/Group Description GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15) MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15) Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15) Total of all reporting groups
Overall Number of Baseline Participants 133 87 92 312
Hide Baseline Analysis Population Description
Full Analysis Set
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 133 participants 87 participants 92 participants 312 participants
54.42  (11.779) 52.17  (12.531) 54.95  (10.750) 54.10  (11.701)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 133 participants 87 participants 92 participants 312 participants
Female
111
  83.5%
73
  83.9%
78
  84.8%
262
  84.0%
Male
22
  16.5%
14
  16.1%
14
  15.2%
50
  16.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 133 participants 87 participants 92 participants 312 participants
American Indian or Alaska Native
0
   0.0%
1
   1.1%
0
   0.0%
1
   0.3%
Asian
12
   9.0%
12
  13.8%
0
   0.0%
24
   7.7%
Native Hawaiian or Other Pacific Islander
1
   0.8%
0
   0.0%
0
   0.0%
1
   0.3%
Black or African American
1
   0.8%
6
   6.9%
6
   6.5%
13
   4.2%
White
117
  88.0%
68
  78.2%
75
  81.5%
260
  83.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
2
   1.5%
0
   0.0%
11
  12.0%
13
   4.2%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Argentina Number Analyzed 133 participants 87 participants 92 participants 312 participants
8 3 9 20
Austria Number Analyzed 133 participants 87 participants 92 participants 312 participants
7 10 3 20
Turkey Number Analyzed 133 participants 87 participants 92 participants 312 participants
4 1 2 7
Romania Number Analyzed 133 participants 87 participants 92 participants 312 participants
9 8 6 23
Belgium Number Analyzed 133 participants 87 participants 92 participants 312 participants
1 4 0 5
United States Number Analyzed 133 participants 87 participants 92 participants 312 participants
10 0 19 29
Brazil Number Analyzed 133 participants 87 participants 92 participants 312 participants
19 12 19 50
Italy Number Analyzed 133 participants 87 participants 92 participants 312 participants
5 3 3 11
France Number Analyzed 133 participants 87 participants 92 participants 312 participants
4 1 0 5
Germany Number Analyzed 133 participants 87 participants 92 participants 312 participants
31 17 14 62
India Number Analyzed 133 participants 87 participants 92 participants 312 participants
12 12 0 24
Spain Number Analyzed 133 participants 87 participants 92 participants 312 participants
13 16 4 33
Russia Number Analyzed 133 participants 87 participants 92 participants 312 participants
6 0 11 17
Hungary Number Analyzed 133 participants 87 participants 92 participants 312 participants
3 0 1 4
Estonia Number Analyzed 133 participants 87 participants 92 participants 312 participants
1 0 1 2
Body Mass Index (BMI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m2
Number Analyzed 133 participants 85 participants 92 participants 310 participants
27.37  (6.230) 27.25  (6.000) 29.66  (6.606) 28.02  (6.353)
[1]
Measure Analysis Population Description: Analysis done on data of BMI available at the baseline visit.
Duration of Rheumatoid Arthritis(RA)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 133 participants 86 participants 92 participants 311 participants
10.53  (8.074) 10.81  (7.137) 11.10  (8.299) 10.78  (7.874)
[1]
Measure Description: Time in years since initial diagnosis of RA
[2]
Measure Analysis Population Description: Analysis done on data of Duration of RA available at the baseline visit
Number of patients having received 1, 2 or >2 TNF inhibitor therapies.  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 133 participants 87 participants 92 participants 312 participants
1
109
  82.0%
70
  80.5%
73
  79.3%
252
  80.8%
2
18
  13.5%
16
  18.4%
13
  14.1%
47
  15.1%
>2
6
   4.5%
1
   1.1%
6
   6.5%
13
   4.2%
Disease Activity Score 28 joint count - C-reactive proteine (DAS28-CRP)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 132 participants 87 participants 91 participants 310 participants
5.83  (0.922) 5.85  (0.880) 5.91  (1.009) 5.86  (0.935)
[1]
Measure Description:

