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Clinical Trial Results:
Randomized, Parallel-group, Double-blind, Comparative Bioequivalence Trial of MabionCD20 (Mabion S.A) Compared to MabThera (rituximab by Hoffman-La Roche) in Patients with Diffuse Large B-cell Lymphoma.

Summary
EudraCT number	2013-005506-56
Trial protocol	PL HR
Global end of trial date	04 Jan 2018

Results information
Results version number	v1(current)
This version publication date	30 Apr 2022
First version publication date	30 Apr 2022
Other versions
Summary report(s)	MabionCD20-002NHL 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

MabionCD20-002NHL

ISRCTN number

US NCT number

NCT02617485

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 Coordination Unit, Mabion SA, +48 422908210, b.czubek@mabion.eu

Scientific contact

Clinical Trial Coordination Unit, Mabion SA, +48 422908210, 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

04 Jan 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Jan 2018

Was the trial ended prematurely?

Main objective of the trial

Primary objective of the study is to demonstrate high level of biosimilarity between MabionCD20 (MABION SA) and the reference product: MabThera (rituximab by Hoffman-La Roche) in patients with CD20-positive diffuse large B-cell lymphoma, based on the percentage of patients achieving the primary pharmacokinetic endpoints.

Protection of trial subjects

Patients received premedication consisting of corticosteroid (prednisone, a component of CHOP), anti-pyretic (acetaminophen) and anti-histamine (diphenhydramine or equivalent) 30-40 minutes prior to each study drug administration in order to lower the incidence of infusion-related reactions related to the release of cytokines and/or other mediators. This clinical trial was conducted in accordance with all local legal and regulatory requirements, as well as the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use(ICH) Independent Ethics Committee guideline E6: Good Clinical Practice (GCP).

Background therapy

All patients concomitantly received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. CHOP was administered every three weeks (21 days) for a total of eight cycles. CHOP was administered on the first day of each of the 8 chemotherapy cycles, in a standard body surface adjusted dosage regimen of 50 mg/m2 of doxorubicin (IV), 1.4 mg/m2 of vincristine, up to a maximal dose of 2 mg(IV), 750 mg/m2 of cyclophosphamide (IV), and 100 mg of prednisone (oral, for a period of five days).

Evidence for comparator

MabThera is an EU-approved brand of rituximab, manufactured by Hoffman-La Roche. It is officially indicated for the treatment of DLBCL in adults.

Actual start date of recruitment

29 Mar 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Georgia: 21

Country: Number of subjects enrolled

Ukraine: 119

Worldwide total number of subjects

140

EEA total number of subjects

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)

107

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The trial was initiated in 7 countries (Croatia, Bosnia and Herzegovina, Georgia, Moldova, Poland, Serbia, and Ukraine), but finally only 5 countries with 21 study sites recruited patients (Bosnia and Herzegovina, Georgia, Moldova, Poland, and Ukraine).

Screening details

Screening lasted 28 days (from Day -35 to -8 before randomization), during which the eligibility status of patients was verified.

Period 1 title

Treatment and observation period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Blinding implementation details

Blinding of study medication packages was performed at the external company, according to the GMP regulation and Sponsor’s applicable standard operating procedures (SOPs). The blinding information was kept under restricted access. Personnel responsible for re-packaging signed a confidentiality statement.

Are arms mutually exclusive

Yes

MabionCD20

Arm description

Patients assigned to this arm received 375 mg/m2 of MabionCD20 intravenously every 3 weeks for 8 cycles on Days 1, 22 (Week 4), 43 (Week 7), 64 (Week 10), 85 (Week 13), 106 (Week 16), 127 (Week 19), and 148 (Week 22).

