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Clinical Trial Results:
Randomized, Double-blind, Parallel-group Comparative Bioequivalence Trial of MabionCD20® (Mabion SA) Compared to MabThera® (rituximab, Roche) in Patients with Rheumatoid Arthritis (MABRA)

Summary
EudraCT number	2012-003194-25
Trial protocol	LT HR
Global end of trial date	26 Oct 2017

Results information
Results version number	v1(current)
This version publication date	28 Apr 2022
First version publication date	28 Apr 2022
Other versions
Summary report(s)	Study Synopsis

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

MabionCD20-001RA

ISRCTN number

US NCT number

NCT02468791

WHO universal trial number (UTN)

Sponsor organisation name

Mabion S.A.

Sponsor organisation address

Langiewicza 60, Konstantynow Lodzki, Poland, 95-050

Public contact

Clinical Trial Contact Point, Mabion S.A., 48 422077890, b.czubek@mabion.eu

Scientific contact

Clinical Trial Contact Point, Mabion S.A., 48 422077890, a.tuszyner@mabion.eu

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

26 Oct 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Oct 2017

Was the trial ended prematurely?

Main objective of the trial

To demonstrate biosimilarity between the Test Product: MabionCD20® and the Reference Product: MabThera® (rituximab) in patients with active rheumatoid arthritis (RA), based on the percentage of patients in each treatment group achieving the primary efficacy endpoint of a 20% improvement on the American College of Rheumatology score (ACR20) at Week 24. To demonstrate bioequivalence in pharmacokinetic (PK) characteristics between MabionCD20® and MabThera® (rituximab).

Protection of trial subjects

To decrease the incidence and severity of infusion-related reactions, patients received standard premedication with corticosteroid, analgesic/antipyretic and antihistamine prior to each MabionCD20®or MabThera®(rituximab) infusion. An independent data and safety monitoring board (DSMB) regularly reviewed the study status and all efficacy and safety data. There were 6 DSMB meetings during the study - at each meeting, patients’ safety as well as treatment efficacy was evaluated positively. DSMB members recommended continuing the study without any changes.

Background therapy

All patients received background treatment with methotrexate at 10-25 mg/week for at least 12 weeks, with the last 4 weeks at a stable dose. Folic acid (5 - 15 mg/week) could be used to counter any undesired effects of methotrexate.

Evidence for comparator

An equivalence study design was used to compare the efficacy and safety of MabionCD20 with the reference drug MabThera. This comparator was used to ensure that MabionCD20 is not less or more effective than original rituximab by a certain clinically relevant margin, when administered to patients with active moderate-to-severe rheumatoid arthritis. MabThera is an EU-authorized brand of rituximab, manufactured by Hoffman-La Roche. It is approved by the EMA for the treatment of adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs (DMARD), including one or more tumour necrosis factor (TNF) inhibitor therapies. MabThera has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.

Actual start date of recruitment

14 May 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bosnia and Herzegovina: 80

Country: Number of subjects enrolled

Poland: 274

Country: Number of subjects enrolled

Lithuania: 4

Country: Number of subjects enrolled

Georgia: 172

Country: Number of subjects enrolled

Ukraine: 139

Country: Number of subjects enrolled

Serbia: 40

Worldwide total number of subjects

709

EEA total number of subjects

278

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

614

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was initiated in 7 countries (Croatia, Bosnia and Herzegovina, Georgia, Lithuania, Poland, Serbia and Ukraine) and conducted at 50 study centers in 6 countries, as no patients were enrolled in Croatia. The first patient was enrolled on 14th May 2013. A total od 993 patients were screened, of which 709 were enrolled.

Screening details

Screening lasted up to 28 days, during which the patients were checked for eligibility criteria. Potential participants were required to undergo washout for all DMARDs, except methotrexate. Patients could re-enter the study for the second time if they were screening failures.

Period 1 title

Double-blind

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Blinding of study medication was performed by external company and treatment identity was concealed during the entire double-blind study period. Sponsor, Investigators and patients were blinded to treatment allocation until Week 24, when the designated Sponsor staff was unblinded for the purpose of data analysis.

Are arms mutually exclusive

Yes

MabionCD20

Arm description

Patients received two intravenous infusions of MabionCD20 on Day 1 and Day 15, at a dose of 1000 mg (standard regimen in rheumatoid arthritis). Active substance: Rituximab

Arm type

Experimental

Investigational medicinal product name

MabionCD20

Investigational medicinal product code

ATC: L01XC02

Other name

Rituximab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Infusion

Dosage and administration details

The infusion solution was prepared by aseptically adding the necessary amount of concentrate into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/mL (0.9%) solution for injection in water.Two intravenous infusions of MabioCD20 at 1000mg/infusion were administered on Day 1 and Day 15.

MabThera

Arm description

Patients received two intravenous infusions of MabThera on Day 1 and Day 15, at a dose of 1000 mg (standard regimen in rheumatoid arthritis). Active substance: Rituximab

Arm type

Active comparator

Investigational medicinal product name

MabThera

Investigational medicinal product code

ATC: L01XC02

Other name

Rituximab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Infusion

Dosage and administration details

The infusion solution was prepared by aseptically adding the necessary amount of concentrate into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/mL (0.9%) solution for injection in water. Two intravenous infusion 1000 mg/ infusion was administered on Day 1 and 15

Number of subjects in period 1	MabionCD20	MabThera
Started	358	351
Completed	345	338
Not completed	13	13
Consent withdrawn by subject	4	4
Physician decision	2	-
Adverse event, non-fatal	3	7
Other reasons	3	-
Lost to follow-up	-	1
Lack of efficacy	1	1

Period 2 title

Open-label

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Patients received MabionCD20 or MabThera in an open-label manner.