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

[2]
Measure Analysis Population Description: Analysis done on data of DAS28-CRP available at the baseline visit
Dose of methotrexate at baseline   [1] 
Mean (Standard Deviation)
Unit of measure:  Mg/week
Number Analyzed 131 participants 84 participants 91 participants 306 participants
15.09  (4.856) 14.65  (5.154) 15.29  (4.888) 15.03  (4.939)
[1]
Measure Analysis Population Description: Analysis done on data of Methotrexate use available at the baseline visit
Anti-drug antibodies (ADA)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 133 participants 87 participants 92 participants 312 participants
Negative
132
  99.2%
85
  97.7%
87
  94.6%
304
  97.4%
Positive
0
   0.0%
2
   2.3%
3
   3.3%
5
   1.6%
Missing
1
   0.8%
0
   0.0%
2
   2.2%
3
   1.0%
1.Primary Outcome
Title AUC(0-inf) of GP2013, MabThera and Rituxan Following IV Infusion in Patients With RA
Hide Description 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
Time Frame From baseline to 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK Analysis Set
Arm/Group Title GP2013 MabThera Rituxan
Hide Arm/Group Description:
GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Overall Number of Participants Analyzed 124 79 80
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: day*mcg/mL
7627.44
(38.60%)
6896.97
(40.56%)
7536.89
(40.28%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GP2013, MabThera
Comments 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.
Type of Statistical Test Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.106
Confidence Interval (2-Sided) 90%
1.010 to 1.210
Estimation Comments GP2013 arm is the numerator and MabThera arm is the denominator
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection GP2013, Rituxan
Comments 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.
Type of Statistical Test Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.012
Confidence Interval (2-Sided) 90%
0.925 to 1.108
Estimation Comments GP2013 arm is the numerator and Rituxan arm is the denominator
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection MabThera, Rituxan
Comments 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.
Type of Statistical Test Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.093
Confidence Interval (2-Sided) 90%
0.989 to 1.208
Estimation Comments Rituxan arm is the numerator and MabThera arm is the denominator
2.Secondary Outcome
Title Maximum Serum Concentration (Cmax) of GP2013, MabThera and Rituxan Following IV Infusion in Patients With RA
Hide Description 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.
Time Frame From baseline to week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK Analysis Set
Arm/Group Title GP2013 MabThera Rituxan
Hide Arm/Group Description:
GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Overall Number of Participants Analyzed 120 78 82
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: mcg/mL
361.53
(40.82%)
319.80
(42.75%)
335.88
(42.65%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GP2013, Rituxan
Comments To conclude bioequivalence the 90% CI must be entirely within the standard equivalence limits of 0.8-1.25.
Type of Statistical Test Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.076
Confidence Interval (2-Sided) 90%
0.979 to 1.184
Estimation Comments GP2013 arm is the numerator and Rituxan arm is the denominator
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection GP2013, MabThera
Comments To conclude bioequivalence the 90% CI must be entirely within the standard equivalence limits of 0.8-1.25
Type of Statistical Test Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.131
Confidence Interval (2-Sided) 90%
1.027 to 1.244
Estimation Comments GP2013 arm is the numerator and MabThera arm is the denominator
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection MabThera, Rituxan
Comments To conclude bioequivalence the 90% CI must be entirely within the standard equivalence limits of 0.8-1.25.
Type of Statistical Test Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.050
Confidence Interval (2-Sided) 90%
0.946 to 1.167
Estimation Comments Rituxan arm is the numerator and MabThera arm is the denominator
3.Secondary Outcome
Title 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
Hide Description 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
Time Frame 14 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK analysis set
Arm/Group Title GP2013 MabThera Rituxan
Hide Arm/Group Description:
GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Overall Number of Participants Analyzed 110 76 80
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: % * day
1226.53
(2.83%)
1201.15
(8.91%)
1240.57
(1.95%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GP2013, Rituxan
Comments To conclude equivalence the 95% CI must be entirely within the standard equivalencelimits of 0.8-1.25
Type of Statistical Test Equivalence
Comments Ratio of geometric means and 95% confidence interval were estimated by an analysis of variance (ANOVA) on log-transformed PD parameter with treatment as the factor. Results were then back-transformed to the original scale.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.989
Confidence Interval (2-Sided) 95%
0.974 to 1.004
Estimation Comments GP2013 arm is the numerator and Rituxan arm is the denominator
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection GP2013, MabThera
Comments To conclude equivalence the 95% CI must be entirely within the standard equivalencelimits of 0.8-1.25
Type of Statistical Test Equivalence
Comments Ratio of geometric means and 95% confidence interval were estimated by an analysis of variance (ANOVA) on log-transformed PD parameter with treatment as the factor. Results were then back-transformed to the original scale.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.021
Confidence Interval (2-Sided) 95%
1.003 to 1.040
Estimation Comments GP2013 arm is the numerator and MabThera arm is the denominator
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection MabThera, Rituxan
Comments To conclude equivalence the 95% CI must be entirely within the standard equivalence limits of 0.8-1.25
Type of Statistical Test Equivalence
Comments Ratio of geometric means and 95% confidence interval were estimated by an analysis of variance (ANOVA) on log-transformed PD parameter with treatment as the factor. Results were then back-transformed to the original scale.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.033
Confidence Interval (2-Sided) 95%
1.016 to 1.050
Estimation Comments Rituxan arm is the numerator and MabThera arm is the denominator
4.Secondary Outcome
Title Change From Baseline in DAS28(CRP) at Week 24
Hide Description