Arm type

Experimental

Investigational medicinal product name

MabionCD20

Investigational medicinal product code

L01FA01

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Infusion

Dosage and administration details

MabionCD20 is a concentrate for solution for infusion and could be administered only after dilution in pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection in water. The prepared solutions were administered in concentration of 1 to 4 mg/ml as an IV infusion through a dedicated line with use of volumetric infusion pump that enabled to control and adjust the rate of infusion. The MabionCD20 dose was adjusted for body weight (body surface area [BSA]) and was based on the standard dose of 375 mg/m2.The maximum allowed dose in the trial was 900 mg. The dosage was 375 mg/m2, administered on Day 1 of each chemotherapy cycle for 8 cycles after administration of premedication.Standard treatment scheme was repeated every 21 days for 8 courses (Trial Days 1, 22, 43, 64, 85, 106, 127, and 148)

MabThera

Arm description

Patients assigned to this arm received 375 mg/m2 of MabThera intravenously every 3 weeks for 8 cycles on Days 1, 22 (Week 4), 43 (Week 7), 64 (Week 10), 85 (Week 13), 106 (Week 16), 127 (Week 19), and 148 (Week 22).

Arm type

Active comparator

Investigational medicinal product name

MabThera

Investigational medicinal product code

L01FA01

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Infusion

Dosage and administration details

(Trial Days 1, 22, 43, 64, 85, 106, 127, and 148) MabThera is a concentrate for solution for infusion and could be administered only after dilution in pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection in water. The prepared solutions were administered in concentration of 1 to 4 mg/ml as an IV infusion through a dedicated line with use of volumetric infusion pump that enabled to control and adjust the rate of infusion. The MabThera dose was adjusted for body weight (body surface area [BSA]) and was based on the standard dose of 375 mg/m2.The maximum allowed dose in the trial was 900 mg.The dosage was 375 mg/m2, administered on Day 1 of each chemotherapy cycle for 8 cycles after administration of premedication.Standard treatment scheme was repeated every 21 days for 8 courses (Trial Days 1, 22, 43, 64, 85, 106, 127, and 148) .

Number of subjects in period 1	MabionCD20	MabThera
Started	100	40
Completed	85	35
Not completed	15	5
Adverse event, serious fatal	7	-
Consent withdrawn by subject	4	1
Physician decision	-	1
Adverse event, non-fatal	2	1
Lack of efficacy	1	2
Patient needed radiotherapy	1	-

Period 2 title

Follow-up

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

The Sponsor, Investigators and patients were blinded to treatment allocation until the last patient completed the visit at Week 26. After database lock at Week 26, the Sponsor was unblinded for the purpose of data analysis and CSR creation.

Are arms mutually exclusive

Yes

MabionCD20

Arm description

Patient randomly assigned to MabionCD20 were followed up until Week 46.

Arm type

Experimental

Investigational medicinal product name

MabionCD20

Investigational medicinal product code

L01FA01

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Infusion

Dosage and administration details

MabionCD20 is a concentrate for solution for infusion and could be administered only after dilution in pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection in water. The prepared solutions were administered in concentration of 1 to 4 mg/ml asan IV infusion through a dedicated line with use of volumetric infusion pump that enabled to control and adjust the rate of infusion. The MabionCD20 dose was adjusted for body weight (body surface area [BSA]) and was based on the standard dose of 375 mg/m2.The maximum allowed dose in the trial was 900 mg. The dosage was 375 mg/m2, administered on Day 1 of each chemotherapy cycle for 8 cycles after administration of premedication.Standard treatment scheme was repeated every 21 days for 8 courses (Trial Days 1, 22, 43, 64, 85, 106, 127, and 148) .

MabThera

Arm description

Patient randomly assigned to MabThera were followed up until Week 46.

Arm type

Active comparator

Investigational medicinal product name

MabThera

Investigational medicinal product code

L01FA01

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Infusion

Dosage and administration details

MabThera is a concentrate for solution for infusion and could be administered only after dilution in pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection in water. The prepared solutions were administered in concentration of 1 to 4 mg/ml as an IV infusion through a dedicated line with use of volumetric infusion pump that enabled to control and adjust the rate of infusion. The MabThera dose was adjusted for body weight (body surface area [BSA]) and was based on the standard dose of 375 mg/m2.The maximum allowed dose in the trial was 900 mg. The dosage was 375 mg/m2, administered on Day 1 of each chemotherapy cycle for 8 cycles after administration of premedication.Standard treatment scheme was repeated every 21 days for 8 courses (Trial Days 1, 22, 43, 64, 85, 106, 127, and 148) .