Are arms mutually exclusive

Yes

MabionCD20 after Mabthera

Arm description

Patients who in double-blind period were treated with MabThera could be treated again (re-treatment) when they had a clinical response followed by a clinical relapse and if assessments at Week 24 indicated that the patient may benefit from re-treatment. An additional course of therapy with MabionCD20 or MabThera was then provided under open-label conditions as two infusions of 1000 mg each, separated by 2 weeks. Active substance: Rituximab

Arm type

Experimental

Investigational medicinal product name

MabionCD20

Investigational medicinal product code

ATC: L01XC02

Other name

Rituximab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Infusion

Dosage and administration details

MabThera after MabionCD20

Arm description

Patients who in double-blind study period were treated with MabionCD20 could be treated again (re-treatment) when they had a clinical response followed by a clinical relapse and if assessments at week 24 indicated that the patient may benefit from re-treatment. An additional course of therapy with MabionCD20 or MabThera was then provided under open-label conditions as two infusions of 1000 mg each, separated by 2 weeks. Active substance: Rituximab

Arm type

Experimental

Investigational medicinal product name

MabThera

Investigational medicinal product code

ATC: L01XC02

Other name

Rituximab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Infusion

Dosage and administration details

The infusion solution was prepared by aseptically adding the necessary amount of concentrate into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/mL (0.9%) solution for injection in water. Two intravenous infusion 1000 mg/ infusion was administered on Day 1 and 15

MabionCD20 after MabionCD20

Arm description

Arm type

Experimental

Investigational medicinal product name

MabionCD20

Investigational medicinal product code

ATC: L01XC02

Other name

Rituximab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Infusion

Dosage and administration details

MabThera after MabThera

Arm description

Patients who in double-blind period were treated with MabThera could be treated again (re-treatment) when they had a clinical response followed by a clinical relapse and if assessments at week 24 indicated that the patient may benefit from re-treatment. An additional course of therapy with MabionCD20 or MabThera was then provided under open-label conditions as two infusions of 1000 mg each, separated by 2 weeks. Active substance: Rituximab

Arm type

Active comparator

Investigational medicinal product name

MabThera

Investigational medicinal product code

ATC: L01XC02

Other name

Rituximab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Infusion

Dosage and administration details

The infusion solution was prepared by aseptically adding the necessary amount of concentrate into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/mL (0.9%) solution for injection in water. Two intravenous infusion 1000 mg/ infusion was administered on Day 1 and 15

MabionCD20 not re-treated

Arm description

Patients who in double-blind study period were treated with MabionCD20 but did not receive re-treatment after Week 24. Active substance: Rituximab

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

MabThera not re-treated

Arm description

Patients who in double-blind study period were treated with MabThera but did not receive re-treatment after Week 24. Active substance: Rituximab

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	MabionCD20 after Mabthera	MabThera after MabionCD20	MabionCD20 after MabionCD20	MabThera after MabThera	MabionCD20 not re-treated	MabThera not re-treated
Started	92	116	87	113	142	133
Completed	90	116	84	109	125	114
Not completed	2	0	3	4	17	19
Consent withdrawn by subject	1	-	2	2	13	14
Physician decision	-	-	-	-	2	1
Adverse event, non-fatal	-	-	-	1	-	2
Other reasons	-	-	-	1	1	2
Lost to follow-up	1	-	1	-	1	-

Baseline characteristics

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Reporting group title

MabionCD20

Reporting group description

Patients received two intravenous infusions of MabionCD20 on Day 1 and Day 15, at a dose of 1000 mg (standard regimen in rheumatoid arthritis). Active substance: Rituximab

Reporting group title

MabThera

Reporting group description

Patients received two intravenous infusions of MabThera on Day 1 and Day 15, at a dose of 1000 mg (standard regimen in rheumatoid arthritis). Active substance: Rituximab

Reporting group values	MabionCD20	MabThera	Total
Number of subjects	358	351	709
Age categorical
Units: Subjects
Adults (18-64 years)	313	301	614
From 65-84 years	45	50	95
Age continuous
Units: years
median (standard deviation)	54.0 ± 11.41	54.0 ± 12.00	-
Gender categorical
Units: Subjects
Female	296	294	590
Male	62	57	119
Weight
Units: kilogram(s)
median (standard deviation)	72.65 ± 14.57	71.00 ± 14.87	-
Body surface area (BSA)
Units: cubic metre
median (standard deviation)	1.8 ± 0.17	1.78 ± 0.17	-

Subject analysis set title

SAF

Subject analysis set type

Safety analysis

Subject analysis set description

In the SAF population, patients were analyzed according to the treatment they actually received. Note: 80 patients randomized in Bosnia were excluded from the primary analysis due to concerns over GCP incompliance.

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

In the ITT set patients were analyzed according to the treatment group that they were randomized to. Note: 80 patients randomized in Bosnia were excluded from the primary analysis due to concerns over GCP incompliance.

Subject analysis set title

Subject analysis set type

Per protocol

Subject analysis set description

In analyses based on the per-protocl set, patients are analyzed according to the treatment that they actually received. Note: 80 patients randomized in Bosnia were excluded from the primary analysis due to concerns over GCP incompliance.

Subject analysis sets values	SAF	ITT	PP
Number of subjects	628	629	590
Age categorical
Units: Subjects
Adults (18-64 years)	548	549	519
From 65-84 years	80	80	71
Age continuous
Units: years
median (standard deviation)	54 ± 11.78	54 ± 11.77	54 ± 11.72
Gender categorical
Units: Subjects
Female	522	522	491
Male	106	107	99
Weight
Units: kilogram(s)
median (standard deviation)	71.8 ± 15	71.8 ± 15	72 ± 15.1
Body surface area (BSA)
Units: cubic metre
median (standard deviation)	1.79 ± 0.17	1.79 ± 0.17	1.79 ± 0.17

End points

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Reporting group title

MabionCD20

Reporting group description

Patients received two intravenous infusions of MabionCD20 on Day 1 and Day 15, at a dose of 1000 mg (standard regimen in rheumatoid arthritis). Active substance: Rituximab

Reporting group title

MabThera

Reporting group description

Patients received two intravenous infusions of MabThera on Day 1 and Day 15, at a dose of 1000 mg (standard regimen in rheumatoid arthritis). Active substance: Rituximab

Reporting group title

MabionCD20 after Mabthera

Reporting group description

Reporting group title

MabThera after MabionCD20

Reporting group description

Reporting group title

MabionCD20 after MabionCD20

Reporting group description

Reporting group title

MabThera after MabThera

Reporting group description

Patients who in double-blind period were treated with MabThera could be treated again (re-treatment) when they had a clinical response followed by a clinical relapse and if assessments at week 24 indicated that the patient may benefit from re-treatment. An additional course of therapy with MabionCD20 or MabThera was then provided under open-label conditions as two infusions of 1000 mg each, separated by 2 weeks. Active substance: Rituximab

Reporting group title

MabionCD20 not re-treated

Reporting group description

Patients who in double-blind study period were treated with MabionCD20 but did not receive re-treatment after Week 24. Active substance: Rituximab

Reporting group title

MabThera not re-treated

Reporting group description

Patients who in double-blind study period were treated with MabThera but did not receive re-treatment after Week 24. Active substance: Rituximab

Subject analysis set title

SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Percentage of patients in each treatment group achieving the primary efficacy endpoint of a ≥20% improvement on the American College of Rheumatology score (ACR20) at Week 24.