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

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.

Time Frame 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PP analysis set
Arm/Group Title GP2013 MabThera Rituxan GP2013 Part I
Hide Arm/Group Description:
GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

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

Overall Number of Participants Analyzed 128 82 85 85
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-2.07  (0.103) -2.23  (0.143) -1.99  (0.126) -2.16  (0.142)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GP2013, Rituxan
Comments To conclude non-inferiority the upper 95% CI should be less than or equal to 0.6. This margin was statistically justified by the results of the REFLEX (Randomized Evaluation of Long-Term Efficacy of Rituximab in RA) trial (Cohen et al 2006) providing a 95% CI for the mean difference between rituximab/MTX and MTX alone of (-1.74;-1.25). The margin of 0.6 was determined by retaining more than 50% of the reference treatment effect which was considered clinically acceptable.
Type of Statistical Test Non-Inferiority
Comments

The non-inferiority margin is further justified by the EULAR criteria which define “no response” as change from baseline being < 0.6.

LS means, standard errors and 95% CI were estimated by a repeated measures mixed model with treatment, time and treatment*time interaction term as categorical variables and baseline DAS28 as a continuous variable.

A negative change from baseline represents an improvement in assessment of rheumatoid arthritis.

Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -0.08
Confidence Interval (2-Sided) 95%
-0.397 to 0.240
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.162
Estimation Comments The direction of comparison is LS mean of GP2013 - LS mean of Rituxan
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MabThera, GP2013 Part I
Comments To conclude non-inferiority the upper 95% CI should be less than or equal to 0.6. This margin was statistically justified by the results of the REFLEX (Randomized Evaluation of Long-Term Efficacy of Rituximab in RA) trial (Cohen et al 2006) providing a 95% CI for the mean difference between rituximab/MTX and MTX alone of (-1.74;-1.25). The margin of 0.6 was determined by retaining more than 50% of the reference treatment effect which was considered clinically acceptable.
Type of Statistical Test Non-Inferiority
Comments

The non-inferiority margin is further justified by the EULAR criteria which define “no response” as change from baseline being < 0.6. LS means, standard errors and 95% CI were estimated by a repeated measures mixed model with treatment, time and treatment*time interaction term as categorical variables and baseline DAS28 as a continuous variable.

A negative change from baseline represents an improvement in assessment of rheumatoid arthritis.

Method of Estimation Estimation Parameter LS Mean difference
Estimated Value 0.07
Confidence Interval (2-Sided) 95%
-0.328 to 0.462
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.201
Estimation Comments The direction of comparison is LS mean of GP2013 Part I - LS mean of MabThera
5.Secondary Outcome
Title Number of Patients With ACR20 (CRP) Response
Hide Description

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)
Time Frame 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PP analysis set
Arm/Group Title GP2013 MabThera Rituxan GP2013 Part I
Hide Arm/Group Description:
GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

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

Overall Number of Participants Analyzed 119 76 80 78
Measure Type: Count of Participants
Unit of Measure: Participants
86
  72.3%
55
  72.4%
50
  62.5%
56
  71.8%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GP2013, Rituxan
Comments To conclude non-inferiority the lower 95% CI should be greater than -15.0%.
Type of Statistical Test Non-Inferiority
Comments The predefined noninferiority margin of 0.15 for ACR20 is based on the historical placebo-controlled phase III study to evaluate the response rate benefit of adding rituximab to the conventional small molecule-based treatment of patients with RA (Cohen et al. 2006).
Method of Estimation Estimation Parameter Response rate difference (%)
Estimated Value 9.77
Confidence Interval (2-Sided) 95%
-3.54 to 23.08
Parameter Dispersion
Type: Standard Error of the Mean
Value: 6.79
Estimation Comments The direction of comparison is response rate of GP2013 - response rate of Rituxan
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MabThera, GP2013 Part I
Comments To conclude non-inferiority the lower 95% CI should be greater than -15.0%.
Type of Statistical Test Non-Inferiority
Comments The predefined noninferiority margin of 0.15 for ACR20 is based on the historical placebo-controlled phase III study to evaluate the response rate benefit of adding rituximab to the conventional small molecule-based treatment of patients with RA (Cohen et al. 2006).
Method of Estimation Estimation Parameter Response rate difference (%)
Estimated Value -0.57
Confidence Interval (2-Sided) 95%
-14.74 to 13.60
Parameter Dispersion
Type: Standard Error of the Mean
Value: 7.23
Estimation Comments The direction of comparison is response rate of GP2013 Part I - response rate of MabThera
6.Secondary Outcome
Title Summary of Disease Activity According to CDAI
Hide Description