Number of subjects in period 2	MabionCD20	MabThera
Started	85	35
Completed	70	29
Not completed	15	6
Adverse event, serious fatal	1	-
Consent withdrawn by subject	1	-
Patient needed BM transplantation	1	-
Need for CNS prophylaxis	1	-
disease progression	2	1
Patient needed radiotherapy	9	5

Baseline characteristics

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Reporting group title

MabionCD20

Reporting group description

Reporting group title

MabThera

Reporting group description

Reporting group values	MabionCD20	MabThera	Total
Number of subjects	100	40	140
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	78	29	107
From 65-84 years	22	11	33
85 years and over	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	51.5 ± 16.2	54.3 ± 13.5	-
Gender categorical
Units: Subjects
Female	54	20	74
Male	46	20	66
Body Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	76.2 ± 17.4	73.6 ± 17.0	-
BSA
Units: cubic metre
arithmetic mean (standard deviation)	1.9 ± 0.2	1.8 ± 0.2	-

Subject analysis set title

SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Safety population – all patients randomized into the study and receiving at least one infusion of MabionCD20 or MabThera.

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Intent to treat population (ITT) – a subset of safety population based on patients who had at least one complete post baseline assessment of the area under the serum concentration-time curve from time zero to final time point (AUC(0-t)), measured after the first administration (Week 1) until the second administration at Week 4(AUC(1-4)).

Subject analysis set title

PP W1-W4

Subject analysis set type

Per protocol

Subject analysis set description

Per-protocol (W1-W4) population –subset of ITT population based on patients without major protocol deviations to Week 4 (visit 4) and having a PK assessment on this visit. Completion of the study was not necessary for inclusion into this population.

Subject analysis set title

PP W13-26

Subject analysis set type

Per protocol

Subject analysis set description

Per-protocol (W13-W26) population –subset of ITT population based on patients without major protocol deviations and having a PK assessment from Week 13 to Week 26

Subject analysis set title

ITT W13-W26

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

A subset of safety population based on patients who had at least one complete post baseline assessment of the area under the serum concentration-time curve from time zero to final time point (AUC(0-t)) measured after Week 13 until Week 26.

Subject analysis sets values	SAF	ITT	PP W1-W4	PP W13-26	ITT W13-W26
Number of subjects	140	136	129	103	125
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	107	104	99	83
From 65-84 years	33	32	30	20
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	52.3 ± 15.5	52.4 ± 15.5	52.3 ± 15.5	51.5 ± 14.3	±
Gender categorical
Units: Subjects
Female	74	71	68	54
Male	66	65	61	49
Body Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	75.5 ± 17.2	75.8 ± 17.3	76.1 ± 17.6	76.1 ± 17.6	±
BSA
Units: cubic metre
arithmetic mean (standard deviation)	1.8 ± 0.2	1.9 ± 0.2	1.9 ± 0.2	1.9 ± 0.2	±

End points

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Reporting group title

MabionCD20

Reporting group description

Reporting group title

MabThera

Reporting group description

Reporting group title

MabionCD20

Reporting group description

Patient randomly assigned to MabionCD20 were followed up until Week 46.

Reporting group title

MabThera

Reporting group description

Patient randomly assigned to MabThera were followed up until Week 46.

Subject analysis set title

SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Safety population – all patients randomized into the study and receiving at least one infusion of MabionCD20 or MabThera.

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

PP W1-W4

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PP W13-26

Subject analysis set type

Per protocol

Subject analysis set description

Per-protocol (W13-W26) population –subset of ITT population based on patients without major protocol deviations and having a PK assessment from Week 13 to Week 26

Subject analysis set title

ITT W13-W26

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Primary: Area under the serum concentration-time curve from time zero to final time point measured after the first administration (Week 1) until Week 4 (AUC(W1-W4))

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End point title

Area under the serum concentration-time curve from time zero to final time point measured after the first administration (Week 1) until Week 4 (AUC(W1-W4))

End point description

Area under the serum concentration-time curve from time zero to final time point measured after the first administration (Week 1) until the Week 4 (AUC(1-4)).