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End point title

Percentage of patients in each treatment group achieving the primary efficacy endpoint of a ≥20% improvement on the American College of Rheumatology score (ACR20) at Week 24.

End point description

Efficacy assessments of disease activity in RA were based on clinically validated response criteria of the American College of Rheumatology (ACR). A patient achieved ACR20 criteria if the following criteria were satisfied: • percent improvement from baseline was ≥ 20% in tender joint count; • percent improvement from baseline was ≥ 20%in swollen joint count; • percent improvement from baseline was ≥ 20% in 3 of the 5 remaining ACR core population measures including: - patient’s assessment of pain, - patient’s global assessment of disease activity, - physician’s global assessment of disease activity, - patient’s assessment of physical functions HAQ-DI, - laboratory evaluation of acute phase reactant (erythrocyte sedimentation rate, ESR) .

End point type

Primary

End point timeframe

Week 24

End point values	MabionCD20	MabThera
Number of subjects analysed	298	292
Units: Percentage
number (not applicable)	79.2	84.9

Difference MabionCD20-MabThera

Statistical analysis description

The two-sided 95% confidence interval (CI) for the between-group difference was calculated and checked for containment within the pre-specified equivalence interval of -13% to 13% (boundaries included).

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence ^[1]

Method

Parameter type

Mean difference (final values)

Point estimate

5.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

Notes
[1] - The difference in percentages between the two treatment groups was computed and the exact 95% confidence limits. The hypothesis: H_0: C-T>M or C-T<-M vs H_1: -M<=C-T<=M with C and T denoting the proportions of patients who achieve ACR20 at week 24 and were randomized to MabThera (C) or MabionCD20 (T) treatment, respectively, and equivalence margin M=13%.

Secondary: Percentage of patients achieving ACR20, ACR50 and ACR70 at Week 48

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End point title

Percentage of patients achieving ACR20, ACR50 and ACR70 at Week 48

End point description

Evaluation of long-term efficacy of the test product (MabionCD20, rituximab) and reference product (MabThera, rituximab) in patients with active rheumatoid arthritis.

End point type

Secondary

End point timeframe

Week 48

End point values	MabionCD20 after Mabthera	MabThera after MabionCD20	MabionCD20 after MabionCD20	MabThera after MabThera	MabionCD20 not re-treated	MabThera not re-treated
Number of subjects analysed	81	116	79	113	111	104
Units: Percentage
number (not applicable)
ACR20	93.8	94.0	86.1	87.6	73.5	66.3
ACR50	77.8	77.6	74.7	69.0	44.9	33.7
ACR70	51.9	52.6	45.6	42.5	19.4	14.6

No statistical analyses for this end point

Secondary: Percentage of patients with good or moderate response on EULAR scale at Week 48

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End point title

Percentage of patients with good or moderate response on EULAR scale at Week 48

End point description

Evaluation of biosimiliarity between test product (MabionCD20, rituximab) and reference product (MabThera, rituximab) in patients with active rheumatoid arthritis.

End point type

Secondary

End point timeframe

Week 48

End point values	MabionCD20 after Mabthera	MabThera after MabionCD20	MabionCD20 after MabionCD20	MabThera after MabThera	MabionCD20 not re-treated	MabThera not re-treated
Number of subjects analysed	79	116	75	109	97	89
Units: Percentage
number (not applicable)
Good	64.6	63.8	49.3	49.5	22.7	15.7
Moderate	35.4	32.8	50.7	47.7	58.8	65.2

No statistical analyses for this end point

Secondary: Percentage of patients achieving ACR20 at weeks: 4, 8, 12, 16, 20

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End point title

Percentage of patients achieving ACR20 at weeks: 4, 8, 12, 16, 20

End point description

Comparison of efficacy between test product (MabionCD20, rituximab) and reference product (MabThera, rituximab) in patients with active rheumatoid arthritis.

End point type

Secondary

End point timeframe

Week 4, 8, 12, 16 and 20

End point values	MabionCD20	MabThera
Number of subjects analysed	298	292
Units: Percentage
number (not applicable)
Week 4	52.0	48.6
Week 8	73.8	75.0
Week 12	85.2	84.9
Week 16	90.6	89.0
Week 20	86.9	88.0

Difference MabionCD20-MabThera at Week 4

Comparison groups

MabThera v MabionCD20

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

-3.4

Confidence interval

level

95%

sides

2-sided

lower limit

-11.5

upper limit

4.8

Difference MabionCD20-MabThera at Week 8

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-5.9

upper limit

8.3

Difference MabionCD20-MabThera at Week 12

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-6.2

upper limit

5.6

Difference MabionCD20-MabThera at Week 16

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

-1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-6.6

upper limit

3.4

Difference MabionCD20-MabThera at Week 20

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4.4

upper limit

6.6

Secondary: Percentage of patients achieving ACR50 at weeks: 4, 8, 12, 16, 20, 24

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End point title

Percentage of patients achieving ACR50 at weeks: 4, 8, 12, 16, 20, 24

End point description

Comparison of efficacy between test product (MabionCD20, rituximab) and reference product (MabThera, rituximab) in patients with active rheumatoid arthritis.