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)

Time Frame At week 24
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Hide Analysis Population Description
PP analysis set
Arm/Group Title GP2013 Rituxan GP2013 Part I MabThera
Hide Arm/Group Description:
GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

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

MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Overall Number of Participants Analyzed 119 80 78 75
Measure Type: Count of Participants
Unit of Measure: Participants
High disease activity
26
  21.8%
20
  25.0%
18
  23.1%
18
  24.0%
Moderate disease activity
45
  37.8%
32
  40.0%
24
  30.8%
26
  34.7%
Low disease activity
41
  34.5%
25
  31.3%
30
  38.5%
19
  25.3%
Remission
7
   5.9%
3
   3.8%
6
   7.7%
12
  16.0%
7.Secondary Outcome
Title Summary of Disease Activity According to SDAI
Hide Description

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))

Time Frame At week 24
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PP analysis set
Arm/Group Title GP2013 Rituxan GP2013 Part I MabThera
Hide Arm/Group Description:
GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

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

MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Overall Number of Participants Analyzed 117 77 77 74
Measure Type: Count of Participants
Unit of Measure: Participants
High disease activity
20
  17.1%
15
  19.5%
13
  16.9%
15
  20.3%
Moderate disease activity
48
  41.0%
34
  44.2%
27
  35.1%
29
  39.2%
Low disease activity
41
  35.0%
26
  33.8%
31
  40.3%
18
  24.3%
Remission
8
   6.8%
2
   2.6%
6
   7.8%
12
  16.2%
8.Secondary Outcome
Title Participant Response as Assessed by EULAR Response Criteria
Hide Description

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).

Time Frame At week 24
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PP analysis set
Arm/Group Title GP2013 Rituxan GP2013 Part I MabThera
Hide Arm/Group Description:
GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)