End point type

Primary

End point timeframe

From Baseline to Week 4.

End point values	MabionCD20	MabThera
Number of subjects analysed	94	35
Units: μg*day/ml
arithmetic mean (standard deviation)	1559.516 ± 358.092	1509.795 ± 382.559

Estimated Geo LS Mean ratio

Statistical analysis description

Geometric least-squares mean ratio between MabionCD20 and MabThera arm for AUC(W1-W4) parameter, estimated with the use of ANOVA model.

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

equivalence ^[1]

Method

Parameter type

Ratio of Geo LS-means

Point estimate

1.0406

Confidence interval

level

90%

sides

2-sided

lower limit

0.9565

upper limit

1.1321

Notes
[1] - Equivalence met if the 90% CI of the Geo LS Means ratio is contained with the pre-specified equivalence margin of 70% - 143%.

Primary: Area under the serum concentration-time curve from time zero to final time point measured after the first administration (Week 13) until Week 26 (AUC(W13-W26))

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End point title

Area under the serum concentration-time curve from time zero to final time point measured after the first administration (Week 13) until Week 26 (AUC(W13-W26))

End point description

Area under the serum concentration-time curve from time zero to final time point (AUC(0-t)) measured after the first administration (Week 13) until the second administration at Week 26 (AUC(13-26))

End point type

Primary

End point timeframe

Week 13 to Week 26.

End point values	MabionCD20	MabThera
Number of subjects analysed	74	29
Units: μg*day
arithmetic mean (standard deviation)	16498.932 ± 3492.394	15647.444 ± 3629.83

Estimated Geo LS Mean ratio

Statistical analysis description

Geometric least-squares mean ratio between MabionCD20 and MabThera arms for AUC(W13-W26) endpoint, estimated with the use of ANOVA model.

Comparison groups

MabThera v MabionCD20

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

equivalence ^[2]

Method

Parameter type

Ratio of Geo LS-means

Point estimate

1.0611

Confidence interval

level

90%

sides

2-sided

lower limit

0.9822

upper limit

1.1464

Notes
[2] - Equivalence met if the 90% CI of the Geo LS Means ratio is contained with the pre-specified equivalence margin of 70% - 143%.

Secondary: Ctrough (before 8th infusion)

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End point title

Ctrough (before 8th infusion)

End point description

Trough serum concentration measured at the end of a dosing interval at steady state, taken directly before eighth infusion.

End point type

Secondary

End point timeframe

Week 22

End point values	MabionCD20	MabThera
Number of subjects analysed	74	29
Units: μg/ml
arithmetic mean (standard deviation)	102.246 ± 43.897	90.61 ± 41.994

No statistical analyses for this end point

Secondary: Cmax (post 5th and 8th infusion)

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End point title

Cmax (post 5th and 8th infusion)

End point description

Maximum serum drug concentration (Cmax) at steady state after the 5th and 8th infusions.

End point type

Secondary

End point timeframe

Week 13 (5th infusion) and Week 22 (8th infusion)

End point values	MabionCD20	MabThera
Number of subjects analysed	74	29
Units: μg/ml
arithmetic mean (standard deviation)
5th infusion	273.356 ± 65.452	266.439 ± 66.086
8th infusion	296.784 ± 58.295	296.462 ± 69.641

No statistical analyses for this end point

Secondary: Kel (post 5th and 8th infusion)

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End point title

Kel (post 5th and 8th infusion)

End point description

Elimination Rate Constant at steady state after the 5th and 8th infusions.

End point type

Secondary

End point timeframe

Week 13 (5th infusion) and Week 22 (8th infusion)

End point values	MabionCD20	MabThera
Number of subjects analysed	74	29
Units: 1/day
arithmetic mean (standard deviation)
5th infusion	0.05663 ± 0.01794	0.05418 ± 0.01884
8th infusion	0.04335 ± 0.01528	0.04379 ± 0.0123

No statistical analyses for this end point

Secondary: T1/2 (post 5th and 8th infusion)

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End point title

T1/2 (post 5th and 8th infusion)

End point description

Elimination Half-Life at steady state after the 5th and 8th infusions.

