Clinical Trial Results:
A randomized, double- blind, controlled, parallel-group, multicenter study to assess the safety and immunogenicity of transitioning to GP2013 or re-treatment with Rituxan® or MabThera® in patients with active rheumatoid arthritis, previously treated with Rituxan® or MabThera®
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Summary
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EudraCT number |
2012-003876-38 |
Trial protocol |
DE HU PL |
Global end of trial date |
12 Oct 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Oct 2017
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First version publication date |
27 Oct 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
GP13-302
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02514772 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
HEXAL AG
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Sponsor organisation address |
Industriestrasse 25, Holzkirchen, Germany, 83607
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Public contact |
Strategic Planning Biopharma Clinical Development, Sandoz, +49 80244760, biopharma.clinicaltrials@sandoz.com
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Scientific contact |
Strategic Planning Biopharma Clinical Development, Sandoz, +49 80244760, biopharma.clinicaltrials@sandoz.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Jul 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
11 Jul 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Oct 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The study objective is to identify potential safety risk of the transition from the originator product (US-licensed Rituxan® or EU-approved MabThera®) to GP2013 (proposed biosimilar product) as compared to continuous treatment with the originator product in terms of general safety and immunogenicity.
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Protection of trial subjects |
This trial was designed, conducted and reported in accordance with the international Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), applicable local regulations (including European Directive 2001/20/EC), and following the ethical principles laid down in the Declaration of Helsinki. Specific ICH adopted and other relevant international guidelines and recommendations were taken into account as far as meaningfully possible. Safety assessments included adverse events (AEs),
vital signs, 12-lead ECG parameters, clinical laboratory, immunogenicity, physical examination and other parameters considered relevant for the safety assessment, of Rituximab.
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Background therapy |
Metothrexate and Folic Acid | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Jun 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 11
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Country: Number of subjects enrolled |
Germany: 50
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Country: Number of subjects enrolled |
Hungary: 11
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Country: Number of subjects enrolled |
United States: 35
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Worldwide total number of subjects |
107
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EEA total number of subjects |
72
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
83
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From 65 to 84 years |
23
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85 years and over |
1
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Recruitment
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Recruitment details |
A total of 194 patients were screened at 54 centers in 4 countries, i.e. USA, Germany, Hungary, and Poland. Of these, 107 patients were randomized to either GP2013 (53 patients) or Rituxan/MabThera (54 patients). | |||||||||||||||||||||
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Pre-assignment
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Screening details |
In the screening period of 4 weeks patients' eligibility and status regarding positivity of anti-drug-antibodies (ADA; since study patients had already been treated previously with either commercial Rituxan® or MabThera® were tested. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Investigator, Monitor, Data analyst, Carer, Subject, Assessor | |||||||||||||||||||||
Blinding implementation details |
Patients, investigators, assessors, and blinded staff of the CRO remained blinded to the identity of the treatment from the time of randomization until database lock. Investigational product was packed in an open label design. Receipt, storage and preparation of the medication were performed by unblinded site staff only. They ensured that no other persons than unblinded staff members (site and CRO) had access to the medication and the documentation of study medication.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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GP2013 | |||||||||||||||||||||
Arm description |
Patients in this group were switched from originator rituximab (which they received before study participation) to GP2013 - biosimilar rituximab | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
GP2013
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Investigational medicinal product code |
rituximab
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Other name |
biosimilar Rituximab
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Pharmaceutical forms |
Solution for solution for infusion
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Routes of administration |
Intravenous drip use
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Dosage and administration details |
10 mg/mL in 500 mg (50 mL) single-use vials. For i.v. administration, two 500 mg vials (1000 mg of active molecule) of concentrate are diluted in 0.9% NaCl solution and infused i.v. The treatment course consists of 2 i.v. infusions 2 weeks apart (at Day 1 and Day 14)
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Arm title
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Rituxan®/MabThera® | |||||||||||||||||||||
Arm description |
Patients in this group received same originator rituximab version as they had received before study participation. | |||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||
Investigational medicinal product name |
Rituxan®/MabThera®
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Investigational medicinal product code |
rituximab
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Other name |
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Pharmaceutical forms |
Solution for solution for infusion
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Routes of administration |
Intravenous drip use
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Dosage and administration details |
10 mg/mL in 500 mg (50 mL) single-use vials. For i.v. administration two 500 mg vials (1000 mg of active molecule) of concentrate are diluted in 0.9% NaCl solution and infused i.v. The treatment course consists of 2 i.v. infusions 2 weeks apart (at Day 1 and Day 14)
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Baseline characteristics reporting groups
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Reporting group title |
GP2013
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Reporting group description |
Patients in this group were switched from originator rituximab (which they received before study participation) to GP2013 - biosimilar rituximab | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rituxan®/MabThera®
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Reporting group description |
Patients in this group received same originator rituximab version as they had received before study participation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
GP2013
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Reporting group description |
Patients in this group were switched from originator rituximab (which they received before study participation) to GP2013 - biosimilar rituximab | ||
Reporting group title |
Rituxan®/MabThera®
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Reporting group description |
Patients in this group received same originator rituximab version as they had received before study participation. | ||
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End point title |
Hypersensitivity reactions | ||||||||||||||||||
End point description |
The standardized MedDRA query (SMQ) - Hypersensitivity reactions (SMQ 20000214) was used for the identification of hypersensitivity reactions in the adverse event database.