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

MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Overall Number of Participants Analyzed 116 77 76 75
Measure Type: Count of Participants
Unit of Measure: Participants
Good response
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Moderate response
101
  87.1%
61
  79.2%
67
  88.2%
63
  84.0%
No response
15
  12.9%
16
  20.8%
9
  11.8%
12
  16.0%
9.Other Pre-specified Outcome
Title Number of Patients With at Least One Anti-Drug-Antibody (ADA) Positive Serum Sample
Hide Description 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).
Time Frame through study completion, an average of 1 year
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Patients with positive ADA results at randomization were excluded from analysis
Arm/Group Title GP2013 MabThera Rituxan
Hide Arm/Group Description:
GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Overall Number of Participants Analyzed 127 84 82
Measure Type: Number
Unit of Measure: participants
21 18 11
Time Frame Treatment emergent adverse events (TEAEs) are reported for the entire study duration, which means at least 52 weeks for patients who completed the study. For patients, who received a second optional treatment course, which could be given at any time between week 24 and week 52 an additional follow-up period of 26 weeks after the first infusion of the second treatment course was required. These patients had respectively longer study duration of maximally 1.5 years.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title GP2013 MabThera Rituxan
Hide Arm/Group Description GP2013: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15) MabThera: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15) Rituxan: 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
All-Cause Mortality
GP2013 MabThera Rituxan
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/133 (0.75%)      0/87 (0.00%)      1/92 (1.09%)    
Show Serious Adverse Events Hide Serious Adverse Events
GP2013 MabThera Rituxan
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   16/133 (12.03%)      14/87 (16.09%)      9/92 (9.78%)    
Blood and lymphatic system disorders       
Anaemia  1  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Bone marrow failure  1 [1]  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Microcytic anaemia  1  0/133 (0.00%)  0 1/87 (1.15%)  2 0/92 (0.00%)  0
Pancytopenia  1 [1]  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Cardiac disorders       
Angina pectoris  1  0/133 (0.00%)  0 2/87 (2.30%)  2 0/92 (0.00%)  0
Acute myocardial infarction  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Myocardial infarction  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Sinus tachycardia  1 [2]  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
General disorders       
Chest pain  1 [2]  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Lipogranuloma  1  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Multiple organ dysfunction syndrome  1 [1]  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Pyrexia  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Immune system disorders       
Drug hypersensitivity  1  0/133 (0.00%)  0 1/87 (1.15%)  1 0/92 (0.00%)  0
Infections and infestations       
Abscess  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Atypical pneumonia  1  0/133 (0.00%)  0 1/87 (1.15%)  1 0/92 (0.00%)  0
Gastroenteritis  1  0/133 (0.00%)  0 1/87 (1.15%)  1 0/92 (0.00%)  0
Groin abscess  1 [3]  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Klebsiella sepsis  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Lyme disease  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Pilonidal cyst  1 [3]  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Pneumonia  1  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Pneumonia haemophilus  1  0/133 (0.00%)  0 1/87 (1.15%)  1 0/92 (0.00%)  0
Purulent pericarditis  1  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Pyelonephritis  1  0/133 (0.00%)  0 1/87 (1.15%)  1 0/92 (0.00%)  0
Sepsis  1 [1]  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Septic shock  1 [1]  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Soft tissue infection  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Injury, poisoning and procedural complications       
Infusion related reaction  1  2/133 (1.50%)  2 1/87 (1.15%)  1 2/92 (2.17%)  2
Rib fracture  1  0/133 (0.00%)  0 0/87 (0.00%)  0 2/92 (2.17%)  2
Spinal fracture  1  0/133 (0.00%)  0 1/87 (1.15%)  1 1/92 (1.09%)  1
Bone fissure  1 [4]  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Femoral neck fracture  1  0/133 (0.00%)  0 1/87 (1.15%)  1 0/92 (0.00%)  0
Fractured sacrum  1 [4]  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Overdose  1 [1]  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Radius fracture  1  0/133 (0.00%)  0 1/87 (1.15%)  1 0/92 (0.00%)  0
Synovial rupture  1  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Tibia fracture  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Metabolism and nutrition disorders       
Vitamin D deficiency  1 [4]  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Musculoskeletal and connective tissue disorders       
Fistula  1 [3]  2/133 (1.50%)  2 0/87 (0.00%)  0 0/92 (0.00%)  0