End point type

Secondary

End point timeframe

Week 13 to Week 16 and Week 22 to Week 26

End point values	MabionCD20	MabThera
Number of subjects analysed	74	29
Units: day
arithmetic mean (standard deviation)
5th infusion	14.801 ± 12.218	15.217 ± 7.889
8th infusion	18.301 ± 7.92	16.997 ± 4.515

No statistical analyses for this end point

Secondary: CLss (post 5th and 8th infusion)

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End point title

CLss (post 5th and 8th infusion)

End point description

Clearance at steady state after the 5th and 8th infusion.

End point type

Secondary

End point timeframe

Week 13 to Week 16 and Week 22 to Week 26

End point values	MabionCD20	MabThera
Number of subjects analysed	74	29
Units: mL/day
arithmetic mean (standard deviation)
5th infusion	198.701 ± 53.427	206.905 ± 78.213
8th infusion	179.168 ± 58.509	191.272 ± 89.016

No statistical analyses for this end point

Secondary: AUC(W1-W26) B-cell

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End point title

AUC(W1-W26) B-cell

End point description

Area under the serum concentration-time curve of CD19+ B cell counts, measured from the first administration to the final time point at Week 26 (AUC(1-26) B-cell)

End point type

Secondary

End point timeframe

Baseline to Week 26

End point values	MabionCD20	MabThera
Number of subjects analysed	98	38
Units: cells*days/mL
arithmetic mean (standard deviation)	3395.824 ± 22364.503	10476.248 ± 56943.014

Estimated LS Mean ratio

Statistical analysis description

LS Mean ratio between MabionCD20 and MabThera arms for AUC(W1-W26) B cell endpoint, calculated with the use of ANOVA model.

Comparison groups

MabionCD20 v MabThera

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

equivalence ^[3]

Method

Parameter type

Ratio of LS-means

Point estimate

0.3447

Confidence interval

level

95%

sides

2-sided

lower limit

0.1501

upper limit

0.7914

Notes
[3] - Equivalence met if 95% CI included in the 70%-143% margin.

Secondary: AUC(W1-W26)

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End point title

AUC(W1-W26)

End point description

Area under the serum concentration-time curve measured after the first administration (Week 1) until Week 26 (AUC(1-26))

End point type

Secondary

End point timeframe

Week 1 until Week 26

End point values	MabionCD20	MabThera
Number of subjects analysed	71	28
Units: μg*day/ml
arithmetic mean (standard deviation)	28413.693 ± 5194.987	26955.355 ± 5849.227

No statistical analyses for this end point

Secondary: Efficacy Assessment at Week 26

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End point title

Efficacy Assessment at Week 26

End point description

An efficacy assessment was made after 8 treatment cycles (at Week 26) based on tumour responses classified according to the International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphomas. Response was assessed based on clinical, radiologic and pathologic (bone marrow) criteria. Possible efficacy responses were: complete response, partial response, stable disease, and progressive disease. Efficacy reported here includes all randomized patients.

End point type

Secondary

End point timeframe

Week 26

End point values	MabionCD20	MabThera
Number of subjects analysed	96 ^[4]	38 ^[5]
Units: percent
number (not applicable)
Complete	35.4	36.8
Partial	43.8	47.4
Stable disease	10.4	10.5
Progressive disease	10.4	5.3

Notes
[4] - 4 patients had missing data.
[5] - 2 patients had missing data.

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 a given category. Data from the entire follow-up are included (Period 1 and Period 2).

End point type

Secondary

End point timeframe

From Baseline to Week 46.