End point type

Secondary

End point timeframe

Week 4, 8, 12, 16, 20 and 24

End point values	MabionCD20	MabThera
Number of subjects analysed	298	292
Units: Percentage
number (not applicable)
Week 4	13.4	9.7
Week 8	29.9	25.7
Week 12	46.6	47.6
Week 16	64.8	65.1
Week 20	66.8	67.8
Week 24	46.0	48.6

Difference MabionCD20-MabThera at Week 4

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

-3.8

Confidence interval

level

95%

sides

2-sided

lower limit

-9.1

upper limit

1.5

Difference MabionCD20-MabThera at Week 8

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

-4.2

Confidence interval

level

95%

sides

2-sided

lower limit

-11.5

upper limit

3.2

Difference MabionCD20-MabThera at Week 12

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-7.2

upper limit

9.1

Difference MabionCD20-MabThera at Week 16

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-7.5

upper limit

8.1

Difference MabionCD20-MabThera at Week 20

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-6.6

upper limit

8.6

Difference MabionCD20-MabThera at Week 24

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

2.7

Confidence interval

level

95%

sides

2-sided

lower limit

-5.5

upper limit

10.7

Secondary: Percentage of patients achieving ACR70 at Week 4, 8, 12, 16, 20, 24

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End point title

Percentage of patients achieving ACR70 at Week 4, 8, 12, 16, 20, 24

End point description

Comparison of efficacy between test product (MabionCD20, rituximab) and reference product (MabThera, rituximab) in patients with active rheumatoid arthritis.

End point type

Secondary

End point timeframe

Week 4, 8, 12, 16, 20 and 24

End point values	MabionCD20	MabThera
Number of subjects analysed	298	292
Units: Percentage
number (not applicable)
Week 4	3.4	3.8
Week 8	8.4	8.2
Week 12	19.5	18.2
Week 16	32.6	33.6
Week 20	29.2	32.5
Week 24	11.1	12.3

Difference MabionCD20-MabThera at Week 4

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2.8

upper limit

3.7

Difference MabionCD20-MabThera at Week 8

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-4.8

upper limit

4.5

Difference MabionCD20-MabThera at Week 12

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-7.7

upper limit

5.1

Difference MabionCD20-MabThera at Week 16

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-6.6

upper limit

8.6

Difference MabionCD20-MabThera at Week 20

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.2

upper limit

10.9

Difference MabionCD20-MabThera at Week 24

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

6.6

Secondary: Percentage of patients with good response on European League Against Rheumatism (EULAR) scale at Week 4, 8, 12, 16, 20, 24

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End point title

Percentage of patients with good response on European League Against Rheumatism (EULAR) scale at Week 4, 8, 12, 16, 20, 24

End point description

Comparison of efficacy between test product (MabionCD20, rituximab) and reference product (MabThera, rituximab) in patients with active rheumatoid arthritis.

End point type

Secondary

End point timeframe

Week 4, 8, 12, 16, 20 and 24

End point values	MabionCD20	MabThera
Number of subjects analysed	298	292
Units: Percentage
number (not applicable)
Week 4	3.4	3.4
Week 8	10.7	7.9
Week 12	22.1	18.2
Week 16	51.0	47.6
Week 20	45.3	48.6
Week 24	6.7	6.5

Difference MabionCD20-MabThera at Week 4

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

3.3

Difference MabionCD20-MabThera at Week 8

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

-2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-7.7

upper limit

1.9

Difference MabionCD20-MabThera at Week 12

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

-3.9

Confidence interval

level

95%

sides

2-sided

lower limit

-10.5

upper limit

2.7

Difference MabionCD20-MabThera at Week 16

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

-3.4

Confidence interval

level

95%

sides

2-sided

lower limit

-11.5

upper limit

4.7

Difference MabionCD20-MabThera at Week 20

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.8

upper limit

11.4

Difference MabionCD20-MabThera at Week 24

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-4.4

upper limit

Secondary: Percentage of patients with moderate response on the European League Against Rheumatism (EULAR) scale at Week 4, 8, 12, 16, 20, 24

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End point title

Percentage of patients with moderate response on the European League Against Rheumatism (EULAR) scale at Week 4, 8, 12, 16, 20, 24

End point description

Comparison of efficacy between test product (MabionCD20, rituximab) and reference product (MabThera, rituximab) in patients with active rheumatoid arthritis.

End point type

Secondary

End point timeframe

Week 4, 8, 12, 16, 20 and 24

End point values	MabionCD20	MabThera
Number of subjects analysed	298	292
Units: Percentage
number (not applicable)
Week 4	53.7	57.2
Week 8	74.8	75.0
Week 12	69.5	73.5
Week 16	43.6	46.6
Week 20	49.7	46.6
Week 24	82.9	86.0

No statistical analyses for this end point

Secondary: Time to reach the minimum level of circulating CD19+ B-cells at Week 24 (Tmin B-cell) and duration of B cell depletion (T B-cell)

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End point title

Time to reach the minimum level of circulating CD19+ B-cells at Week 24 (Tmin B-cell) and duration of B cell depletion (T B-cell)

End point description

Comparison of pharmacodynamic properties of the test product (MabionCD20, rituximab) and reference product (MabThera, rituximab) in patients with active rheumatoid arthritis.

End point type

Secondary

End point timeframe

Week 24

End point values	MabionCD20	MabThera
Number of subjects analysed	54	59
Units: days
geometric mean (full range (min-max))
TminB-cell	12.513 (0.92 to 167.72)	9.423 (0.93 to 171.63)
T B-cell	165.136 (125.09 to 170.99)	163.909 (124.45 to 172.93)

No statistical analyses for this end point

Secondary: Area under the circulating CD19+ B-cell level (AUC0-t B-cell)

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End point title

Area under the circulating CD19+ B-cell level (AUC0-t B-cell)

End point description

Comparison of pharmacodynamic properties between the test product (MabionCD20, rituximab) and reference product (MabThera, rituximab) in patients with active rheumatoid arthritis.

End point type

Secondary

End point timeframe

baseline to week 24

End point values	MabionCD20	MabThera
Number of subjects analysed	54	59
Units: calls*days/mL
least squares mean (full range (min-max))	192.4 (2.08 to 3490.34)	243.81 (29.68 to 3247.63)

No statistical analyses for this end point

Secondary: Mean change from baseline in Disease Activity Score (DAS28-ESR) at Week 48

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End point title

Mean change from baseline in Disease Activity Score (DAS28-ESR) at Week 48

End point description

Comparison of long-term efficacy between test product (MabionCD20, rituximab) and reference product (MabThera, rituximab) in patients with active rheumatoid arthritis.