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End point type |
Primary
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End point timeframe |
24 weeks study duration
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Statistical analysis title |
Analysis of hypersensitivity reactions | ||||||||||||||||||
Comparison groups |
Rituxan®/MabThera® v GP2013
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Number of subjects included in analysis |
107
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||||||||
Point estimate |
-1.7
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
-20.6 | ||||||||||||||||||
upper limit |
16.9 | ||||||||||||||||||
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End point title |
Incidence of anaphylactic reactions | ||||||||||||||||||
End point description |
2006 NIAID/FAAN criteria were used for identification of anaphylactic reactions
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End point type |
Primary
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End point timeframe |
Within 24 hours of each study drug infusion
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Statistical analysis title |
Analysis of anaphylactic reactions | ||||||||||||||||||
Comparison groups |
Rituxan®/MabThera® v GP2013
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Number of subjects included in analysis |
107
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||||||||
Point estimate |
-1.9
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
-20.6 | ||||||||||||||||||
upper limit |
16.9 | ||||||||||||||||||
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End point title |
Incidence of potential infusion-related reactions | ||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
On days of and on days after study drug infusions
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Statistical analysis title |
Analysis of potential infusion-related reactions | ||||||||||||||||||
Comparison groups |
GP2013 v Rituxan®/MabThera®
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Number of subjects included in analysis |
107
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||||||||
Point estimate |
-7.2
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
-26 | ||||||||||||||||||
upper limit |
11.4 | ||||||||||||||||||
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End point title |
Immunogenicity | |||||||||
End point description |
Incidence of anti-drug-antibodies (ADA). Patients with negative ADA results at screening and at least one evaluable post-randomization ADA assessment are included in the analysis
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End point type |
Primary
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End point timeframe |
24 weeks study duration
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| Notes [1] - Patients with a negative ADA result at screening and an evaluable post-randomization ADA assessment [2] - Patients with a negative ADA result at screening and an evaluable post-randomization ADA assessment |
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Statistical analysis title |
Analysis of anti-drug antibodies | |||||||||
Comparison groups |
GP2013 v Rituxan®/MabThera®
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Number of subjects included in analysis |
104
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||
Method |
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Parameter type |
Mean difference (final values) | |||||||||
Point estimate |
-1.9
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Confidence interval |
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95% | |||||||||
sides |
2-sided
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lower limit |
-21.2 | |||||||||
upper limit |
17.6 | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
AEs are reported from date patient has provided informed consent and until 30 days after the patient has stopped study participation. AEs are analyzed from start date of study treatment to date of study completion/early discontinuation.
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Adverse event reporting additional description |
The investigator was additionally requested to consult with the patient via phone on the next day after the infusion to document AEs, occurred within 24h of the infusion.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
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Reporting groups
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Reporting group title |
GP2013
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Reporting group description |
Patients in this group were switched from originator rituximab (which they received before study participation) to GP2013 - biosimilar rituximab | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rituxan®/MabThera®
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Reporting group description |
Patients in this group received same originator rituximab version as they had received before study participation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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05 Aug 2015 |
After finalization of the study protocol FDA recommended to include unscheduled Anti-Drug-Antibody (ADA) blood sampling triggered by suspected immunologically related adverse events, to assess the clinical relevance of ADAs.
In order to fulfill the recommendation of the methotrexate label for males on methotrexate to prevent fathering a child, respective recommendations were included in the protocol and ICF. Additionally, the informed consent procedure for following up of partner pregnancies of male study participants was introduced. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