End point values	MabionCD20	MabThera
Number of subjects analysed	100	40
Units: percent
number (not applicable)
All AEs	71.0	67.5
Treatment-emergent AEs (TEAEs)	71.0	65.0
Treatment-emergent SAEs (TESAEs)	19.0	12.5
Severe TEAEs	40.0	22.5
Related TEAEs	53.0	42.5
Related severe TEAEs	29.0	22.5
Related TESAEs	13.0	5.0
TEAEs leading to death	8.0	0.0
Related TEAEs leading to death	2.0	0.0

No statistical analyses for this end point

Other pre-specified: Immunogenicity

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End point title

Immunogenicity

End point description

Percentage of patients with positive ADA or NAb results in a given category. Data pertain to the entire follow-up period (from Baseline to Week 46).

End point type

Other pre-specified

End point timeframe

From Baseline to Week 46.

End point values	MabionCD20	MabThera
Number of subjects analysed	99	40
Units: percent
number (not applicable)
Treatment-induced ADA	6	1
Persistent ADA	4	1
Transient ADA	2	0
Treatment-boosted ADA	0	0
NAb positive	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Baseline to Week 46.

Adverse event reporting additional description

AEs were collected at each trial visit and followed up 30 days after patients completed the trial.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

MabionCD20

Reporting group description

Patient who received MabionC20 in treatment and observation period and then were followed up up to Week 46.

Reporting group title

MabThera

Reporting group description

Patient who received MabThera in treatment and observation period and then were followed up up to Week 46.