End point type

Secondary

End point timeframe

From Baseline to Week 48

End point values	MabionCD20 after Mabthera	MabThera after MabionCD20	MabionCD20 after MabionCD20	MabThera after MabThera	MabionCD20 not re-treated	MabThera not re-treated
Number of subjects analysed	79	116	75	109	97	89
Units: score on a scale
least squares mean (full range (min-max))	-3.4 (-5.6 to -1.4)	-3.5 (-6 to -0.1)	-3.4 (-5.8 to -1.3)	-3.5 (-6.1 to -1)	-2.4 (-6.5 to 0.6)	-2.3 (-6.6 to 0.4)

No statistical analyses for this end point

Secondary: Adverse events

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End point title

Adverse events

End point description

Percentage of patients with at least one AE in the given category.

End point type

Secondary

End point timeframe

From Baseline to Week 48

End point values	MabionCD20	MabThera	MabionCD20 after Mabthera	MabThera after MabionCD20	MabionCD20 after MabionCD20	MabThera after MabThera	MabionCD20 not re-treated	MabThera not re-treated
Number of subjects analysed	319 ^[2]	309 ^[3]	81	116 ^[4]	79	112	110	105 ^[5]
Units: percent
number (not applicable)
All AEs	43.9	43.0	21.00	32.5	24.1	38.4	11.8	9.5
Treatment-emergent adverse events (TEAEs)	42.6	42.1	21.00	32.5	24.1	38.4	11.8	9.5
Severe TEAEs	1.3	1.9	2.5	0.9	1.3	0.9	0.0	0.0
Related TEAEs	28.2	28.5	12.3	22.2	16.5	25.9	2.7	2.9
Related severe TEAEs	0.6	1.3	2.5	0.0	1.3	0.0	0.0	0.0
Serious AEs (SAEs)	2.2	1.9	2.5	0.0	1.3	0.0	0.9	0.0
Treatment-emergent SAEs (TESAEs)	2.2	1.9	2.5	0.0	1.3	0.0	0.9	0.0
Related TESAEs	0.3	0.6	1.2	0.0	1.3	0.0	0.0	0.0

Notes
[2] - 359 patients included in SAF population (classified according to the actually received treatment)
[3] - 349 patients included in SAF population (classified according to the actually received treatment)
[4] - 117 patients included in SAF population (classified according to the actually received treatment)
[5] - 134 patients included in SAF population (classified according to the actually received treatment)

No statistical analyses for this end point

Secondary: Immunogenicity

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End point title

Immunogenicity

End point description

Anti-drug antibodies (ADAs) and neutralizing antibodies (nAbs) in serum samples were analyzed with the use of validated assays. *Values for arms: MabionCD20 after Mabthera, MabThera after MabionCD20; MabionCD20 after MabionCD20;Mabthera after Mabthera were specifed for whole study period.

End point type

Secondary

End point timeframe

Immunogenicity endpoints were analyzed from Day 1 to Week 48.

End point values	MabionCD20	MabThera	MabionCD20 after Mabthera	MabThera after MabionCD20	MabionCD20 after MabionCD20	MabThera after MabThera	MabionCD20 not re-treated	MabThera not re-treated
Number of subjects analysed	316 ^[6]	306 ^[7]	81	115	79	112	110	105 ^[8]
Units: percent
number (not applicable)
Treatment-induced ADA	14.2	13.4	16.0	24.0	12.7	19.6	21.8	23.8
Treatment-boosted ADA	0.9	1	2.5	2.0	1.3	0.9	0.0	0.0
ADA positive response	15.2	14.4	18.5	26.00	13.9	20.5	21.8	23.8
Persistently positive ADA	12.7	12.7	9.9	5.2	6.3	8.9	15.5	21.9
Transiently positive ADA	1.6	0.7	6.2	15.7	6.3	10.7	6.4	1.9

Notes
[6] - 355 patients included in the ADA evaluable set.
[7] - 346 patients included in the ADA evaluable set.
[8] - 134 patients included in the ADA evaluable set.

No statistical analyses for this end point

Secondary: Mean change from baseline in Disease Activity Score (DAS28-ESR) at weeks: 4, 8, 12, 16, 20, 24

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End point title

Mean change from baseline in Disease Activity Score (DAS28-ESR) at weeks: 4, 8, 12, 16, 20, 24

End point description

Mean change from baseline in Disease Activity Score (DAS28-ESR) from Baseline to weeks: 4, 8, 12, 16, 20 and 24.

End point type

Secondary

End point timeframe

Week 4, 8, 12, 16, 20 and 24

End point values	MabionCD20	MabThera
Number of subjects analysed	298	292
Units: score on the scale
least squares mean (full range (min-max))
Week 4	-1.49 (-5.6 to 0.3)	-1.47 (-5 to 1)
Week 8	-2.15 (-6.4 to 0.3)	-2.08 (-5.3 to 0.6)
Week 12	-2.69 (-6.9 to 0.00)	-2.64 (-6.6 to 0.2)
Week 16	-3.23 (-7.3 to 0.8)	-3.14 (-6.2 to -0.2)
Week 20	-3.13 (-7.2 to 0.5)	-3.14 (-6.3 to 0.4)
Week 24	-2.47 (-7 to 0.4)	-2.52 (-6.9 to 0.6)

Difference in LS-Mean MabionCD20-MabThera at W4

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Mean difference (final values)

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.125

upper limit

0.15

Difference in LS-Mean MabionCD20-MabThera at W8

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Mean difference (final values)

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.078

upper limit

0.223

Difference in LS-Mean MabionCD20-MabThera at W12

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Mean difference (final values)

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.11

upper limit

0.208

Difference in LS-Mean MabionCD20-MabThera at W16

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Mean difference (final values)

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.061

upper limit

0.252

Difference in LS-Mean MabionCD20-MabThera at W20

Comparison groups

MabThera v MabionCD20

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Mean difference (final values)

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.171

upper limit

0.148

Difference in LS-Mean MabionCD20-MabThera at W24

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

590

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

Mean difference (final values)

Point estimate

-0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.184

upper limit

0.077

Secondary: Minimum level (Cmin B-cell) of circulating CD19+ B-cells

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End point title

Minimum level (Cmin B-cell) of circulating CD19+ B-cells

End point description

Comparison of pharmacodynamic properties of the test product (MabionCD20, rituximab) and reference product (MabThera, rituximab) in patients with active rheumatoid arthritis.