Osteoarthritis  1  0/133 (0.00%)  0 2/87 (2.30%)  2 0/92 (0.00%)  0
Arthritis  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Fracture pain  1  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Rheumatoid arthritis  1  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Spinal osteoarthritis  1  1/133 (0.75%)  2 0/87 (0.00%)  0 0/92 (0.00%)  0
Synovial cyst  1  0/133 (0.00%)  0 1/87 (1.15%)  1 0/92 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Basal cell carcinoma  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Nervous system disorders       
Syncope  1  1/133 (0.75%)  1 0/87 (0.00%)  0 1/92 (1.09%)  1
Cerebrovascular accident  1  0/133 (0.00%)  0 1/87 (1.15%)  1 0/92 (0.00%)  0
Ischaemic stroke  1  0/133 (0.00%)  0 1/87 (1.15%)  1 0/92 (0.00%)  0
Meningoradiculitis  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Seizure  1  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Psychiatric disorders       
Depression  1  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Dissociative disorder  1  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
Reproductive system and breast disorders       
Urogenital prolapse  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Pleural effusion  1  0/133 (0.00%)  0 1/87 (1.15%)  3 0/92 (0.00%)  0
Pulmonary fibrosis  1  1/133 (0.75%)  1 0/87 (0.00%)  0 0/92 (0.00%)  0
Vascular disorders       
Vasculitis  1  0/133 (0.00%)  0 1/87 (1.15%)  1 0/92 (0.00%)  0
Venous thrombosis  1  0/133 (0.00%)  0 0/87 (0.00%)  0 1/92 (1.09%)  1
1
Term from vocabulary, MedDRA Version 19.1
Indicates events were collected by systematic assessment
[1]
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.
[2]
SAEs chest pain and sinus tachycardia were diagnosed in same patient at the same time
[3]
SAEs Fistula, Groin Abscess and Pilonidal cyst occurred in same patient as a sequence of events
[4]
SAEs: Bone fissure, Vitamid D defficiency and Fractured sacrum occurred in same patient as a sequence of events
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
GP2013 MabThera Rituxan
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   87/133 (65.41%)      56/87 (64.37%)      60/92 (65.22%)    
Blood and lymphatic system disorders       
Leukopenia  1  1/133 (0.75%)  1 1/87 (1.15%)  1 3/92 (3.26%)  3
Gastrointestinal disorders       
Nausea  1  9/133 (6.77%)  9 3/87 (3.45%)  3 5/92 (5.43%)  10
Diarrhoea  1  4/133 (3.01%)  4 3/87 (3.45%)  3 1/92 (1.09%)  1
General disorders       
Fatigue  1  6/133 (4.51%)  6 0/87 (0.00%)  0 1/92 (1.09%)  1
Pyrexia  1  2/133 (1.50%)  3 3/87 (3.45%)  3 1/92 (1.09%)  1
Infections and infestations       
Nasopharyngitis  1  9/133 (6.77%)  12 5/87 (5.75%)  6 9/92 (9.78%)  11
Urinary tract infection  1  11/133 (8.27%)  12 5/87 (5.75%)  7 2/92 (2.17%)  2
Upper respiratory tract infection  1  6/133 (4.51%)  7 5/87 (5.75%)  5 6/92 (6.52%)  6
Bronchitis  1  5/133 (3.76%)  6 5/87 (5.75%)  6 1/92 (1.09%)  1
Oral herpes  1  5/133 (3.76%)  6 2/87 (2.30%)  2 1/92 (1.09%)  1
Sinusitis  1  0/133 (0.00%)  0 1/87 (1.15%)  1 5/92 (5.43%)  5
Respiratory tract infection  1  0/133 (0.00%)  0 3/87 (3.45%)  4 1/92 (1.09%)  1
Injury, poisoning and procedural complications       
Infusion related reaction  1  4/133 (3.01%)  4 3/87 (3.45%)  6 2/92 (2.17%)  2
Investigations       
Alanine aminotransferase increased  1  3/133 (2.26%)  4 1/87 (1.15%)  1 3/92 (3.26%)  4
Metabolism and nutrition disorders       
Dyslipidaemia  1  2/133 (1.50%)  3 2/87 (2.30%)  2 5/92 (5.43%)  5
Musculoskeletal and connective tissue disorders       
Rheumatoid arthritis  1  6/133 (4.51%)  6 5/87 (5.75%)  5 8/92 (8.70%)  14
Back pain  1  4/133 (3.01%)  4 4/87 (4.60%)  5 3/92 (3.26%)  3
Nervous system disorders       
Headache  1  6/133 (4.51%)  6 5/87 (5.75%)  7 6/92 (6.52%)  10
Psychiatric disorders       
Depression  1  0/133 (0.00%)  0 0/87 (0.00%)  0 3/92 (3.26%)  3
Respiratory, thoracic and mediastinal disorders       
Cough  1  5/133 (3.76%)  5 4/87 (4.60%)  4 7/92 (7.61%)  7
Throat irritation  1  0/133 (0.00%)  0 2/87 (2.30%)  2 3/92 (3.26%)  4
Skin and subcutaneous tissue disorders       
Pruritus  1  5/133 (3.76%)  5 4/87 (4.60%)  5 1/92 (1.09%)  1
Rash  1  2/133 (1.50%)  3 6/87 (6.90%)  6 1/92 (1.09%)  2
Vascular disorders       
Hypertension  1  5/133 (3.76%)  5 5/87 (5.75%)  8 3/92 (3.26%)  3
1
Term from vocabulary, MedDRA Version 19.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Sponsor shall have the right to the first publication or presentation of the results of the study which is intended to be a joint, multi-center publication of the study results. Following the first publication, institutions and/or Principal Investigators may publish or present data or results from the study per the terms of the clinical trial agreement.
Results Point of Contact
Name/Title: Global Program Medical Director
Organization: Sandoz
Phone: +49 8024 476 ext 0
Responsible Party: Sandoz
ClinicalTrials.gov Identifier: NCT01274182     History of Changes
Other Study ID Numbers: GP13-201
2010-021184-32 ( EudraCT Number )
GPN013A2301 ( Other Identifier: Novartis )
First Submitted: January 10, 2011
First Posted: January 11, 2011
Results First Submitted: November 9, 2017
Results First Posted: January 24, 2018
Last Update Posted: January 24, 2018