Serious adverse events	MabionCD20	MabThera
Total subjects affected by serious adverse events
subjects affected / exposed	19 / 100 (19.00%)	5 / 40 (12.50%)
number of deaths (all causes)	8	0
number of deaths resulting from adverse events	2	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-Hodgkin's lymphoma
subjects affected / exposed	3 / 100 (3.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0
Injury, poisoning and procedural complications
Brain contusion
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	2 / 100 (2.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	2 / 100 (2.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiovascular insufficiency
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Haemorrhagic stroke
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 100 (1.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Disease progression
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic necrosis
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchospasm
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 100 (2.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 100 (1.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 100 (3.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	MabionCD20	MabThera
Total subjects affected by non serious adverse events
subjects affected / exposed	67 / 100 (67.00%)	28 / 40 (70.00%)
Vascular disorders
Hypertension
subjects affected / exposed	2 / 100 (2.00%)	1 / 40 (2.50%)
occurrences all number	3	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 100 (1.00%)	1 / 40 (2.50%)
occurrences all number	1	2
Chest pain
subjects affected / exposed	2 / 100 (2.00%)	0 / 40 (0.00%)
occurrences all number	2	0
Chills
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Face oedema
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Fatigue
subjects affected / exposed	5 / 100 (5.00%)	1 / 40 (2.50%)
occurrences all number	8	1
Hyperthermia
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	2
Pyrexia
subjects affected / exposed	5 / 100 (5.00%)	0 / 40 (0.00%)
occurrences all number	5	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	2 / 100 (2.00%)	0 / 40 (0.00%)
occurrences all number	2	0
Psychiatric disorders
Insomnia
subjects affected / exposed	2 / 100 (2.00%)	0 / 40 (0.00%)
occurrences all number	2	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	4 / 100 (4.00%)	1 / 40 (2.50%)
occurrences all number	6	1
Aspartate aminotransferase increased
subjects affected / exposed	3 / 100 (3.00%)	1 / 40 (2.50%)
occurrences all number	4	1
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 100 (1.00%)	1 / 40 (2.50%)
occurrences all number	3	2
Blood bilirubin increased
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Monocyte count increased
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	2
Neutrophil count decreased
subjects affected / exposed	8 / 100 (8.00%)	4 / 40 (10.00%)
occurrences all number	54	16
Platelet count decreased
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	6
Transaminases increased
subjects affected / exposed	3 / 100 (3.00%)	2 / 40 (5.00%)
occurrences all number	3	5
White blood cell count decreased
subjects affected / exposed	9 / 100 (9.00%)	4 / 40 (10.00%)
occurrences all number	57	18
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	3 / 100 (3.00%)	1 / 40 (2.50%)
occurrences all number	3	1
Cardiac disorders
Cardiomyopathy
subjects affected / exposed	1 / 100 (1.00%)	1 / 40 (2.50%)
occurrences all number	1	1
Sinus tachycardia
subjects affected / exposed	1 / 100 (1.00%)	1 / 40 (2.50%)
occurrences all number	1	2
Supraventricular tachycardia
subjects affected / exposed	2 / 100 (2.00%)	0 / 40 (0.00%)
occurrences all number	2	0
Nervous system disorders
Headache
subjects affected / exposed	4 / 100 (4.00%)	0 / 40 (0.00%)
occurrences all number	5	0
Neurotoxicity
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	14 / 100 (14.00%)	5 / 40 (12.50%)
occurrences all number	33	10
Febrile neutropenia
subjects affected / exposed	3 / 100 (3.00%)	0 / 40 (0.00%)
occurrences all number	3	0
Leukopenia
subjects affected / exposed	22 / 100 (22.00%)	10 / 40 (25.00%)
occurrences all number	59	17
Neutropenia
subjects affected / exposed	29 / 100 (29.00%)	10 / 40 (25.00%)
occurrences all number	76	23
Thrombocytopenia
subjects affected / exposed	1 / 100 (1.00%)	1 / 40 (2.50%)
occurrences all number	7	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	3 / 100 (3.00%)	3 / 40 (7.50%)
occurrences all number	3	3
Gastritis
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Pancreatitis chronic
subjects affected / exposed	2 / 100 (2.00%)	0 / 40 (0.00%)
occurrences all number	2	0
Stomatitis
subjects affected / exposed	3 / 100 (3.00%)	2 / 40 (5.00%)
occurrences all number	3	2
Vomiting
subjects affected / exposed	2 / 100 (2.00%)	1 / 40 (2.50%)
occurrences all number	2	1
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	1 / 100 (1.00%)	1 / 40 (2.50%)
occurrences all number	1	2
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	15 / 100 (15.00%)	5 / 40 (12.50%)
occurrences all number	15	5
Dermal cyst
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Dermatitis allergic
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Musculoskeletal discomfort
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Infections and infestations
Acute sinusitis
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Bronchitis
subjects affected / exposed	2 / 100 (2.00%)	0 / 40 (0.00%)
occurrences all number	2	0
Conjunctivitis
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Gingivitis
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Infection
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Influenza
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Lung infection
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Pharyngitis
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Pneumonia
subjects affected / exposed	5 / 100 (5.00%)	0 / 40 (0.00%)
occurrences all number	5	0
Respiratory tract infection
subjects affected / exposed	7 / 100 (7.00%)	1 / 40 (2.50%)
occurrences all number	8	1
Respiratory tract infection viral
subjects affected / exposed	1 / 100 (1.00%)	1 / 40 (2.50%)
occurrences all number	1	1
Viral infection
subjects affected / exposed	2 / 100 (2.00%)	0 / 40 (0.00%)
occurrences all number	2	0
Metabolism and nutrition disorders
Tumour lysis syndrome
subjects affected / exposed	2 / 100 (2.00%)	0 / 40 (0.00%)
occurrences all number	2	0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 100 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

09 Jun 2014

The conduct of the study was changed to reflect the following major changes: - An update of the paragraph with Secondary Study Endpoints by removal of section about Complete Response unconfirmed because this did not represent separate secondary study endpoint. - An update of the Dose Modifications of Concomitant Medication section to clarify the Study Procedures related to consideration of necessity of G-CSF support after chemotherapy administration and reduction of chemotherapy dose depending on the patient’s condition. - A change of Inclusion Criterion 8 to indicate that the patients with prior immunotherapy for DLBCL (>1,5 years prior to screening) can be included into the study. - An update of Inclusion Criterion 13 for safety reasons:the parameters of adequate haematological function were changed. - An update of Inclusion Criterion 18 for safety reasons the need of both serum and urine pregnancy tests was added. An update of Exclusion Criteria 3, 8 and 14 to clarify the conditions of exclusion to provide treatment options to more patients. - The addition of new Exclusion Criterion 24 for safety reasons: excluding patients with hypersensitivity to the active substance or to any other excipients of the medicine. - An update of the criteria of withdrawal a patient from the study for safety reasons: adding that the patient can be removed from the study by the Investigator when he/she enters into another clinical study with the treatment that in the Investigator’s opinion excludes patient’s participation. - A clarification of study procedures for to safety reasons: Related to Efficacy Assessment and adding new Laboratory Safety Tests due to safety reasons. - An update of the screening, visit 7, visit 13 and Early Terminated Visit procedures to simplify and accelerate the procedures of tumour assessment