End point type

Secondary

End point timeframe

Baseline to Week 24

End point values	MabionCD20	MabThera
Number of subjects analysed	54	59
Units: cells/millilitre
least squares mean (standard error)	-0.247 ± 0.109	-1.087 ± 0.089

LS-mean ratio

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

ratio of LS-means

Point estimate

2.31

Confidence interval

level

95%

sides

2-sided

lower limit

1.37

upper limit

3.91

Secondary: Area under the plasma concentration-time curve from the first administration to final time point at Week 24 (AUC0-t)

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End point title

Area under the plasma concentration-time curve from the first administration to final time point at Week 24 (AUC0-t)

End point description

Demonstration of pharmacokinetic (PK) equivalence between MabionCD20 and MabThera based on the primary PK parameters.

End point type

Secondary

End point timeframe

Day 1 to Week 24

End point values	MabionCD20	MabThera
Number of subjects analysed	66	58
Units: (μg*h)/mL
least squares mean (full range (min-max))	211893.08 (101574.95 to 395666.17)	207906.22 (95735.34 to 390675.61)

Ratio of LS-mean

Statistical analysis description

PK equivalence demonstrated if the 90% confidence interval of LS-means ratio is contained within the pre-specified 80%-125% equivalence margin.

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

ratio of LS-means

Point estimate

1.0192

Confidence interval

level

90%

sides

2-sided

lower limit

0.9347

upper limit

1.1113

Secondary: Maximum measured plasma concentration after the second infusion of the treatment course (Cmax second) at week 24.

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End point title

Maximum measured plasma concentration after the second infusion of the treatment course (Cmax second) at week 24.

End point description

Demonstration of pharmacokinetic (PK) equivalence between MabionCD20 and MabThera based on the primary PK endpoints.

End point type

Secondary

End point timeframe

Day 1 to Week 24

End point values	MabionCD20	MabThera
Number of subjects analysed	66	58
Units: μg/mL
least squares mean (full range (min-max))	414.44 (236.31 to 677.67)	417.76 (281.91 to 588.03)

Ratio LS-mean

Statistical analysis description

PK equivalence demonstrated if the 90% confidence interval of LS means ratio is contained within the pre-specified equivalence margin of 80%-125%.

Comparison groups

MabThera v MabionCD20

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

equivalence

Method

Parameter type

ratio of LS-means

Point estimate

0.992

Confidence interval

level

90%

sides

2-sided

lower limit

0.9349

upper limit

1.0527

Adverse events

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Timeframe for reporting adverse events

From randomization until the end of follow-up (up to 48 weeks after randomization)

Adverse event reporting additional description

All adverse events spontaneously reported by the patient and/or in response to an open question from study personnel or revealed by observation, physical examination or other diagnostic procedures were recorded on the appropriate page of the eCRF.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

MabionCD20 (double-blind period)

Reporting group description

Patients in MabionCD20 group received two 1000 mg intravenous infusions of MabionCD20 on Day 1 and Day 15. Active substance: Rituximab

Reporting group title

MabThera (double-blind period)

Reporting group description

Patients in MabThera group received two 1000 mg intravenous infusions of MabThera on Day 1 and Day 15. Active substance: Rituximab

Reporting group title

MabionCD20 after MabThera (open-label period)

Reporting group description

Patients in this group received MabThera in the double-blind period and MabionCD20 in the open-label. Active substance: Rituximab

Reporting group title

MabThera after MabionCD20 (open-label period)

Reporting group description

Patients in this group received MabionCD20 in the double-blind period and MabThera in the open-label. Active substance: Rituximab

Reporting group title

MabionCD20 after MabionCD20 (open-label period)

Reporting group description

Patients in this group received MabionCD20 in both double-blind and open-label periods. Active substance: Rituximab

Reporting group title

MabThera after MabThera (open-label period)

Reporting group description

Patients in this group received MabThera in both double-blind and open-label periods. Active substance: Rituximab

Reporting group title

MabionCD20 not re-treated (open-label period)

Reporting group description

Patients in this group received MabionCD20 in the double-blind period and no treatment in the open-label.

Reporting group title

MabThera not re-treated (open-label period)

Reporting group description

Patients who in double-blind study period were treated with MabThera but didn't have sufficient clinical response and didn't receive second course of treatment.Active substance: Rituximab