11 Aug 2015

The conduct of the study was changed to reflect the following major changes: - A clarification of Inclusion Criterion 3 for safety reasons and to make the protocol consistent by removal the time of biopsy performance. - An update of the content of the box in Pharmaceutical Form and Packaging and Labelling sections from two 10 ml vials to one 10 ml vial. - An update of the section Storage and Stability to clarify the shelf life of MabionCD20. - The addition of a new additional blood samples collection to Screening Visit procedures for purpose of validation and optimization of analytical methods. - Clarifying the purpose of blood samples collection in Ethical Consideration section.

21 Sep 2016

The conduct of the study was changed to reflect the following major changes: - An update of the Inclusion Criterion 12 by extending the screening window to make the protocol consistent. - An update ofthe HACA/ADA samples schedule in accordance with EMA recommendations by adding additional blood sampling to the Visit 2, Visit 6 and Visit 11 procedures. - An update of the period when the bone marrow biopsy can be performed before the Screening visit. The period was changed to 60 days and could be extended to 90 days when the re-biopsy is highly invasive,and the previous results are expected to be up to date in screening, basing on Investigator’s and Medical Monitor’s decision. - The change of the Screening Window from 28 to 35 days for safety reasons:to provide treatment to every patient included into the trial but did not receive the trial treatment within 28 days from Screening Visit. - The addition of the Efficacy Assessment to the Visit 1 procedures for safety reasons.

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, Parallel-group, Double-blind, Comparative Bioequivalence Trial of MabionCD20 (Mabion S.A) Compared to MabThera (rituximab by Hoffman-La Roche) in Patients with Diffuse Large B-cell Lymphoma.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Area under the serum concentration-time curve from time zero to final time point measured after the first administration (Week 1) until Week 4 (AUC(W1-W4))

Primary: Area under the serum concentration-time curve from time zero to final time point measured after the first administration (Week 1) until Week 4 (AUC(W1-W4))

Primary: Area under the serum concentration-time curve from time zero to final time point measured after the first administration (Week 13) until Week 26 (AUC(W13-W26))

Primary: Area under the serum concentration-time curve from time zero to final time point measured after the first administration (Week 13) until Week 26 (AUC(W13-W26))

Secondary: Ctrough (before 8th infusion)

Secondary: Ctrough (before 8th infusion)

Secondary: Cmax (post 5th and 8th infusion)

Secondary: Cmax (post 5th and 8th infusion)

Secondary: Kel (post 5th and 8th infusion)

Secondary: Kel (post 5th and 8th infusion)

Secondary: T1/2 (post 5th and 8th infusion)

Secondary: T1/2 (post 5th and 8th infusion)

Secondary: CLss (post 5th and 8th infusion)

Secondary: CLss (post 5th and 8th infusion)

Secondary: AUC(W1-W26) B-cell

Secondary: AUC(W1-W26) B-cell

Secondary: AUC(W1-W26)

Secondary: AUC(W1-W26)

Secondary: Efficacy Assessment at Week 26

Secondary: Efficacy Assessment at Week 26

Secondary: Adverse events

Secondary: Adverse events

Other pre-specified: Immunogenicity

Other pre-specified: Immunogenicity

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Randomized, Parallel-group, Double-blind, Comparative Bioequivalence Trial of MabionCD20 (Mabion S.A) Compared to MabThera (rituximab by Hoffman-La Roche) in Patients with Diffuse Large B-cell Lymphoma.