Serious adverse events	MabionCD20 (double-blind period)	MabThera (double-blind period)	MabionCD20 after MabThera (open-label period)	MabThera after MabionCD20 (open-label period)	MabionCD20 after MabionCD20 (open-label period)	MabThera after MabThera (open-label period)	MabionCD20 not re-treated (open-label period)	MabThera not re-treated (open-label period)
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 319 (2.19%)	6 / 309 (1.94%)	2 / 81 (2.47%)	0 / 117 (0.00%)	1 / 79 (1.27%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 105 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Investigations
Neutrophil count decreased
subjects affected / exposed	1 / 319 (0.31%)	0 / 309 (0.00%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 319 (0.00%)	1 / 309 (0.32%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	1 / 319 (0.31%)	0 / 309 (0.00%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Humerus fracture
subjects affected / exposed	0 / 319 (0.00%)	1 / 309 (0.32%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint injury
subjects affected / exposed	1 / 319 (0.31%)	0 / 309 (0.00%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Cerebral ischaemia
subjects affected / exposed	0 / 319 (0.00%)	1 / 309 (0.32%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Cataract operation
subjects affected / exposed	1 / 319 (0.31%)	0 / 309 (0.00%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Knee operation
subjects affected / exposed	0 / 319 (0.00%)	0 / 309 (0.00%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 319 (0.00%)	1 / 309 (0.32%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Aneamia
subjects affected / exposed	1 / 319 (0.31%)	0 / 309 (0.00%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Idiopathic pulmonary fibrosis
subjects affected / exposed	1 / 319 (0.31%)	0 / 309 (0.00%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 319 (0.00%)	0 / 309 (0.00%)	0 / 81 (0.00%)	0 / 117 (0.00%)	1 / 79 (1.27%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal colic
subjects affected / exposed	0 / 319 (0.00%)	1 / 309 (0.32%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 319 (0.00%)	0 / 309 (0.00%)	1 / 81 (1.23%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 319 (0.00%)	1 / 309 (0.32%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 319 (0.31%)	0 / 309 (0.00%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	0 / 319 (0.00%)	1 / 309 (0.32%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 319 (0.00%)	0 / 309 (0.00%)	1 / 81 (1.23%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	MabionCD20 (double-blind period)	MabThera (double-blind period)	MabionCD20 after MabThera (open-label period)	MabThera after MabionCD20 (open-label period)	MabionCD20 after MabionCD20 (open-label period)	MabThera after MabThera (open-label period)	MabionCD20 not re-treated (open-label period)	MabThera not re-treated (open-label period)
Total subjects affected by non serious adverse events
subjects affected / exposed	59 / 319 (18.50%)	54 / 309 (17.48%)	11 / 81 (13.58%)	11 / 117 (9.40%)	9 / 79 (11.39%)	14 / 112 (12.50%)	5 / 110 (4.55%)	5 / 105 (4.76%)
Vascular disorders
Hypertension
subjects affected / exposed	7 / 319 (2.19%)	2 / 309 (0.65%)	1 / 81 (1.23%)	0 / 117 (0.00%)	1 / 79 (1.27%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 105 (0.00%)
occurrences all number	8	2	1	0	1	0	1	0
General disorders and administration site conditions
Infusion related reaction
subjects affected / exposed	15 / 319 (4.70%)	11 / 309 (3.56%)	1 / 81 (1.23%)	1 / 117 (0.85%)	3 / 79 (3.80%)	1 / 112 (0.89%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences all number	15	12	1	1	3	1	0	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 319 (0.31%)	1 / 309 (0.32%)	0 / 81 (0.00%)	1 / 117 (0.85%)	1 / 79 (1.27%)	3 / 112 (2.68%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences all number	1	1	0	1	1	3	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 319 (0.31%)	5 / 309 (1.62%)	1 / 81 (1.23%)	1 / 117 (0.85%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences all number	1	6	1	1	0	0	0	0
Investigations
Low density lipoprotein increased
subjects affected / exposed	7 / 319 (2.19%)	4 / 309 (1.29%)	0 / 81 (0.00%)	3 / 117 (2.56%)	0 / 79 (0.00%)	2 / 112 (1.79%)	1 / 110 (0.91%)	1 / 105 (0.95%)
occurrences all number	8	7	0	3	0	2	1	1
Injury, poisoning and procedural complications
Joint injury
subjects affected / exposed	1 / 319 (0.31%)	0 / 309 (0.00%)	0 / 81 (0.00%)	0 / 117 (0.00%)	1 / 79 (1.27%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences all number	2	0	0	0	1	0	0	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 319 (0.00%)	0 / 309 (0.00%)	1 / 81 (1.23%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	4 / 319 (1.25%)	9 / 309 (2.91%)	3 / 81 (3.70%)	1 / 117 (0.85%)	0 / 79 (0.00%)	2 / 112 (1.79%)	1 / 110 (0.91%)	0 / 105 (0.00%)
occurrences all number	4	9	6	1	0	2	1	0
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	7 / 319 (2.19%)	7 / 309 (2.27%)	2 / 81 (2.47%)	3 / 117 (2.56%)	0 / 79 (0.00%)	2 / 112 (1.79%)	0 / 110 (0.00%)	1 / 105 (0.95%)
occurrences all number	7	7	2	3	0	2	0	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	4 / 319 (1.25%)	2 / 309 (0.65%)	1 / 81 (1.23%)	0 / 117 (0.00%)	1 / 79 (1.27%)	1 / 112 (0.89%)	0 / 110 (0.00%)	1 / 105 (0.95%)
occurrences all number	4	3	1	0	1	1	0	1
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	1 / 319 (0.31%)	3 / 309 (0.97%)	1 / 81 (1.23%)	0 / 117 (0.00%)	1 / 79 (1.27%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences all number	2	3	1	0	1	0	0	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	6 / 319 (1.88%)	4 / 309 (1.29%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	1 / 112 (0.89%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences all number	6	4	0	0	0	1	0	0
Renal and urinary disorders
Leukocyturia
subjects affected / exposed	3 / 319 (0.94%)	1 / 309 (0.32%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	2 / 112 (1.79%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences all number	3	1	0	0	0	3	0	0
Endocrine disorders
Goitre
subjects affected / exposed	0 / 319 (0.00%)	0 / 309 (0.00%)	1 / 81 (1.23%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 319 (0.00%)	3 / 309 (0.97%)	0 / 81 (0.00%)	0 / 117 (0.00%)	0 / 79 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	1 / 105 (0.95%)
occurrences all number	0	4	0	0	0	0	1	1
Infections and infestations
Influenza
subjects affected / exposed	4 / 319 (1.25%)	9 / 309 (2.91%)	0 / 81 (0.00%)	0 / 117 (0.00%)	3 / 79 (3.80%)	0 / 112 (0.00%)	1 / 110 (0.91%)	1 / 105 (0.95%)
occurrences all number	4	9	0	0	3	0	1	1
Metabolism and nutrition disorders
Hyperlipidaemia
subjects affected / exposed	6 / 319 (1.88%)	2 / 309 (0.65%)	0 / 81 (0.00%)	1 / 117 (0.85%)	1 / 79 (1.27%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 105 (0.00%)
occurrences all number	6	2	0	2	1	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

14 Feb 2014

Version 2.0 of the protocol was quickly integrated into version 2.1 (03-Mar-2014 amendment).

03 Mar 2014

Conduct of the study was changed to reflect the following: - Additional and updated study contact information, changed study visit windows, additional information about non-clinical study results, an update to the newly approved indication of MabThera and an update of information on AEs in the new SmPC of MabThera - Inclusion criterion 4 and exclusion criterion 10 were changed to precise the naivety of patient population from patients who were naive of TNF antagonists or any other biological agents to patients who were naive of TNF antagonists or any other mAb therapies. Exclusion criterion 20 was changed to reflect that patients could re-enter the study for a second time after failing previous screening procedures in this trial. The screening period was prolonged to 28 days and situations in which screening procedures could be repeated were further specified. The indications for MabThera were updated to include granulomatosis with polyangiitis and macroscopic polyangiitis. The time window permitted for premedication was changed from 30 min into 30±10 min prior to study drug infusion - Further changes reflected a prolonged shelf-life of MabionCD20®, new information on the sensitivity of the investigational products to temperature changes, and the additional specification of storage temperature. - The description of actions to be taken if an infusion related reaction occurred were updated and time windows for PK sampling periods were added. - A new blood test for hepatitis B (anti-HBc antibody) was added to the screening procedures. Pregnancy testing at Week 24 was further specified; a urine test was to be performed only in the patients who were to receive a second course of therapy, which was changed into a serum test that was to be performed in all patients.

08 Aug 2015

Conduct of the study was changed to reflect the following: - Procedures to accommodate sampling for validation and optimization of analytical methods. - The second course of treatment was originally planned with MabionCD20®, but to compensate for production delays, the protocol was changed to allow open-label treatment with MabThera depending on the sponsor’s decision, as second course of treatment. - The shelf-life of MabionCD20 was changed to reflect results of stability tests. - The human anti-chimeric antibodies (HACA) against rituximab measurements were not performed at Mabion R&D Centre anymore but left unspecified. The contact information for SAE and pregnancy reporting was changed to the new safety contact.

29 Sep 2016

Conduct of the study was changed to reflect the following: - An update of the sponsor contact information and that the sponsor’s approval of the protocol was transferred to another person. - Screening procedures could be repeated once, but were allowed to be repeatedtwice, in exceptional cases and after the sponsor’s approval. - Depending on the sponsor’s decision, less patients than the planned 863 patients(with a screening failure rate of 15%) could be enrolled into the study, in case the drop-out rate was less than expected. - During the second course of treatment, PK sampling before infusions were additionally clarified in the study procedures. - The procedure for the pregnancy test was changed to include the testing at Week 24 in all women participating in the study. - In special cases, labelling of the IMP was allowed with a single page label, dedicated for each individual country. - Study status was to be additionally reviewed by the DSMB. • The MM was assigned to receive the investigator’s SAE report and SAE form (which was a single document: Notification of Serious Adverse Event / Pregnancy From). The MM was responsible for reviewing the SAE form for minimal required information and sending it to Mabion Pharmacovigilance Unit.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Randomized, Double-blind, Parallel-group Comparative Bioequivalence Trial of MabionCD20® (Mabion SA) Compared to MabThera® (rituximab, Roche) in Patients with Rheumatoid Arthritis (MABRA)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of patients in each treatment group achieving the primary efficacy endpoint of a ≥20% improvement on the American College of Rheumatology score (ACR20) at Week 24.

Primary: Percentage of patients in each treatment group achieving the primary efficacy endpoint of a ≥20% improvement on the American College of Rheumatology score (ACR20) at Week 24.

Secondary: Percentage of patients achieving ACR20, ACR50 and ACR70 at Week 48

Secondary: Percentage of patients achieving ACR20, ACR50 and ACR70 at Week 48

Secondary: Percentage of patients with good or moderate response on EULAR scale at Week 48

Secondary: Percentage of patients with good or moderate response on EULAR scale at Week 48

Secondary: Percentage of patients achieving ACR20 at weeks: 4, 8, 12, 16, 20

Secondary: Percentage of patients achieving ACR20 at weeks: 4, 8, 12, 16, 20

Secondary: Percentage of patients achieving ACR50 at weeks: 4, 8, 12, 16, 20, 24

Secondary: Percentage of patients achieving ACR50 at weeks: 4, 8, 12, 16, 20, 24

Secondary: Percentage of patients achieving ACR70 at Week 4, 8, 12, 16, 20, 24

Secondary: Percentage of patients achieving ACR70 at Week 4, 8, 12, 16, 20, 24

Secondary: Percentage of patients with good response on European League Against Rheumatism (EULAR) scale at Week 4, 8, 12, 16, 20, 24

Secondary: Percentage of patients with good response on European League Against Rheumatism (EULAR) scale at Week 4, 8, 12, 16, 20, 24

Secondary: Percentage of patients with moderate response on the European League Against Rheumatism (EULAR) scale at Week 4, 8, 12, 16, 20, 24

Secondary: Percentage of patients with moderate response on the European League Against Rheumatism (EULAR) scale at Week 4, 8, 12, 16, 20, 24

Secondary: Time to reach the minimum level of circulating CD19+ B-cells at Week 24 (Tmin B-cell) and duration of B cell depletion (T B-cell)

Secondary: Time to reach the minimum level of circulating CD19+ B-cells at Week 24 (Tmin B-cell) and duration of B cell depletion (T B-cell)

Secondary: Area under the circulating CD19+ B-cell level (AUC0-t B-cell)

Secondary: Area under the circulating CD19+ B-cell level (AUC0-t B-cell)

Secondary: Mean change from baseline in Disease Activity Score (DAS28-ESR) at Week 48

Secondary: Mean change from baseline in Disease Activity Score (DAS28-ESR) at Week 48

Secondary: Adverse events

Secondary: Adverse events

Secondary: Immunogenicity

Secondary: Immunogenicity

Secondary: Mean change from baseline in Disease Activity Score (DAS28-ESR) at weeks: 4, 8, 12, 16, 20, 24

Secondary: Mean change from baseline in Disease Activity Score (DAS28-ESR) at weeks: 4, 8, 12, 16, 20, 24

Secondary: Minimum level (Cmin B-cell) of circulating CD19+ B-cells

Secondary: Minimum level (Cmin B-cell) of circulating CD19+ B-cells

Secondary: Area under the plasma concentration-time curve from the first administration to final time point at Week 24 (AUC0-t)

Secondary: Area under the plasma concentration-time curve from the first administration to final time point at Week 24 (AUC0-t)

Secondary: Maximum measured plasma concentration after the second infusion of the treatment course (Cmax second) at week 24.

Secondary: Maximum measured plasma concentration after the second infusion of the treatment course (Cmax second) at week 24.

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Randomized, Double-blind, Parallel-group Comparative Bioequivalence Trial of MabionCD20® (Mabion SA) Compared to MabThera® (rituximab, Roche) in Patients with Rheumatoid Arthritis (MABRA)